Third Of Tumors Research Articles

Abstract P1-02-11: Somatic alterations and PD-L1 positivity in advanced breast cancer

Abstract Background: With the recent FDA approvals of atezolizumab and pembrolizumab for the treatment of unresectable locally advanced or metastatic triple-negative breast cancer, immuno-oncology (IO) therapy has become feasible for the first time in breast cancer, and PD-L1 immunohistochemistry (IHC) has become an essential assay in breast cancer diagnostics. However, relatively little is known about the molecular profile of PD-L1+ breast cancers compared to other tumors, such as lung cancer. Furthermore, although the initial data have shown the most benefit in triple-negative patients, it is unclear whether additional subgroups of patients with advanced breast cancer enriched for PD-L1 expression can be identified, and, therefore, might benefit from IO therapy. Methods: We identified 60 women with locally advanced or metastatic breast cancer who underwent next generation sequencing (NGS) of tumor samples obtained at our institution as part of their clinical care and performed PD-L1 testing using the Ventana SP142 platform. Samples were considered positive for PD-L1 if ≥1%. The NGS assay was designed to detect single nucleotide variants, insertions and deletions, copy number variants, and specific translocations in approximately 600 genes. Associations between PD-L1 status, molecular alterations, and tumor histopathologic features were assessed, with P < 0.05 considered statistically significant. Results: Our cohort consisted of 60 women at a median age of 56 years (range 31-81). 50% of samples were from primary tumors within the breast, 15% were from regional lymph node metastases, and 35% were from distant metastatic sites. Most tumors showed ductal histology (80%) and were either grade 2 (38%) or grade 3 (57%), while half showed focal (27%) or extensive (23%) necrosis. Based on IHC, most tumors were Luminal B (54%), followed by triple-negative (25%), Luminal A (13%), and HER2-enriched (8%) tumors. About one third of tumors had either moderate (25%) or marked (8%) TILs, and about half showed positivity for PD-L1 (48%). Most tumors had a low tumor mutational burden (TMB), with 83% having <5, 14% having 5-9, and 3% having ≥10 mutations per Mb. The median number of genes with reportable somatic alterations was 2 (IQR 1-3). The most common genes with somatic alterations were TP53 (51%), PIK3CA (23%), ERBB2 (16%), ESR1 (14%), FGFR1 (9%), AKT1 (7%), CDH1 (7%), GATA3 (7%), MYC (7%), and CCND1 (5%). 50% of luminal A, 38% of luminal B, 50% of HER2-enriched, and 75% of triple-negative tumors were PD-L1+, although this difference was not statistically significant (P = 0.22). PD-L1 positivity was more likely in grade 3 tumors (62% vs 31% grade 1-2, P = 0.02), and in tumors with extensive necrosis (85% vs 37% absent/focal, P = 0.004). Of all the genes tested, only TP53 was significantly associated with being PD-L1+ (69% TP53-mutant vs 32% TP53-wild-type; P = 0.008). Neither number of somatic alterations (P = 0.60) or TMB (P = 0.08) were significantly associated with PD-L1+ tumors. Of note, 53% of non-triple-negative PD-L1+ tumors had mutations in TP53, and 60% of non-triple-negative tumors with TP53 mutations were PD-L1+. Conclusions: Our data suggest that PD-L1 positivity is relatively common in patients with locally advanced or metastatic breast cancer, not only in triple-negative breast cancer but in all breast cancer subtypes. In addition, TP53 mutation is significantly associated with an increased likelihood of positivity for PD-L1, including in non-triple-negative tumors. This correlation could potentially be a useful marker for selecting non-triple-negative breast cancer patients for PD-L1 testing and, if positive, potentially offer them IO options for optimizing their response to therapy. Citation Format: Brian S Finkelman, Massimo Cristofanilli, Luis Z Blanco, Jr, Amir Behdad, Leonidas C Platanias, William J Gradishar, Kalliopi P Siziopikou. Somatic alterations and PD-L1 positivity in advanced breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-02-11.

Radiological Assessment of Giant Cell Tumour of Bone in the Sacrum: From Diagnosis to Treatment Response Evaluation.

Giant cell tumour of bone (GCTB) typically occurs in young adults from 20-40 years old. Although the majority of lesions are located in the epi-metaphyses of the long bones, approximately one third of tumours are located in the axial skeleton, of which only 4% in the sacrum. Sacral tumours tend to be large at the time of presentation, and they present with aggressive features such as marked cortical destruction and an associated soft tissue component. The 2020 World Health Organisation classification of Soft Tissue and Bone Tumours describes GCTB as a neoplasm which is locally aggressive and rarely metastasizing. The tumour contains three different cell types: neoplastic mononuclear stromal cells, macrophages and osteoclast-like giant cells. Two tumour subtypes were defined: conventional GCTB and malignant GCTB. Only 1-4% of GCTB is malignant. In this review article, we will discuss imaging findings at the time of diagnosis to guide the musculoskeletal radiologist in reporting these tumours. In addition, imaging for response evaluation after various treatment options will be addressed, such as surgery, radiotherapy, embolization and denosumab. Specific findings will be presented per imaging modality and illustrated by cases from our tertiary sarcoma referral center. Common postoperative and post-radiotherapy findings in GCTB of the sacrum on MRI will be discussed.

