Multi-platform molecular profiling identifies subgroups of TNBC with different biomarker profiles, suggesting numerous potentially targetable alterations in TNBC. TNBC is further characterized by different gene mutations and proliferative activity relative to AR expression, highlighting a need for comprehensive pathologic examination with potential to develop different, individualized treatment options.

Background: Appendiceal cancers are rare and consist of carcinoid, mucocele, pseudomyxoma peritonei (PMP), goblet cell carcinoma, lymphoma, and adenocarcinoma histologies. Current treatment involves surgical resection or debulking, but no standard exists for adjuvant chemotherapy or treatment for metastatic disease. Methods: Samples were identified from approximately 60,000 global tumors analyzed at a referral molecular profiling CLIA-certified laboratory. A total of 588 samples with appendix primary tumor sites were identified (male/female ratio of 2:3; mean age =55). Sixty-two percent of samples were adenocarcinomas (used for analysis); the rest consisted of 9% goblet cell, 15% mucinous; 6% pseudomyxoma, and less than 5% carcinoids and 2% Results: Profiling across all appendiceal cancer histological subtypes for IHC revealed: 97% BRCP, 81% MRP1, 81% COX-2, 71% MGMT, 56% TOPO1, 5% PTEN, 52% EGFR, 40% ERCC1, 38% SPARC, 35% PDGFR, 35% TOPO2A, 25% RRM1, 21% TS, 16% cKIT, and 12% for TLE3. NGS revealed mutations in the following genes: 50.4% KRAS, 21.9% P53, 17.6% GNAS, 16.5% SMAD4, 10% APC, 7.5% ATM, 5.5% PIK3CA, 5.0% FBXW7, and 1.8% BRAF.Conclusions: Appendiceal cancers show considerable heterogeneity with high levels of drug resistance proteins (BCRP and MRP1), which highlight the difficulty in treating these tumors and suggest an individualized approach to treatment. The incidence of low TS (79%) could be used as a backbone of therapy (using inhibitors such as 5FU/capecitabine or newer agents). Therapeutic options includeTOPO1 inhibitors (irinotecan/topotecan), EGFR inhibitors (erlotinib, cetuximab), PDGFR antagonists (regorafenib, axitinib), KRAS, p53, GNAS, SMAD4, APC, ATM, PIK3CA, FBXW7, and BRAF may be also considered. Overall, appendiceal cancers have similar patterns in their molecular profile to pancreatic cancers (can we say this, any statistical analysis done?) and have differential expression from colorectal cancers. These findings indicate the need to evaluate patient samples for patterns in marker expression and alteration, in order to better understand the molecular biology and formulate a personalized therapy approach in these difficult to treat cancers (supported by a grant from Caris Life Sciences). MGMT (temozolomide). Clinical trials targeting pathways involving IntroductionCancers arising from the appendix are rare. In reports of appendectomy specimens, the incidence of malignancy has been reported to be between 0.58% to 0.9% (1,2). The histological spectrum is quite varied, with recent reports through large database studies indicating adenocarcinoma being the most common subtype (3,4). Other histological variants include carcinoid or neuroendocrine and a mixed histology tumor of both carcinoid and adenocarcinoma subtype termed goblet cell carcinoma (5). Finally, another epithelial variant of appendiceal cancer is pseudomyxoma peritonei (PMP), a mucinous neoplasm that clinically presents as gelatinous ascites (6,7). Due to the rarity of these malignancies limited prospective trials exist gu...

Targeted immunotherapy based on PD-1/PD-L1 suppression has revolutionized the treatment of various solid tumors. A remarkable improvement has also been observed in the treatment of patients with refractory/relapsing classical Hodgkin lymphoma (cHL). We investigated PD-L1 status in a variety of treatment resistant lymphomas. Tumor samples from 78 patients with therapy resistant lymphomas were immunohistochemically (IHC) investigated for the expression of PD-L1 using two antibody clones (SP142 and SP263, Ventana). Thirteen PD-L1+ cases were further analyzed for gene copy number variations (CNV) by NGS and for PD-L1/JAK2/PD-L2 co-amplification using fluorescent in-situ hybridization assay (FISH). PD-L1 positivity (≥5% positive cancer cells, IHC) was present in 32/77 (42%) and 33/71 cases (46%) using SP142 and SP263 antibodies, respectively. Concordance between the two anti-PD-L1 clones was high with only three (4%) discrepant cases. The strongest and consistent (10/11 cases) expression was observed in cHL and primary mediastinal B-cell lymphomas (3/3). Diffuse large B-cell lymphomas (DLBCL) were frequently positive (13/26) irrespective of subtype. Follicular (1/8), peripheral T-cell (3/11) and mantle cell (1/8) lymphomas were rarely positive, while small lymphocytic lymphoma/CLL and marginal zone lymphomas were consistently negative (3/3). Co-amplification/CNVs of PD-L1/JAK2/PD-L2 were observed in 3 cases of DLBCL and cHL, respectively. Of note, all three cHL-amplified cases were positive by FISH, but not by NGS. Since only a fraction of the IHC positive lymphoma cases were positive by FISH and NGS assays, other mechanisms are involved in PD-L1 upregulation, especially in DLBCL. FISH assay may be more suitable than NGS assay for determination of PD-L1 alterations in cHL.

