Molecular variances between rectal and left-sided colon cancers.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 522-522 ◽  
Author(s):  
John Marshall ◽  
Heinz-Josef Lenz ◽  
Joanne Xiu ◽  
Wafik S. El-Deiry ◽  
Jeffrey Swensen ◽  
...  
Keyword(s):  
Tumor Infiltrating Lymphocytes ◽  
Genetic Alterations ◽  
Recent Analysis ◽  
Missense Mutations ◽  
Chi Square ◽  
Primary Tumors ◽  
Colon Cancers ◽  
Nextgen Sequencing ◽  
Disease Biology ◽  
Infiltrating Lymphocytes

522 Background: Recent analysis of CALGB 80405 showed that left sided colon tumors (LT) respond differently to biologics compared with right-sided tumors, likely due to molecular differences. Molecular variations between LT and rectal tumors remain undefined. Herein, we report our exploration of these variations. Methods: Tumors with origins clearly defined as splenic flexure to descending colon (SFT), sigmoid colon (SgT), or rectum (RT) were included. Protein expression, gene amplification and NextGen sequencing was tested. Microsatellite instability (MSI) was measured by PCR. Tumor mutational load (TML) was calculated using only somatic nonsynonymous missense mutations. Chi-square tests were used for comparative analyses. Results: In total, 1,457 primary tumors (SFT 125; SgT 460, and RT 872) were examined. When compared with SFT, RT had a higher frequency of TP53 (71% vs. 57%, p = 0.03) and APC (66% vs. 49%, p = 0.01); a lower frequency of PIK3CA (11% vs. 22%, p = 0.02), BRAF (3% vs. 15% p = 0.0001), GNAS (0.9% vs. 4%, p = 0.04), HNF1A (0.7% vs. 5%, p = 0.01), and CTNNB1(0.3% vs. 4%, p = 0.003); and a higher expression of TOPO1 (52% vs. 31%, p = 0.0001), ERCC1 (29% vs. 15%, p = 0.03), and MGMT (64% vs. 53%, p = 0.048). When compared with SgT, RT had higher expression of TLE3 (33% vs. 23%, p = 0.007), TOPO1 (52% vs. 35%, p < 0.001), TUBB3 (41% vs. 28%, p = 0.003), and MGMT (64% vs. 54%, p = 0.003). There were no differences between SFT, SgT, and RT in the frequency of PD-L1 expression (5%, 2%, and 2%) on tumor cells, PD-1 expression on tumor-infiltrating lymphocytes (54%, 42%, and 42%), or Her-2 expression (1%, 2%, and 3%) and amplification (3%, 3%, and 5%). MSI was seen in 7% of SFT, 4% of SgT, and 0.7% of RT (total LT vs. RT, p = 0.01). Mean TML was 23, 6.5, and 7 mutations (mut)/MB (332 tumors), and the portion of tumors carrying a TML of > 17mut/MB was 9%, 1.6%, and 4% for SFT, SgT, and RT, respectively. In all 3 cohorts, a TML > 17 mut/MB was highly concordant with MSI. There was a correlation between PD-1 and TML in RT (p = 0.04) but not in SFT or SgT. There were no correlations between PD-L1 and TML. Conclusions: Tumors arising in the rectum may carry genetic alterations that are distinct from LT. A better understanding of disease biology may help to identify therapeutic targets and advance precision medicine

scholarly journals Clinical Impact of Tumor-Infiltrating Lymphocytes and PD-L1-Positive Cells as Prognostic and Predictive Biomarkers in Urological Malignancies and Retroperitoneal Sarcoma

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3153
Author(s):  
Makito Miyake ◽  
Shunta Hori ◽  
Takuya Owari ◽  
Yuki Oda ◽  
Yoshihiro Tatsumi ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Tumor Infiltrating Lymphocytes ◽  
Retroperitoneal Sarcoma ◽  
Prognostic Impact ◽  
Lymphocyte Migration ◽  
Primary Tumors ◽  
Urological Malignancies ◽  
Infiltrating Lymphocytes ◽  
Shed Light