Abstract IA020: Mechanics, multinucleation, and EMT

Abstract Multinucleation is found in more than one third of tumors and is linked to increased tolerance for mutation, resistance to chemotherapy, and invasive potential. The integrity of the genome depends on proper execution of the cell cycle, which can be altered through mechanotransduction pathways as the tumor microenvironment stiffens during tumorigenesis. We recently found that inducers of epithelial-mesenchymal transition (EMT), including transforming growth factor-beta (TGFbeta), also promote multinucleation in stiff microenvironments through Snail-dependent expression of the filament-forming protein septin-6, resulting in midbody persistence, abscission failure, and multinucleation. Consistently, we observed elevated expression of Snail and septin-6 as well as multinucleation in a human patient sample of metaplastic carcinoma of the breast, a rare classification characterized by deposition of collagen fibers and active EMT. In contrast, a soft microenvironment protected mammary epithelial cells from becoming multinucleated by preventing Snail-induced upregulation of septin-6. I will describe data suggesting that tissue stiffening during tumorigenesis synergizes with oncogenic signaling to promote genomic abnormalities that drive cancer progression. Citation Format: Celeste M. Nelson. Mechanics, multinucleation, and EMT [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr IA020.

Characterization of ERBB2 alterations in non-small cell lung cancer.

e21553 Background: ERBB2 alteration (mutation and/or amplification) is associated with poor survival in non-small cell lung cancer (NSCLC) and is commonly reported as a resistance mechanism to EGFR tyrosine kinase inhibitors. Several clinical trials are ongoing for the management of ERBB2-altered NSCLC. Here we report the prevalence of different ERBB2 alterations in NSCLC. Methods: We retrospectively analyzed ERBB2 alterations in NSCLC tumors that underwent next-generation sequencing (NGS) with Caris Life Sciences. De-identified pathological and molecular information was collected. ERBB2 copy number of greater than 6 was defined as amplification; mutations were classified among 7 groups based on their mechanism of action. Results: A total of 12946 NSCLC tumors with ERBB2 NGS results were available. Among them, 12492 had ERBB2 copy number alteration (CNA) data available. 321 tumors (2.5%) had ERBB2 alteration (mutation or amplification). Among them, ERBB2 was mutated in 197 tumors (1.5%) and amplified in 134 (1.1%) tumors. Type of ERBB2 mutation, respective median age and distribution among sex is in the table. 10 tumors with ERBB2 mutation (7.46%) also showed ERBB2 amplification. Six percent of tumors (8/135) with ERBB2 exon 20 insertion mutations had co-occurring ERBB2 amplification. One tumor for each extracellular domain (ECD) and transmembrane group had co-occurring ERBB2 amplification. Eight tumors with ERBB2 mutation had an overlapping EGFR L858R or exon19del mutation. Seven of these 8 tumors were from the ECD group (7/21) and all had mutations in the S310 locus. One tumor was from the transmembrane group. Conclusions: Exon 20 insertion mutation is the most commonly found ERBB2 mutation among NSCLC, a few of them had co-occurring ERBB2 amplification. One third of tumors with extracellular domain ERBB2 mutation had EGFR mutation. Tarloxitinib (NCT03805841), trastuzumab deruxtucan (NCT03505719), pyrotinib (NCT02500199), poziotinib (NCT03318939) are just a few of the novel ERBB2 inhibitors available in clinical trials. It will be critical to utilize next generation sequencing to effectively capture uncommon mutations and amplifications in ERBB2 so that patients may be offered therapy directly targeted to their genomic alterations. [Table: see text]

Abstract 3690: Measuring functional signal transduction pathway activity on breast cancer tissue samples to determine intra-tumor heterogeneity and heterogeneity between primary and metastatic tumors

