Positive Tumor Expression Research Articles

Abstract 2911: Prevalence of potential antibody drug conjugate targets and co-expression with PD-L1 in breast cancer and lung cancer patients with clinical response information

Abstract Breast and non-small cell lung cancer (NSCLC) are two of the most important diseases for antibody drug conjugate (ADC) development. ADCs targeting HER2 and TROP2 are currently approved in select breast and lung subgroups with ADC’s to many other tumor targets currently in clinical development. Based on TCGA mRNA expression data, ADC tumor targets currently under investigation for treatment of solid tumors have variable overlap in breast and lung cancers, however little is known about the overlap of ADC targets with PD-L1 which is a predictive biomarker in TNBC and for pembrolizumab monotherapy. In the current study, the prevalence and co-expression of ADC targets (HER2, TROP2, Nectin-4, B7-H3, B7-H4, HER3, FOLR1) were investigated in the context of PD-L1 status and clinical response data for standard-of-care (SOC) and immunotherapy, in breast and NSCLC cancer subtypes. Tissue microarrays (TMAs) comprising treatment naïve tumor samples (1mm cores) and including TNBC (26 patients), ER+ BC (90 patients), and NSCLC (adeno & squamous subtypes; 146 patients), all with full clinical follow-up information, were examined by immunohistochemistry (IHC) in serial sections for each ADC target and PD-L1, applying widely used and well optimized IHC assays on the Ventana and Dako Link 48 platforms. Established scoring methods were employed for analysis of PD-L1 and HER2, except for the addition of an exploratory ultra-low score for HER2. All other ADC targets were scored by digital image analysis to deliver percentage positive tumor expression at high (3+), moderate (2+), weak (1+) and negative (0) intensities. Taken together, this analysis revealed variable prevalence for each target in breast and lung cancer histologies by subtype, including differing overlap between ADC targets within tumor indications. In addition, prevalence of each ADC target in breast cancer characterized by HR status and HER2 subgroups (HER2-positive, low, ultra-low, negative) indicated potential opportunities for ADC clinical development in these subgroups. Co-prevalence of the selected ADC targets with PD-L1 CPS>10 (predictive for Pembrolizumab response in TNBC) and PD-L1 CPS categories of interest for NSCLC revealed patterns of expression in support of combination therapies. Furthermore, expression and co-prevalence data for each ADC target +/- PD-L1 was characterized in association with response to immunotherapy or other SOC. In summary, these data provide better understanding of which breast and lung cancer subtypes express the selected ADC targets uniquely and competitively which may be key to future clinical and diagnostic development. Citation Format: Marie Cumberbatch, Woo Ho Kim, Milan Bhagat, John Cogswell. Prevalence of potential antibody drug conjugate targets and co-expression with PD-L1 in breast cancer and lung cancer patients with clinical response information [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 2911.

High ratio of pCXCR4/CXCR4 tumor infiltrating immune cells in primary high grade ovarian cancer is indicative for response to chemotherapy