Over the past decade, an “immunotherapy tsunami”, more specifically that involving immune checkpoint inhibitors (ICIs), has overtaken the oncological field. The interaction and cross-talk among tumor cells and several immune cells in the tumor microenvironment are dynamic and complex processes. As immune contexture can vary widely across different types of primary tumors and tumor microenvironments, there is still a significant lack of clinically available definitive biomarkers to predict patient response to ICIs, especially in urogenital malignancies. An increasing body of evidence evaluating urological malignancies has proven that tumor-infiltrating lymphocytes (TILs) are a double-edged sword in cancer. There is an urgent need to shed light on the functional heterogeneity in the tumor-infiltrating immune system and to explore its prognostic impact following surgery and other treatments. Notably, we emphasized the difference in the immunological profile among urothelial carcinomas arising from different primary origins, the bladder, renal pelvis, and ureter. Significant differences in the density of FOXP3-positive TILs, CD204-positive tumor-infiltrating macrophages, PD-L1-positive cells, and colony-stimulating factors were observed. This review discusses two topics: (i) the prognostic impact of TILs and (ii) predictive biomarkers for ICIs, to shed light on lymphocyte migration in four solid tumors, the urothelial carcinoma, renal cell carcinoma, prostate cancer, and retroperitoneal sarcoma.

Molecular characterization of colorectal tumors in young patients compared with older patients and impact on outcome.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 505-505 ◽  
Author(s):  
Arielle Celeste Heeke ◽  
Joanne Xiu ◽  
Sandeep K. Reddy ◽  
Jiji Jiang ◽  
Hongkun Wang ◽  
...  
Keyword(s):  
Age Groups ◽  
Young Patients ◽  
Tumor Infiltrating Lymphocytes ◽  
Genetic Alterations ◽  
Mutation Rates ◽  
Molecular Profile ◽  
Nras Mutation ◽  
Fragment Analysis ◽  
Disease Biology ◽  
Kaplan Meier

505 Background: The incidence of colorectal cancer (CRC) among young individuals is rising. The effect of an individual’s age on their tumor molecular profile is unknown. Methods: Molecular profiles of 4,821 tumors obtained from younger and older CRC patients (pts) were reviewed and correlated with pt outcome. Protein expression (IHC), gene amplification (ISH), sequencing (NGS and Sanger), and fragment analysis were performed. T and Fisher’s exact tests determined differences between age groups; Kaplan-Meier methodology estimated survival. Results: Tumors from 1,277 younger (median age 40; range 15-45 yr) and 3,544 older (72; 65-98) pts were studied. Most frequently mutated genes included TP53, APC, KRAS, PIK3CA, SMAD4, and BRCA1/2. Mutation rates for BRAF (14.4% vs. 4.8%, p < 0.001), APC (62% vs. 54%, p = 0.0034), FBXW7 (9.6% vs. 5.5%, p = 0.01), and KRAS (45% vs. 41%, p = 0.02) were higher in older pts; NRAS mutation rates (4.5% vs. 3.9%) were similar in both groups. Younger pts had higher overexpression rates of HER-2/neu (3.2% vs. 1.8%, p = 0.017) and MGMT (64% vs. 58%, p = 0.001). Microsatellite instability (MSI), determined by IHC (MLH1, MSH2, MLH6 and PMS2) and fragment analysis, was similar between cohorts (10.3% vs. 8.1%), but somatic MSI high (determined by concurrent BRAF mutation) was higher in older pts (6% vs. 0%, p < 0.0001). There was no difference in TS (37% vs. 34%), ERCC1 (25% vs. 26%) or TOPO1 (49% vs. 46%) expression between age groups. Older pts showed a trend toward higher PD-L1 expression (2.9% vs. 0.7%, p = 0.0512) but there was no difference in the frequency of PD-1 expression on tumor-infiltrating lymphocytes (39% vs. 43%). Outcome was evaluable for 82 pts (younger, 47; older, 35). Most pts received FOLFOX + Bev as first line Rx. Median OS was worse in younger pts (p = 0.03). Low ERCC1 expression was associated with prolonged survival in older (p < 0.01) but not in younger (p = 0.3) pts. There was no association between TOPO1 expression and OS (p = 0.8). Pts with low TS expression showed a trend toward longer OS (p = 0.08). Conclusions: Young pts with CRC may carry genetic alterations that are distinct from older pts. A better understanding of disease biology may help to identify therapeutic targets for younger pts.