Abstract Background Treatment with targeted drugs is increasingly used in breast cancer aiming to block the tumor driving pathway(s). Drug choice is often based on a single primary tumor biopsy. It is important to ascertain that biopsied tumor material is representative for the tumor or metastases to treat with respect to tumor driving signaling pathway. Little is known about pathway heterogeneity within primary breast cancer, and between primary and metastatic tumors. A novel analysis method was developed to identify and quantify activity of signal transduction pathways in cancer tissue, based on Bayesian models which infer a pathway activity score from transcription factor target gene mRNA levels (Cancer Res 2014 Jun 1;74(11):2936-45). Methods Originally for AffymetrixU133Plus2.0, the pathway analysis was adapted for RT-qPCR enabling use on FFPE tissue. Calibration was performed using tissue samples with known pathway activity. Functional pathway activity of ER, AR, PI3K-FOXO, Hedgehog (HH), TGFbeta, and Wnt pathways was analyzed to assess (1) intra-tumor heterogeneity: 2-5 FFPE blocks of 17 primary breast cancers (9 luminal A, 4 luminal B, 1 HER2, 3 triple negative (TN), as defined by surrogate immunohistochemistry); (2) heterogeneity between primary and associated metastases: 9 patients with FFPE blocks from primary and 12 metastases. Results Intra-tumor heterogeneity: In 11 out of 13 Luminal A- and B-like tumors the ER pathway was active in all samples, 1 showed ER pathway heterogeneity; 11 had an active TGFbeta pathway, heterogeneic in 3; in one ER inactive tumor one (out of 5) samples was AR active. In 2 TN tumors TGFbeta and PI3K pathways were combined active, in one TN tumor heterogeneic TGFbeta activity was observed. PI3K pathway activity increased with malignancy grade and showed most intra-tumor variation. Overall, pathway heterogeneity was detected in over one third of tumors, least in Luminal A-like (2/9) compared to Luminal B-like (3/4) and triple negative (1/3) tumors. Extensive heterogeneity was found between primary breast cancer and metastases, and between metastatic locations of the same patient. ER pathway activity decreased in 5/9 patients and increased in 4/9 patients in one or more metastatic tumors; PI3K became active in metastasis of 2 patients and inactive in 1; the Wnt pathway became active in 3 patients in bone and ileum metastases; TGFbeta was lost in 5 patients, and became active in 1 bone metastasis; HH became active in 1 ovarian and AR in 1 bone metastasis. Conclusion Intra-tumor heterogeneity was lower in ER active compared to TN breast cancer, suggesting a need for multiple biopsies to adequately characterize TN for neoadjuvant therapy. Between primary tumor and metastases, heterogeneity was extensive indicating the need for pathway analysis on metastatic tumors prior to targeted treatment. Citation Format: Anja Van De Stolpe, Anne van Brussel, Cathy Moelans, Marcia A. Inda, Wim Verhaegh, Eveline den Biezen, Paul van Diest. Measuring functional signal transduction pathway activity on breast cancer tissue samples to determine intra-tumor heterogeneity and heterogeneity between primary and metastatic tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3690.

A Soft Microenvironment Protects from Failure of Midbody Abscission and Multinucleation Downstream of the EMT-Promoting Transcription Factor Snail.

Multinucleation is found in more than one third of tumors and is linked to increased tolerance for mutation, resistance to chemotherapy, and invasive potential. The integrity of the genome depends on proper execution of the cell cycle, which can be altered through mechanotransduction pathways as the tumor microenvironment stiffens during tumorigenesis. Here, we show that signaling downstream of matrix metalloproteinase-3 (MMP3) or TGFβ, known inducers of epithelial-mesenchymal transition (EMT), also promotes multinucleation in stiff microenvironments through Snail-dependent expression of the filament-forming protein septin-6, resulting in midbody persistence, abscission failure, and multinucleation. Consistently, we observed elevated expression of Snail and septin-6 as well as multinucleation in a human patient sample of metaplastic carcinoma of the breast, a rare classification characterized by deposition of collagen fibers and active EMT. In contrast, a soft microenvironment protected mammary epithelial cells from becoming multinucleated by preventing Snail-induced upregulation of septin-6. Our data suggest that tissue stiffening during tumorigenesis synergizes with oncogenic signaling to promote genomic abnormalities that drive cancer progression.Significance: These findings reveal tissue stiffening during tumorigenesis synergizes with oncogenic signaling to promote genomic abnormalities that drive cancer progression. Cancer Res; 78(9); 2277-89. ©2018 AACR.

Evidence-based data and rare cancers: The need for a new methodological approach in research and investigation

Rare cancers are not so rare, their incidence is increasing and, as a group, they have worse survival than the common cancers. These factors emphasise the societal need to ensure sufficient focus on research into their biological basis, aetiological factors, new more effective therapies and organisation of healthcare to improve access to best practice and innovation. Accuracy of diagnosis is one of the first hurdles to be overcome, with around one third of tumours being reclassified – by type or risk group – when subject to a centralised pathology review process. Timely access to appropriate expert knowledge is a second challenge for patients – in Europe this is being addressed by the establishment of European Reference Networks (ERNs) as part of the EU cross border healthcare initiative. There are ERNs for adult solid and haematological cancers and childhood cancers, all of which are individually rare. These ERNs will facilitate creation of large databases of rare tumours that will incorporate knowledge of their molecular features and build an evidence base for the effectiveness of innovative, biology-directed therapies. With an increasing focus on ‘real world’ outcome data, research methodologies are evolving, to include randomised registry trials and data linkage approaches that exploit the ever-richer information held on patients in routine health care data. The inclusion of genomic analysis into cancer diagnosis, treatment and risk prediction raises many issues for the conduct of clinical research and cohort studies and personal data sharing. Sophisticated means of pseudonymisation, together with full involvement of affected and ‘at risk’ patients, are supporting novel research designs and access to data that will continue to build the evidence base to improve outcomes for patients with rare cancers.

HLA Class I Antigen Expression in Conjunctival Melanoma Is Not Associated With PD-L1/PD-1 Status.