BackgroundOvarian cancer (OC) is the fifth most common malignant female cancer with a high mortality, mainly because of aggressive high-grade serous carcinomas (HGSOC), but also due to absence of specific early symptoms and effective detection strategies. The CXCL12-CXCR4 axis is considered to have a prognostic impact and to serve as potential therapeutic target. Therefore we investigated the role of pCXCR4 and CXCR4 expression of the tumor cells and of tumor infiltrating immune cells (TIC) in high-grade serous OC and their association with the recurrence-free (RFS) and overall survival (OS).MethodsA tissue microarray of 47 primary high grade ovarian serous carcinomas and their recurrences was stained with primary antibodies directed against CXCR4 and pCXCR4. Beside the evaluation of the absolute tumor as well as TIC expression in primary and recurrent cancer biopsies the corresponding ratios for pCXCR4 and CXCR4 were generated and analyzed. The clinical endpoints were response to chemotherapy, OS as well as RFS.ResultsPatients with a high pCXCR4/CXCR4 TIC ratio in primary cancer biopsies showed a significant longer RFS during the first two years (p = 0.025). However, this effect was lost in the long-term analysis including a follow-up period of 5 years (p = 0.128). Interestingly, the Multivariate Cox regression analysis showed that a high pCXCR4/CXCR4 TIC ratio in primary cancer independently predicts longer RFS (HR 0.33; 95CI 0.13 - 0.81; p = 0.015). Furthermore a high dichotomized distribution of CXCR4 positive tumor expression in recurrent cancer biopsies showed a significantly longer 6-month RFS rate (p = 0.018) in comparison to patients with low CXCR4 positive tumor expression. However, this effect was not independent of known risk factors in a Multivariate Cox regression (HR 0.57; 95CI 0.24 - 1.33; p = 0.193).ConclusionsTo the best of our knowledge we show for the first time that a high pCXCR4/CXCR4 TIC ratio in primary HGSOC biopsies is indicative for better RFS and response to chemotherapy.Highlights• We observed a significant association between high pCXCR4/CXCR4 TIC ratio and better RFS in primary cancer biopsies, especially during the early postoperative follow-up and independent of known risk factors for recurrence.• High CXCR4 tumor expression in recurrent HGSOC biopsies might be indicative for sensitivity to chemotherapy. We found evidence that at the beginning of the disease (early follow-up) the role of the immune response seems to be the most crucial factor for progression. On the other hand in recurrent/progressive disease the biology of the tumor itself becomes more important for prognosis.• We explored for the first time the predictive and prognostic role of pCXCR4/CXCR4 TIC ratio in high-grade serous ovarian cancer.

879P - Loss of ARID1A expression is associated with poor prognosis in patients with stage I/II clear cell carcinoma of the ovary

Clear cell carcinoma of the ovary (CCC) has a poor prognosis because of its resistance to conventional platinum- or taxane-based chemotherapy. Consequently, there is a need to discover biomarkers for predicting the outcome of patients with CCC and develop novel treatment strategies for this disease. Recent studies have shown that somatic mutations in the AT-rich interactive domain 1A (SWI-like) gene (ARID1A) are the most common genetic changes in CCC. This gene is located in chromosome 1p36 and encodes a member of the switch/sucrose-nonfermentable (SWI/SNF) family protein BAF250a (ARID1A). Here, we investigated whether ARID1A could be a prognostic biomarker for this disease. Paraffin-embedded specimens were collected from 220 Japanese patients with epithelial ovarian cancer, including 112 CCC and 108 high-grade serous adenocarcinoma of the ovary (HG-SAC). We analyzed the protein expression of ARID1A in these samples by immunohistochemical staining, and evaluated the association of these molecular parameters with clinical outcome. The loss of ARID1A expression was found in 39.3 % (44/112) of CCC, and strong expression of the protein was not observed. ARID1A protein was present mainly in the cell nuclei of the tumors; however, in tumors with HG-SAC, only 8 (7.4 %) tumors showed loss of ARID1A expression. The rate of absent expression of ARID1A in CCC tumors was significantly higher than in HG-SAC tumors (P < 0.0001). We found no significant association between ARID1A expression and patient age, FIGO stage, and status of residual tumor in CCC. The 5-year survival rate for FIGO stage I or II CCC patients with negative tumor expression of ARID1A was lower than those with positive tumor expression of ARID1A (74 % vs 91 %), but this difference was not observed in FIGO stage III or IV patients. Multivariable analysis revealed that FIGO stage and residual tumor were independent prognostic factors, but ARID1A expression was not. However, ARID1A expression was an independent prognostic factor in FIGO stage I or II CCC patients. The ARID1A protein may be a promising prognostic marker for FIGO stage I and II CCC.

Loss of ARID1A expression is associated with poor prognosis in patients with stage I/II clear cell carcinoma of the ovary.