Molecular characterization of early vs. late onset gastroesophageal cancers.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 46-46
Author(s):  
Sadaf Qureshi ◽  
Joanne Xiu ◽  
Maryam Sarraf Yazdy ◽  
Anthony Frank Shields ◽  
Philip Agop Philip ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Late Onset ◽  
Young Patients ◽  
Molecular Profile ◽  
Missense Mutations ◽  
Environmental Carcinogens ◽  
Nras Mutation ◽  
Chi Square ◽  
Primary Tumors ◽  
Egfr Expression

46 Background: Gastric and esophageal adenocarcinomas (GA and EA) in young patients (pts) are more likely driven by genetic factors than environmental carcinogens. Tumor molecular variations defining individual differences in age of onset have not been well elucidated. Methods: Protein expression (IHC), gene amplification (ISH), and next generation sequencing (NGS) were tested on GA and EA tumors. Tumor mutational load (TML) was calculated using only somatic nonsynonymous missense mutations sequenced with a 592-gene panel. Chi-square and t-tests were used for comparative analyses. Results: In total, 1670 tumors were examined; older (age >60) vs. younger (<45)comparisons were made in 599 GA and 491 EA (Table). In GA, significantly higher TOPO2A and TOPO1 expression was seen in older vs. younger pts, while higher mutation rates of FGFR2, IDH1, and NRAS were seen in younger pts. In EA, EGFR expression was higher in the older pts, while ATM and BRCA1 mutations were higher in the younger pts. When only primary tumors were studied, younger GA had a higher NRAS mutation rate (4.5% vs. 0, p=0.02) than older GA, and younger EA had higher cMET amplification (10% vs. 0, p=0.002) and ATM mutations (25% vs. 0, p=0.01) than older EA. In metastatic EA, higher BRCA1mutations (1/2 [50%] vs. 0/12 [0%], p=0.01) and lower EGFR overexpression (81% vs. 29%, p = 0.004) were seen in younger vs. older pts. No differences were seen in the PD-1 or PD-L1 expression rates between the two groups. Mean TML was lower in young GA than old GA (6.2 mutation/megabase vs. 10.4, p=0.005) but was not different between young EA and old EA (5.3 vs. 6.9, p=0.1). Conclusions: Younger GA/EA has a molecular profile unique from older pts, suggesting molecular aberrations play a different part in early-onset disease. Prevalence of aberrations in the young, such as cMET amplification and FGFR2, IDH1, BRCA1mutations may indicate important therapeutic targets. [Table: see text]

Colorectal cancer: Impact of primary tumor location on genetic alterations.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3578-3578 ◽  
Author(s):  
Mohamed E. Salem ◽  
Heinz-Josef Lenz ◽  
Joanne Xiu ◽  
Jimmy J. Hwang ◽  
Philip Agop Philip ◽  
...  
Keyword(s):  
Tumor Location ◽  
Genetic Alterations ◽  
Hepatic Flexure ◽  
Missense Mutations ◽  
Chi Square ◽  
Molecular Alterations ◽  
Clear Cut ◽  
Comparison Results ◽  
Her 2 ◽  
The Right