Antitumor T cells need expression of HLA class I molecules but can be inhibited by ligands such as programmed death ligand 1 (PD-L1). We determined expression and regulation of these molecules in human conjunctival melanoma (CM) samples, cell lines, and murine xenografts. Immunofluorescence staining was performed to examine the expression of HLA-A, HLA-B/C, and β-2-microglobulin (B2M) in 23 primary CM samples. HLA class I expression was compared with clinicopathologic characteristics, the presence of tumor-infiltrating leukocytes, and PD-L1/PD-1 status. The effect of interferon γ (IFN-γ) on HLA class I expression was tested on three CM cell lines using quantitative PCR and flow cytometry. Furthermore, HLA class I expression was determined in CM cell line-derived murine xenografts. One third of tumors had positive HLA-A, HLA-B/C, and B2M expression. A positive expression was especially seen in thin and epibulbar tumors but was not associated with recurrences. HLA class I expression was correlated with M2 macrophage density and tended to associate with CD8+ T-cell density but was independent of PD-L1 or PD-1 expression. IFN-γ upregulated HLA class I expression and genes involved in HLA transcription and transportation on CM cell lines. Murine xenografts showed a comparable HLA class I expression as their respective cell lines. Our data indicate that subsets of CM have positive HLA class I expression, and HLA class I and PD-L1/PD-1 are expressed independently. When one considers immunotherapy, one should also analyze HLA class I expression, whose downregulation can limit the efficacy of T cell-mediated therapies.

Targeting PTEN in Colorectal Cancers.

Phosphatase and tensin homolog (PTEN) is a tumour suppressor that represents one of the most common targets for genetic defect in human cancer. PTEN controls an array of physiopathological processes related to cell proliferation, differentiation, DNA/chromosome integrity, apoptosis and invasiveness. PTEN dephosphorylates not only proteins, but also phosphoinositides generated by phosphatidylinositol 3-kinase, thus counteracting the Akt signalling pathway. Interestingly, PTEN can also exert some biological functions independently of its catalytic activity.A feature of colorectal cancers is the relatively low incidence of PTEN mutation or deletion, whereas PTEN downregulation occurs in approximately one third of tumours. PTEN inactivation may be even higher when changes in posttranslational modifications and/or mislocalization of the tumour suppressor are accounted for. Strategies based on pharmacologically-induced restoration of wild-type PTEN function in colon cancer cells could therefore be considered, to impact cell growth, trigger apoptosis, and sensitize tumour cells to therapeutic agents.This review details current knowledge of the mechanisms regulating PTEN expression, activity and function. It also focuses on the use of small molecules targeting positive or negative PTEN regulators and summarizes alternative strategies that could be used to alter PTEN conformation/activity. Finally, we propose an outline of a personalized approach to restore PTEN function in colon cancer cells.

Near-Infrared Photoimmunotherapy Targeting Prostate Cancer with Prostate-Specific Membrane Antigen (PSMA) Antibody.

Prostate-specific membrane antigen (PSMA) is a membrane protein that is overexpressed manifold in prostate cancer and provides an attractive target for molecular therapy. Near-infrared photoimmunotherapy (NIR-PIT) is a highly selective tumor treatment that employs an antibody-photoabsorber conjugate (APC). Here, we describe the efficacy of NIR-PIT, using a fully human IgG1 anti-PSMA monoclonal antibody (mAb), conjugated to the photoabsorber, IR700DX, in a PSMA-expressing PC3 prostate cancer cell line. Anti-PSMA-IR700 showed specific binding and cell-specific killing was observed after exposure of the cells to NIR light in vitro In the in vivo study, anti-PSMA-IR700 showed high tumor accumulation and high tumor-background ratio. Tumor-bearing mice were separated into 4 groups: (i) no treatment; (ii) 100 μg of anti-PSMA-IR700 i.v.; (iii) NIR light exposure; (iv) 100 μg of anti-PSMA-IR700 i.v., NIR light exposure was administered. These were performed every week for up to 3 weeks. Tumor growth was significantly inhibited by NIR-PIT treatment compared with the other control groups (P < 0.001), and significantly prolonged survival was achieved (P < 0.0001 vs. other control groups). More than two thirds of tumors were cured with NIR-PIT. In conclusion, the anti-PSMA antibody is suitable as an APC for NIR-PIT. Furthermore, NIR-PIT with the anti-PSMA-IR700 antibody is a promising candidate of the treatment of PSMA-expressing tumors and could be readily translated to humans.Implications: NIR-infrared photoimmunotherapy (NIR-PIT) using a fully human anti-PSMA-IR700 conjugate showed potential therapeutic effects against a PSMA-expressing prostate cancer that is readily translated to humans. Mol Cancer Res; 15(9); 1153-62. ©2017 AACR.

Abstract CT007: Tumor treating fields added to standard chemotherapy in newly diagnosed glioblastoma (GBM): Final results of a randomized, multi-center, phase III trial