Recent studies have shown that somatic mutations in the AT-rich interactive domain 1A (SWI-like) gene (ARID1A) are the most common genetic changes in clear cell carcinoma of the ovary (CCC). A gene mutation of ARID1A was found in approximately half of CCC cases, and led to absence of the encoded protein and inactivation of the putative tumor suppressor. Here, we investigated whether ARID1A could be a prognostic biomarker for this disease. We analyzed the protein expression of ARID1A in CCC from 112 patients by immunohistochemical staining, and evaluated the association of these molecular parameters with clinical outcome. The loss of ARID1A expression was found in 39 % (44/112) of CCC, and was not associated with patient age, FIGO stage, and status of residual tumor. The 5-year survival rate for FIGO stage I or II patients with negative tumor expression of ARID1A was lower than those with positive tumor expression of ARID1A (74 % vs 91 %), but this difference was not observed in FIGO stage III or IV patients. Multivariable analysis revealed that ARID1A expression was an independent prognostic factor in FIGO stage I or II CCC patients. ARID1A may be a biomarker that is predictive of the outcome of FIGO stage I and II CCC.

Comparative analysis of clinicopathological correlations of cyclooxygenase-2 expression in resectable pancreatic cancer

To perform a comparative analysis of clinicopathological correlations of cyclooxygenase-2 (COX-2) expression in pancreatic cancer, examined by monoclonal and polyclonal antibodies. The COX-2 expression in 85 resection specimens of pancreatic ductal adenocarcinoma was immunohistochemically examined using both monoclonal and polyclonal antibodies. The final immunoscores were obtained by multiplying the percentage of positive cells with the numeric score reflecting the staining intensity. COX-2 expression levels were classified into three categories (0, 1+, and 2+) and the clinicopathological correlations were statistically evaluated and analyzed. The positive tumor expression rates of COX-2 were 80.5% using monoclonal antibody and 69.4% using polyclonal antibody. In the Kaplan-Meier analysis, no significant correlations were found between levels of COX-2 expression and overall survival (OS), but trends to longer OS were found in COX-2 negative cases using monoclonal antibody. Significantly longer disease free survival was revealed in COX-2 negative cases using monoclonal antibody (P = 0.019). No correlations between COX-2 expression levels and grade (G), tumor (T) status and nodal (N) status were demonstrated. Low histological grade showed a strong association with a longer OS (P < 0.001). Correlation of survival and T status revealed a shorter OS in T3 tumors, but the results reached only marginal statistical significance (P = 0.070). In the multivariate Cox proportional hazards regression model, histological grade, T and N status remained valuable predictors of a worse survival with borderline significance for T [hazards ratio (HR) = 4.18 for G (if G = 3, P < 0.001); HR = 1.64 for T (if T = 3, P = 0.065); HR = 2.53 for N (if N = 1, P = 0.006)]. Higher grade, T or N status was associated with a worse OS. The immunohistochemically assessed level of COX-2 expression does not seem to represent a valuable independent prognostic factor and is not superior to the conventional prognostic factors.

Clinicopathological Correlations of Cyclooxygenase-2, MDM2, and p53 Expressions in Surgically Resectable Pancreatic Invasive Ductal Adenocarcinoma

Cyclooxygenase-2 (COX-2) and p53 represent molecules linked to oncogenesis of pancreatic cancer, and there is also a known regulatory loop between mouse double minute 2 (MDM2) and p53. The complex cross talks between p53 and COX-2 and scenarios explaining patterns of p53 and COX-2 expressions in precursor and cancer lesions have been recently reported. The expressions of COX-2, p53, and MDM2 were examined using immunohistochemistry in 85 resection specimens of pancreatic ductal adenocarcinoma. The positive tumor expression rates of COX-2, p53, and MDM2 were 69.4%, 60.0%, and 41.2%, respectively. Significant correlations between COX-2 and p53 expressions and between p53 and MDM2 expressions were revealed. In the Kaplan-Meier analysis, no statistically significant correlations were found among the levels of COX-2, p53, and MDM2 expressions and survival rates. In the multivariate Cox proportional hazards regression model, grade and nodal status showed to be a valuable predictor of a worse overall survival. The reported findings confirmed the relationship of p53, MDM2, and COX-2 with the biological process of pancreatic cancer. The expression of none of the examined proteins showed to be a valuable independent prognostic factor. On the contrary, grade and nodal status showed to be a valuable predictor of a worse survival.