3578 Background: Recent data show that patients with left sided colon tumors (LT) have better survival and respond differently to biologics compared to patients with right-sided tumors (RT), likely due to molecular differences. We sought to examine these differences. Methods: Primary colorectal tumors (n = 1730) with origins clearly defined as RT (cecum to hepatic flexure; n = 273), LT (splenic flexure to sigmoid colon; n = 585), or rectal (RC; n = 872) were examined by NextGen sequencing, protein expression and gene amplification. Tumor mutational load (TML) was calculated in 1001 of these tumors using only somatic nonsynonymous missense mutations. Chi-square was used for comparison. Results: When compared to LT, RT carried a significantly higher rate of BRAF (25% vs 7%; p < 0.0001), PTEN (5.4% vs 1.3%; p = 0.008), and ATM (4% vs 1%; p = 0.04) mutations. RT were likely to have more MSI-high tumors (22% vs 5%; p < 0.0001) and PD-1 overexpression (58% vs 44%; p = 0.01). There were no differences in the rate of KRAS (50% vs 42%; p = 0.07) or NRAS mutations (2.2% vs 3.4%; p = 0.4). When compared to RC, RT had a higher rate of BRAF (25% vs 3%; p = 7E-07), PIK3CA (22% vs 11%; p = 0.001), CTNNB1 (3% vs 0.3%; p = 0.02); ATM (3% vs 1%; p = 0.04), PTEN (5% vs 1%; p = 0.004), and BRCA1 mutations (4% vs 0%; p = 0.02), and a lower rate of TP53 (56% vs 71%; p = 0.001) and APC (53% vs 66%; p = 0.003) mutations. When compared to RC, LT showed higher rates of BRAF (6.7% vs 3.2%; p = 0.04) and CTNNB1 (2.1% vs 0.3%; p = 0.04) mutations, and a higher rate of MSI-high tumors (4.6% vs 0.7%; p = 0.04), whereas RC had a higher rate of KRAS mutation (50% vs 42%; p = 0.04). There were no differences between RT, LT, and RC for the frequency of PD-L1 (2%, 2%, and 1%) or Her-2 (1%, 2%, and 3%) overexpression, although Her-2 amplification was significantly different (1%, 3%, and 5%, RT vs RC; p = 0.03). Mean TML was 12, 11, and 8 mutations/megabase for RT, LT, and RC, respectively (RT vs RC; p = 0.01). There was a correlation between TML and PD-L1 (p = 0.04) and PD-1 (p = 0.01). Conclusions: Tumors arising in the right colon carry genetic alterations that are different from LT as well as RC. However, it appears that CRCs carry a continuum of molecular alterations from the right to the left side, rather than displaying sharp, clear-cut differences.

Number of tumor-infiltrating lymphocytes in breast cancer brain metastases compared to matched breast primaries.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2049-2049 ◽  
Author(s):  
Jessie Narloch ◽  
Catherine Luedke ◽  
Gloria Broadwater ◽  
Nolan Priedigkeit ◽  
Allison Hall ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Tumor Infiltrating Lymphocytes ◽  
Cox Proportional Hazards Model ◽  
Her2 Status ◽  
Primary Tumors ◽  
Metastatic Setting ◽  
Breast Cancer Brain Metastasis ◽  
Infiltrating Lymphocytes