Abstract Background: Tumor Treating Fields (TTFields) is a novel, anti-mitotic, physical treatment. Alternating electrical fields (TTFields) at an intermediate frequency of 200 MHz (1-3 V/cm) are delivered continuously to the brain by a patient-operated, wearable medical device (Optune™, Novocure Ltd.). An international, multicenter, prospective, randomized phase 3 trial (EF-14) is testing the efficacy of adding TTFields to standard adjuvant temozlomide (TMZ) chemotherapy in newly diagnosed GBM. We report the final and mature results of all 695 patients (pts) enrolled (median follow-up &amp;gt; 3 years, minimum follow-up &amp;gt; 24 months) including five year survival rates. Methods: Within 7 weeks after the end of concomitant chemo-radiotherapy (TMZ/RT) and stratification for extent of resection and MGMT status, pts were randomized (at a 1:2 ratio) to either standard adjuvant TMZ alone (150-200 mg/m2/d x 5d) or TMZ and TTFields. Eligible pts had a newly diagnosed GBM, non-progressive after TMZ/RT, performance status of ≥70%, adequate hematological, liver and renal function. The primary endpoint is progression free survival (PFS; determined by blinded central radiology review), with overall survival (OS) as a powered secondary endpoint. Results: 695 pts were randomized (7/09 - 11/14). Patient characteristics are balanced, median age 56 years (range 19-83), 87 % had undergone tumor resection, 13 % a biopsy only. One third of tumors were MGMT methylated. Median time from end of radiotherapy to randomization was 37 days. The median number of adjuvant (maintenance) TMZ cycles was 6 and 5 cycles, for TTFields/TMZ and TMZ alone, respectively. All analyses are intent-to-treat. The median PFS is 6.7 months (95%CI 6.1-8.1) for the pts treated with TTFields/TMZ versus 4.0 months (CI 3.8 - 4.4) for TMZ alone (hazard ratio 0.63, p=0.00005). Median OS from randomization is 20.9 months versus 16 months for the TTFields/TMZ and TMZ alone, respectively, with a hazard ratio of 0.63 (CI 0.53-0.76), p=0.00006. Median time from initial diagnosis until completion of TMZ/RT with subsequent randomization was 3.7 months, equal in both arms. The landmark 2 and 5-year survival rates are 43% (CI 39-48%) vs 31% (CI 25-38) and 13% (CI 9-18) vs 5% (CI 2-11); p=0.0008 and 0.0037, respectively. The significant improvement in OS was seen across all patient subgroups regardless of age, extent of resection, performance status, gender, geography or MGMT methylation status. Only compliance with TTFields treatment was predictive of outcome, with pts who were treated for more than 18 hours/day (monthly average) living significantly longer than pts treated for less than 18 hours/day. Conclusions: This final analysis of the EF-14 trial demonstrate consistent superior PFS and OS in pts treated with maintenance therapy including both TTFields and TMZ compared with maintenance TMZ alone. With a hazard ratio for survival of 0.63, the magnitude of improvement when adding TTFields is comparable to the benefit observed with TMZ 12 years ago. Tumor Treating Fields are a welcome addition to the treatment armamentarium in GBM, and defines a new standard of care. This innovative regional treatment modality that can due to the absence of overlapping toxicity easily be combined with standard chemotherapy holds promise as a regional tumor treatment modality in other solid tumors. Citation Format: Roger Stupp, Monika E. Hegi, Ahmed Idbaih, David M. Steinberg, Benoit Lhermitte, William Read, Steven A. Toms, Gene H. Barnett, Garth Nicholas, Chae-Yong Kim, Karen Fink, Andrea Salmaggi, Frank S. Lieberman, Jay-Jiguang Zhu, Lynne Taylor, Giuseppe Stragliotto, Andreas F. Hottinger, Eilon D. Kirson, Uri Weinberg, Yoram Palti, Zvi Ram, on behalf of the EF-14 trial investigators. Tumor treating fields added to standard chemotherapy in newly diagnosed glioblastoma (GBM): Final results of a randomized, multi-center, phase III trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT007. doi:10.1158/1538-7445.AM2017-CT007

The lack of the organic cation transporter OCT1 at the plasma membrane of tumor cells precludes a positive response to sorafenib in patients with hepatocellular carcinoma.

BackgroundSorafenib is the drug of choice in the treatment of advanced hepatocellular carcinoma (HCC). Beneficial effects are limited by mechanisms of chemoresistance, which include downregulation and/or impaired function of plasma membrane transporters accounting for drug uptake. The organic cation transporter 1 (OCT1) plays a major role in sorafenib uptake and decreased expression in HCC has been associated with poorer response.MethodsThe multicenter retrospective TRANSFER study involved tumor biopsies from 39 patients with advanced HCC and sorafenib therapy for ≥4 wk. Endpoint was the relationship between clinicopathological features and immunohistological result. Immunostaining was performed using specific primary anti-OCT1-head and anti-OCT1-tail antibodies. Tumors were classified according to a simplified staining score as absent, weak, moderate or strong, taking into account the localization of the staining at the plasma membrane as positive or negative.ResultsResults confirmed OCT1 downregulation in half of the cases investigated (10% absent, 38% weak). However, only one third of tumors expressing OCT1 displayed plasma membrane location (15% vs. 36% cytosolic expression). When comparing HCC with and without OCT1 expression, no different sorafenib response was found. When tumors expressing OCT1 at the plasma membrane were considered separately, a marked longer survival was found (Log Rank p<0.001). No association between OCT1 expression at the plasma membrane with tumor stage, previous treatment with TACE or radiological response was seen.In conclusion, these results indicate that the presence of OCT1 at the plasma membrane, rather than its expression levels, is related to better outcome of HCC patients treated with sorafenib.