Associação entre a expressão das proteínas p53 e Ki-67 e os achados clínico-patológicos em pacientes com carcinoma invasor do colo uterino

PURPOSE: to evaluate the association between p53 and Ki-67 expression in the tumor and clinicopathological features in patients with carcinoma of the cervix. METHODS: samples were taken from the tumor of 36 patients with stage IB (FIGO) cervical carcinoma submitted to radical hysterectomy. Tissue samples were taken from the tumor, fixed in formalin and embedded in paraffin. The specimens were analyzed by histopathology (hematoxylin and eosin) and immunohistochemically evaluated using monoclonal antibodies for p53 and Ki-67. Data were analyzed statistically by the c2 test to evaluate eventual differences between the groups. RESULTS: the age of the patients ranged from 27 to 73 years (48.7±10.4 years). Clinical stage (FIGO) was IB1 in 27 cases (75%) and IB2 in 9 cases (25%). A positive tumoral expression of the p53 protein was found in half of the cases. In relation to the Ki-67 expression, a high cell proliferation index was shown in 73.3% of the cases. There was no association between tumoral p53 and Ki-67 expression with age (p=0.091 and 0.900), clinical stage (p=0.054 and 0.667), histological classification (p=0.674 and 0.674), grade of differentiation (p=0.070 and 0.282), presence of lymphatic vascular space invasion (p=0.248 and 0.667), parametrial involvement (p=0.729 and 0.763) and pelvic lymph node metastasis (p=0.729 and 0.636, respectively). CONCLUSIONS: tumoral expression of p53 and Ki-67 was not associated with the clinicopathological features in patients with stage IB carcinoma of the cervix.

CA19‐9 as a predictor of recurrence in patients with colorectal cancer

Background and Objectives CA19-9 is a cancer-associated carbohydrate antigen that plays a role in the process of tumor progression as an adhesion molecule. Methods We evaluated the prognostic value of CA19-9 tumor expression and CA19-9 preoperative and postoperative serum levels in colorectal cancer patients treated by complete resection. The most powerful discrimination was achieved using the three CA19-9 markers in combination. Results CA19-9 tumor expression was identified by immunostaining in 71.0% (86/121) of primary carcinomas. Positive CA19-9 serum levels (≥37 U/ml) were restricted to cases with positive tumor expression, and CA19-9 was detected more frequently in preoperative serum (20.6%, 25/121) than in 1-month postoperative serum (6.6%, 8/121). Positive tumor expression, positive preoperative serum level, and positive postoperative serum level were all predictive of increased cancer mortality. Patients with three negative parameters had no recurrences and 97.1% 5-year survival, whereas patients with three positive parameters had 62.5% recurrence and 42.8% 5-year survival. Conclusions CA19-9 detection in tumor tissue and serum identified patients at high risk of cancer recurrence and death and may be useful in selecting patients for adjuvant therapy. J. Surg. Oncol. 1997;66:238–243. © 1997 Wiley-Liss, Inc.

CA19-9 as a predictor of recurrence in patients with colorectal cancer.

CA19-9 is a cancer-associated carbohydrate antigen that plays a role in the process of tumor progression as an adhesion molecule. We evaluated the prognostic value of CA19-9 tumor expression and CA19-9 preoperative and postoperative serum levels in colorectal cancer patients treated by complete resection. The most powerful discrimination was achieved using the three CA19-9 markers in combination. CA19-9 tumor expression was identified by immunostaining in 71.0% (86/121) of primary carcinomas. Positive CA19-9 serum levels (> or = 37 U/ml) were restricted to cases with positive tumor expression, and CA19-9 was detected more frequently in preoperative serum (20.6%, 25/121) than in 1-month postoperative serum (6.6%, 8/121). Positive tumor expression, positive preoperative serum level, and positive postoperative serum level were all predictive of increased cancer mortality. Patients with three negative parameters had no recurrences and 97.1% 5-year survival, whereas patients with three positive parameters had 62.5% recurrence and 42.8% 5-year survival. CA19-9 detection in tumor tissue and serum identified patients at high risk of cancer recurrence and death and may be useful in selecting patients for adjuvant therapy.