2049 Background: Breast cancer brain metastasis (BCBM) is frequent in advanced disease, has limited therapies, and is associated with poor prognosis. Increased stromal tumor infiltrating lymphocytes (sTILs) are prognostic in triple-negative breast cancer (TNBC) and predictive of therapeutic response in early breast cancer (BC). However, little is known about sTILs in the metastatic setting. We compared %sTILs between the largest known cohort of matched primary tumors and BCBM and correlated the results with clinical endpoints. Methods: We retrospectively investigated 37 matched primary tumors and BCBM tissue from three institutions. In addition, we identified 29 primary tumors from patients later diagnosed with BCBM. H&E-stained sections were manually measured for %sTILs using standard criteria. Wilcoxon signed rank tests assessed for changes in %sTILs between primary and metastatic lesions. A Cox proportional hazards model was used to determine if %sTILs in the breast tissue predicts time from primary tumor biopsy to diagnosis of brain metastasis (TTDBM) while adjusting for clinicopathologic features. Results: Average age at time of BCBM diagnosis was 53.6 (SD 12.3). 52% (34/66) of primary tumors were hormone receptor (HR) positive. Of 60 patients with known HER2 status, 28% (17) were HER2 positive and 40% (24) TNBC. Median %sTILS was significantly different between all primary tumors (15, IQR 5-20) and brain metastases (10, IQR 5-10), p = 0.001. The TNBC subtype (n = 11) showed the largest decrease in %sTILs between primary tumors (20, IQR 10-20) and brain metastases (5, IQR 5-10), p = 0.022. Comparing primary tumors and brain metastases, there was a 5% decrease in %sTILs in HR-/HER2+ (n = 5, p = 0.13) and HR+/HER2- (n = 7, p = 0.13), and a 5% increase in %sTILs in the HR+/Her2+ subtype (n = 9, p = 0.69). Percent sTILs in the primary tumors was not a significant predictor of TTDBM, when adjusting for race, age, HR status, and HER2 status, p = 0.87. Conclusions: BCBM have a significantly decreased %sTILs compared to their primary tumors, most prominent in TNBC. These results suggest altered tumor immunogenicity in the metastatic setting which has broad implications for the development of immunotherapy.

scholarly journals Identification of shared TCR sequences from T cells in human breast cancer using emulsion RT-PCR

2016 ◽  
Vol 113 (29) ◽  
pp. 8272-8277 ◽  
Author(s):  
Daniel J. Munson ◽  
Colt A. Egelston ◽  
Kami E. Chiotti ◽  
Zuly E. Parra ◽  
Tullia C. Bruno ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Bilateral Breast Cancer ◽  
Tumor Infiltrating Lymphocytes ◽  
Specific Response ◽  
Rt Pcr ◽  
Primary Tumors ◽  
Infiltrating Lymphocytes

Infiltration of T cells in breast tumors correlates with improved survival of patients with breast cancer, despite relatively few mutations in these tumors. To determine if T-cell specificity can be harnessed to augment immunotherapies of breast cancer, we sought to identify the alpha–beta paired T-cell receptors (TCRs) of tumor-infiltrating lymphocytes shared between multiple patients. Because TCRs function as heterodimeric proteins, we used an emulsion-based RT-PCR assay to link and amplify TCR pairs. Using this assay on engineered T-cell hybridomas, we observed ∼85% accurate pairing fidelity, although TCR recovery frequency varied. When we applied this technique to patient samples, we found that for any given TCR pair, the dominant alpha- or beta-binding partner comprised ∼90% of the total binding partners. Analysis of TCR sequences from primary tumors showed about fourfold more overlap in tumor-involved relative to tumor-free sentinel lymph nodes. Additionally, comparison of sequences from both tumors of a patient with bilateral breast cancer showed 10% overlap. Finally, we identified a panel of unique TCRs shared between patients’ tumors and peripheral blood that were not found in the peripheral blood of controls. These TCRs encoded a range of V, J, and complementarity determining region 3 (CDR3) sequences on the alpha-chain, and displayed restricted V-beta use. The nucleotides encoding these shared TCR CDR3s varied, suggesting immune selection of this response. Harnessing these T cells may provide practical strategies to improve the shared antigen-specific response to breast cancer.

Association of tumor infiltrating lymphocytes (TILs) with molecular subtype and prognosis in stage III colon cancers (CC) from a FOLFOX-based adjuvant chemotherapy trial.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. 3518-3518 ◽  
Author(s):  
Frank A. Sinicrope ◽  
Thomas C. Smyrk ◽  
Nathan R. Foster ◽  
Jeffrey P. Meyers ◽  
Stephen N. Thibodeau ◽  
...  
Keyword(s):  
Adjuvant Chemotherapy ◽  
Molecular Subtype ◽  
Tumor Infiltrating Lymphocytes ◽  
Stage Iii ◽  
Colon Cancers ◽  
Infiltrating Lymphocytes
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