Tumor Biology Rather Than Surgical Technique Dictates Prognosis in Colorectal Cancer Liver Metastases

IntroductionThe interplay of tumor biology and surgical margin status after resection for colorectal liver metastasis (CRLM) remains controversial. Consequently, we sought to determine the impact of surgical margin status on overall survival (OS) stratified by KRAS mutational status. Materials and MethodsFour hundred eighty-five patients with known KRAS mutational status were identified. Clinicopathologic and long-term survival data were collected and assessed. ResultsOn pathology, most patients (n = 380; 78.3 %) had an R0 margin, while 105 (21.7 %) had an R1. Roughly two thirds of tumors were KRAS wild type (wtKRAS) (n = 307, 63.3 %), while 36.7 % (n = 178) had KRAS mutations (mutKRAS). Median and 5-year OS of the entire cohort was 65.8 months and 53.8 %, respectively. An R1 resection was associated with worse 5-year OS compared with R0 (42.4 % vs. 57.1 %; hazard ratio (HR) 1.82, 95 % CI 1.28–2.57; P = 0.001). After controlling for KRAS status, the survival benefit associated with an R0 resection persisted only among patients with wtKRAS tumors (HR 2.16, 95 % CI 1.42–3.30; P < 0.001). In contrast, surgical margin had no impact on OS among patients with mutKRAS tumors (5-year OS R0, 40.7 % vs. R1, 46.7 %; HR 1.34, 95 % CI 0.73–2.48; P = 0.348). ConclusionThe impact of margin status differed by KRAS mutation status. An R0 margin only provided a survival benefit to patients with wtKRAS tumors. Tumor biology and not surgical technique determined prognosis.

Palbociclib for the treatment of postmenopausal breast cancer – an update

ABSTRACTIntroductionBreast cancer is a heterogeneous disease comprising different biological subtypes. In two thirds of tumours, expression of steroid-receptors is present, allowing for targeted treatment with endocrine therapy. In metastatic breast cancer, sequential administration of different non-cross resistant drugs offers a chance to delay cytotoxic chemotherapy. Activity of endocrine therapy, however, decreases with time as indicated by a shorter progression-free survival interval with every further treatment line, suggesting onset of resistance. Current research therefore focuses on prevention or delay of resistance by combining endocrine therapy with other targeted treatment approaches such as small-molecule pathway-inhibitors. Indeed, combining the steroidal aromatase-inhibitor exemestane with the mTor-inhibitor everolimus doubles activity of endocrine therapy in a pretreated population albeit at the price of increased toxicity.Data from several clinical trials suggest that inhibitors of the cycline-dependent kinases (CDK) 4 and 6 are able to delay or reverse resistance to endocrine therapy as well, while tolerability may be superior.Areas CoveredThis review provides a summary of clinical data on CDK 4/6 inhibitors, summarizes the biological rational for their use and provides an outlook to future developments in this field. A systematic literature search was performed in order to identify publications concerning the use of CDK 4/6 inhibitors in breast cancer. The search included original research articles, abstracts from major conferences and reviews published from 2005 to 2015 and was limited to English-language publications.Expert opinionBased upon available data regarding activity and tolerability, it is believed that CDK 4/6 inhibitors will evolve to become a valuable addition to the therapeutic options in metastatic breast cancer.

NRF2 Pathway Activation and Adjuvant Chemotherapy Benefit in Lung Squamous Cell Carcinoma.

Genomic profiling of lung squamous cell carcinomas (SCC) has identified NRF2 pathway alterations, which activate oxidative response pathways, in one third of tumors. Preclinical data suggest these tumors may be resistant to platinum-based chemotherapy. We evaluated the clinical relevance of these findings and assessed whether NRF2 activation predicts benefit from adjuvant chemotherapy in SCC. Logistic regression (LR) and significance analysis of microarrays (SAM) were applied to all 104 TCGA (The Cancer Genome Atlas) SCC cases that had microarray gene expression and mutation data to identify genes associated with somatic NRF2 pathway alterations. The resulting signature (NRF2(ACT)) was tested in 3 independent SCC datasets to evaluate its prognostic and predictive effects. IHC and sequencing for NRF2 and KEAP1 were evaluated in one cohort (n = 43) to assess the relationship between gene expression, mutational status, and protein expression. Twenty-eight genes were identified by overlap between LR (291 genes) and SAM (30 genes), and these consistently separated SCC into 2 groups in all datasets, corresponding to putatively NRF pathway-activated and wild-type (WT) tumors. NRF2(ACT) was not prognostic. However, improved survival with adjuvant chemotherapy in the JBR.10-randomized trial appears limited to patients with the WT signature (HR 0.32, P = 0.16; NRF2(ACT) HR 2.28, P = 0.48; interaction P = 0.15). NRF2(ACT) was highly correlated with mutations in NRF2 and KEAP1, and with high NRF2 protein expression. A gene expression signature of NRF2 pathway activation is associated with benefit from adjuvant cisplatin/vinorelbine in SCC. Patients with NRF2 pathway-activating somatic alterations may have reduced benefit from this therapy.