Multiple myeloma (MM), the second most common hematologic malignancy, is characterized by the clonal expansion of plasma cells. Despite dramatic improvements in patients′ survival over the past decade due to advances in therapy exploiting novel molecular targets (immunomodulatory drugs, proteasome inhibitors and monoclonal antibodies), the treatment of relapsed and refractory disease remains challenging. Recent studies confirmed complex, dynamic, and heterogeneous genomic alterations without unifying gene mutations in MM patients. In the current review, we survey recent therapeutic strategies, as well as molecular profiling data on MM, with emphasis on relapsed and refractory cases. A critical appraisal of novel findings and of their potential therapeutic implications will be discussed in detail, along with the author’s own experiences/views.

Targeted immunotherapy based on PD-1/PD-L1 suppression has revolutionized the treatment of various solid tumors. A remarkable improvement has also been observed in the treatment of patients with refractory/relapsing classical Hodgkin lymphoma (cHL). We investigated PD-L1 status in a variety of treatment resistant lymphomas. Tumor samples from 78 patients with therapy resistant lymphomas were immunohistochemically (IHC) investigated for the expression of PD-L1 using two antibody clones (SP142 and SP263, Ventana). Thirteen PD-L1+ cases were further analyzed for gene copy number variations (CNV) by NGS and for PD-L1/JAK2/PD-L2 co-amplification using fluorescent in-situ hybridization assay (FISH). PD-L1 positivity (!5% positive cancer cells, IHC) was present in 32/77 (42%) and 33/71 cases (46%) using SP142 and SP263 antibodies, respectively. Concordance between the two anti-PD-L1 clones was high with only three (4%) discrepant cases. The strongest and consistent (10/11 cases) expression was observed in cHL and primary mediastinal B-cell lymphomas (3/3). Diffuse large B-cell lymphomas (DLBCL) were frequently positive (13/26) irrespective of subtype. Follicular (1/8), peripheral T-cell (3/11) and mantle cell (1/8) lymphomas were rarely positive, while small lymphocytic lymphoma/CLL and marginal zone lymphomas were consistently negative (3/3). Co-amplification/CNVs of PD-L1/ JAK2/PD-L2 were observed in 3 cases of DLBCL and cHL, respectively. Of note, all three cHL-amplified cases were positive by FISH, but not by NGS. Since only a fraction of the IHC positive lymphoma cases were positive by FISH and NGS assays, other mechanisms are involved in PD-L1 upregulation, especially in DLBCL. FISH assay may be more suitable than NGS assay for determination of PD-L1 alterations in cHL.

We have developed a novel, versatile, multiplexed exosome-based diagnostic platform that can identify highly specific and sensitive disease biosignatures. This platform has been used to identify a plasma-based exosome biosignature for prostate cancer (PCa) that is superior to current tests, which rely on increased levels of either PSA in the blood or elevated levels of the PCA3 transcript in the urine. Unfortunately, PSA levels can also be elevated due to confounding conditions like benign prostate hyperplasia (BPH) and prostatitis. PCA3, while appearing to be prostate cancer specific, only offers moderate benefit over the performance of PSA, and requires a digital rectal exam to obtain a suitable specimen for analysis. The screening and diagnosis of PCa would be significantly improved by identifying biomarkers that are both highly specific and sensitive as well as easily surveyed from the blood or urine. Exosomes are endosome-derived vesicles between 40-100 nm in diameter that are secreted by many cell types including the epithelial cells of the prostate. Exosomes appear to participate in cellular communication by transporting mRNAs, microRNAs and proteins from their cell of origin to target cells where they can elicit biological responses. The quantity and protein topography of exosomes shed from cancer cells varies considerably compared to those shed from normal cells. Thus, the concentration of plasma exosomes with molecular markers indicative of the disease state can be used as a robust and informative blood-based biosignature for PCa and other diseases. In this study we report the results of a novel multiplexed diagnostic platform for quantifying and profiling exosomes in plasma that was used to develop an exosome-derived biosignature composed of 7 different surface membrane protein biomarkers. These biomarkers include proteins specific to: exosomes generally (CD9, CD81, and CD63), exosomes from prostate epithelial cells (PSMA and PCSA), and tumor-associated exosomes (EpCam and B7H3). We used this exosome-specific PCa biosignature to profile 29 PCa patients and 31 age-matched men from the general population. Our blood-based exosome assay correctly identified PCa patients with a sensitivity of 83% and specificity of 90%, AUC = 0.881. Additionally, the assay distinguished between PCa and BPH patients. When we included patients with BPH (n=15) the sensitivity was 83% and the specificity of the test remained significant at 85%, AUC = 0.844. Further analysis revealed that 2 of the exosome-associated markers (PCSA and B7H3) showed significant differences between stage II and stage III disease using a nonparametric t-test (p = 0.009, 0.0271). This initial study demonstrates the ability of an exosome-derived biosignature patient profile to distinguish PCa from both normal and BPH and may ultimately allow PCa progression and therapeutic monitoring to be analyzed through a simple blood test. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 821.

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