MP36-08 GENOMIC AND IMMUNOHISTOCHEMICAL CHARACTERIZATION OF TYPES 1 AND 2 PAPILLARY RENAL CELL CARCINOMA: EVIDENCE FOR DISTINCT GROUPS OF DISEASES AND DIFFERENT PROGNOSTIC FEATURES

You have accessJournal of UrologyKidney Cancer: Evalution/Staging III1 Apr 2014MP36-08 GENOMIC AND IMMUNOHISTOCHEMICAL CHARACTERIZATION OF TYPES 1 AND 2 PAPILLARY RENAL CELL CARCINOMA: EVIDENCE FOR DISTINCT GROUPS OF DISEASES AND DIFFERENT PROGNOSTIC FEATURES Alexandre Marsaud, Damien Ambrosetti, Matthieu Durand, Xavier Carpentier, Aurélie Floc'h, Yohann Rouscoff, Brannwel Tibi, Florence Dupre, Emmanuel Chamorey, Daniel Chevallier, Jean Amiel, Jean François Michiels, and Florence Pedeutour Alexandre MarsaudAlexandre Marsaud More articles by this author , Damien AmbrosettiDamien Ambrosetti More articles by this author , Matthieu DurandMatthieu Durand More articles by this author , Xavier CarpentierXavier Carpentier More articles by this author , Aurélie Floc'hAurélie Floc'h More articles by this author , Yohann RouscoffYohann Rouscoff More articles by this author , Brannwel TibiBrannwel Tibi More articles by this author , Florence DupreFlorence Dupre More articles by this author , Emmanuel ChamoreyEmmanuel Chamorey More articles by this author , Daniel ChevallierDaniel Chevallier More articles by this author , Jean AmielJean Amiel More articles by this author , Jean François MichielsJean François Michiels More articles by this author , and Florence PedeutourFlorence Pedeutour More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1072AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Papillary renal cell carcinomas (pRCC) are the second most common type of RCC. The World Health Organization classification of renal tumors distinguishes two types of pRCC based on morphological microscopic, immunohistochemical and genetic features. However, the accurate diagnosis of these tumors is often challenging, and their evolution still remains indefinite. Our aim was to identify molecular biomarkers useful for diagnostic workup and prognosis assessment in pRCC. METHODS Among a series of renal cell tumors in patients who underwent nephrectomy at a cancer reference center between 2005 and 2012, 32 consecutive pRCC cases were selected. Immunohistochemical analyses and genetic investigations consisting of karyotype, fluorescence in situ hybridization (FISH) and comparative genomic hybridization on arrays (array-CGH) were carried out on the specimens. RESULTS Out of 32 tumors, 15 were of type 1 and 17 of type 2. Cytokeratin-7 was expressed in 100% and 68% of type 1 and 2, respectively. CD 10, Vimentin, p504S and TFE3 were of similar expression in both types (70%, 100%, 100% and 0% respectively). Association of gains of chromosomes 7 and 17 (and loss of chromosome Y) were reported in all 15 cases of type 1-pRCC but only in 64 % of type 2-pRCC. We identified three different genomic subgroups in type 2-pRCC: -i) similar genetic profiles to type1-pRCC; -ii) partial common genetic features; -iii) genetic profiles different from type1-pRCC. Our results pointed out that one third of tumors diagnosed as type2-pRCC may be unrelated to type1-pRCC despite papillary architecture. We observed significant differences in survival correlated to some specific genetic alterations (cf figure 1). In contrast, no significant difference was detected regarding the gender, papillary subtype and immunochemistry. CONCLUSIONS Our results showed that type2-pRCC did not constitute a homogeneous group. While some type2-pRCCs were genetically related to type1-pRCCs, some others may have established distinct diseases. Moreover, we observed significant difference in survival correlated to genetic alterations. A longer cohort is expected to confirm these results likely leading to personalized treatments based on genetic profiles. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e381-e382 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Alexandre Marsaud More articles by this author Damien Ambrosetti More articles by this author Matthieu Durand More articles by this author Xavier Carpentier More articles by this author Aurélie Floc'h More articles by this author Yohann Rouscoff More articles by this author Brannwel Tibi More articles by this author Florence Dupre More articles by this author Emmanuel Chamorey More articles by this author Daniel Chevallier More articles by this author Jean Amiel More articles by this author Jean François Michiels More articles by this author Florence Pedeutour More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Abdominoplasty Access for Desmoid Tumor Resection in the Rectus Abdominis Muscle

Soft tissue masses of the abdominal wall may arise from different etiologies. Among the benign lesions, desmoid tumors count up for almost one third of tumors localized in the abdominal region. Commonly they are resected through a direct approach, often leaving an unpleasant and stigmatizing scar. The abdominoplasty access route for desmoid tumor resection is described as a means to achieve aesthetically pleasing results and to provide good overview for radical tumor resection and the reconstruction of the abdominal wall. It yielded unparalleled cosmetic outcomes in our hands and minimal donor site morbidity achieved by a single-stage procedure while simultaneously respecting the standards of surgical oncology.

Aryl Hydrocarbon Receptor Interacting Protein (AIP) Mutations Occur Rarely in Sporadic Parathyroid Adenomas

The molecular pathogenesis of primary hyperparathyroidism is still largely unknown. The aryl hydrocarbon receptor interacting protein (AIP) gene has a major role in the pathogenesis of familial isolated pituitary adenoma. We evaluated the involvement of the AIP gene in sporadic parathyroid adenomas. We performed direct sequencing and multiplex ligation-dependent probe amplification analyses of the AIP gene in a large series of sporadic parathyroid adenomas. Loss of heterozygosity (LOH) at the AIP locus was studied, and aryl hydrocarbon receptor interacting protein immunostaining was also performed. In addition, alterations in the MEN1 gene were studied. A somatic AIP mutation, substitution of arginine with glutamine at codon 304 (R304Q), was identified in 2 of 132 tumors. The mutation was germline in both cases despite the nonfamilial presentation. Heterozygous AIP large deletions were detected in 29 cases including 1 of the 2 mutated tumors, confirming a biallelic inactivation of the AIP gene. The AIP-mutated tumor with LOH showed decreased AIP immunostaining compared with normal parathyroid. LOH at the MEN1 locus, which often shared LOH at the AIP locus, was found in one third of tumors. Somatic MEN1 mutations were found in the 1 of the 2 AIP-mutated tumors and in 22 parathyroid adenomas. In addition, multiplex ligation-dependent probe amplification analysis revealed 1 large deletion of the MEN1 gene in 1 patient. The AIP gene is rarely involved in parathyroid adenomas, but the germline nature of the mutations suggests that it might predispose to primary hyperparathyroidism. MEN1 gene alterations occur in a substantial proportion of sporadic parathyroid adenomas.

Abstract 4022: BRCA1-like signature in triple negative breast cancers within the RATHER (Rational Therapy for Breast Cancer) Consortium.

Abstract Background: More than 75% of BRCA1 mutated breast cancers are either triple negative (lacking estrogen, progesterone receptors and HER2 receptor overexpression), basal-like or both (1). BRCA1 is required for proper function of the homologous recombination (HR)-mediated DNA repair pathway and deficiency results in genomic instability(2). BRCA1 mutated tumors have a specific pattern of alterations, which has been used to develop a BRCA1-like classifier to distinguish between BRCA1-like and breast cancers without BRCA1 deficiency (sporadic-like)(3). Previously it has been shown that over one third of tumors classified as BRCA1-like by comparative genomic hybridization (CGH) have no BRCA1 mutation or promoter methylation(4). Methods: 135 triple negative breast cancer samples (fresh frozen) with long-term follow-up were collected from two institutes within the EU funded RATHER project. All samples were processed following one standard operating protocol to isolate RNA, DNA and protein of high quality. We collected BRCA1 mutation information by next generation sequencing, BRCA1-like classification by multiplex ligation-dependent probe amplification (MLPA) status which makes use of the most informative classifying regions from CGH and full genome expression data for all patients. We analyzed if tumors that classify as BRCA1-like with no mutation or methylation possess a mutation or dysregulation in another gene or genes involved in DNA repair, which is responsible for the BRCA1-like phenotype. Results: In this patient cohort, 17 of the 135 TN patients had a BRCA1 mutation while 65 patients were classified as BRCA1-like. We have determined 15.4% of the BRCA1-like samples are BRCA1 mutated. Using whole genome expression analysis, we found a set of highly significant differentially expressed genes between the BRCA1-like and sporadic-like tumors. These genes are involved in virtually all biological processes including a selection of DNA repair genes. When performing supervised analysis on significantly differentially expressed DNA repair genes, we find two groups, one enriched for BRCA1-like status and one for sporadic-like status. Conclusions: We have identified several genes not previously known to be involved in repair pathways which are significantly differentially expressed between the BRCA1-like and sporadic-like groups. Patients with tumors, which have DNA damage repair deficiencies, may be more susceptible to specific treatments such as PARP inhibitors. Citation Format: Tesa Severson, Justine Peeters, Ian Majewski, Astrid Bosma, Suet-Feung Chin, Carlos Caldas, Iris Simon, Rene Bernards, Sabine Linn. BRCA1-like signature in triple negative breast cancers within the RATHER (Rational Therapy for Breast Cancer) Consortium. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4022. doi:10.1158/1538-7445.AM2013-4022

Analysis of the mRNA expression of chemotherapy-related genes in colorectal carcinoma using the danenberg tumor profile method.

The establishment of individualized chemotherapy for colorectal carcinoma based on the expression of genes involved in chemotherapeutic sensitivity or prognosis is necessary. To achieve this, the expression profiles of genes within tumors and their relationship to clinicopathological factors must be elucidated. Here, we selected 10 genes (TS, DPD, TP, FPGS, GGH, DHFR, ERCC1, TOPO-1, VEGF, and EGFR), examined differences in their mRNA expression between the upper and lower thirds of tumors by laser-captured microdissection and real-time RT-PCR (the Danenberg tumor profile), and analyzed the relationships between their expression profiles and clinicopathological factors. Interestingly, the mRNA expression of DPD, TP, and VEGF was significantly higher in the lower third than in the upper third of tumors (P = 0.044, 0.023, and 0.013, resp.). Furthermore, increased ERCC1 mRNA expression in the lower third of tumors correlated with recurrence (P = 0.049), and VEGF mRNA expression was significantly higher in cases with recurrence than in cases without recurrence, both in the upper and lower thirds of tumors (P = 0.018 and 0.036, resp.). These results implied that heterogeneity in DPD, TP, and VEGF expression may exist in colorectal carcinoma and that ERCC-1 and VEGF may be markers predicting recurrence after curative operation.