Untreated Cancers Research Articles

Comparative Efficacy and Safety of Programmed Death-1 Pathway Inhibitors in Advanced Gastroesophageal Cancers: A Systematic Review and Network Meta-Analysis of Phase III Clinical Trials.

Simple SummaryThe use of checkpoint inhibitors has changed the treatment landscape for gastroesophageal cancer in the third-line setting. However, success rates in earlier treatment lines are highly variable across trials. Herein, we compare the efficacy and safety of the different anti-PD-1/PD-L1 regimens with or without chemotherapy.Background: The use of checkpoint inhibitors has changed the treatment landscape for gastroesophageal cancer in the third-line setting. However, success rates in earlier treatment lines are highly variable across trials. Herein, we compare the efficacy and safety of the different anti-PD-1/PD-L1 regimens with or without chemotherapy; Methods: We performed a network meta-analysis (NMA) of anti-PD-1/PD-L1 monotherapy or combined with chemotherapy (chemoimmunotherapy) for gastroesophageal cancers without ERBB2 overexpression; Results: The first-line NMA included four trials (N = 3817), showing that chemoimmunotherapy improved OS and PFS without significant safety difference: Nivolumab-chemotherapy, OS (HR: 0.83 [95% CI, 0.75–0.92]), PFS (HR 0.68 [95% CI, 0.57–0.81]), Pembrolizumab-chemotherapy: OS (HR 0.77 [95% CI, 0.67–0.88]), PFS (HR: 0.72 [95% CI, 0.60–0.85]. Pembrolizumab monotherapy was the safest first-line treatment, SAE (OR 0.02 [95% CI, 0.00–0.2]) but showed no survival benefit. The second-line NMA encompassed four trials (N = 2087), showing that anti-PD-1 significantly improved safety but not survival: camrelizumab, SAE (OR 0.37; [95% CI, 0.24–0.56]); nivolumab, SAE (OR 0.13, [95% CI, 0.08–0.2]) pembrolizumab, SAE (OR 0.4; [95% CI, 0.30–0.53]); Conclusions: chemoimmunotherapy improves OS and PFS in previously untreated gastroesophageal cancers. Anti-PD-1 monotherapies improve safety in refractory disease, with no significant survival benefit.

Efficacy and safety of PD-1 inhibitors as first- and second- line treatments for advanced gastroesophageal cancers: A network meta-analysis of phase III clinical trials.

e16032 Background: Advanced gastroesophageal tumors are among the most prevalent and burdensome cancers worldwide. They have a poor prognosis and limited treatment options. Recent studies show that PD-1/PD-L1 inhibitors can improve outcomes, but the results are inconsistent across trials. Herein, we compare the effectiveness and safety of PD-1/PD-L1 inhibitors with chemotherapy in patients with ERBB2 negative advanced/metastatic gastric and esophageal cancers. Methods: We searched bibliographic databases (PubMed, Embase, Cochrane Central, Web of Science, Medline, Scopus) and ClinicalTrials.gov from January 1, 2010, to November 23, 2020. We included phase III randomized clinical trials comparing anti-PD-1/PD-L1 single-agent or in combination with chemotherapy (chemoimmunotherapy) for advanced gastric or esophageal cancers in the first- or second-line settings. We performed a network meta-analysis with a frequentist approach and a random-effects model using the package ‘netmeta’ for R statistical software. A prospective protocol was uploaded to PROSPERO (CRD42020221822). Results: The final analysis included a total of 8 trials that compared different anti-PD-1 agents; none of them involved anti-PD-L1 agents. The four first-line studies involved 3817 patients. Chemoimmunotherapy improved OS and PFS with no significant safety difference: Nivolumab + chemotherapy, OS (HR, 0.83; 95% CI, 0.75-0.92), PFS (HR, 0.68; 95% CI, 0.57-0.81), SAE (OR 0.54; 0;95% CI, 0.1-2.92); Pembrolizumab + chemotherapy: OS (HR, 0.77; 95% CI, 0.67-0.88), PFS (HR, 0.72; 95% CI, 0.60-0.85), SAE (OR, 1.31; 0;95% CI, 0.23-7.35). Pembrolizumab monotherapy was the safest first-line treatment, SAE (OR, 0.02; 95% CI, 0.00-0.2), but did not improve survival, OS (HR, 0.91; 95% CI, 0.71-1.16), PFS (HR, 1.62; 95% CI, 1.23-2.14). The four second-line studies totalized 2087 individuals. Anti-PD-1 drugs were significantly safer but did not significantly improve survival: camrelizumab, OS (HR 0.71; 95% CI, 0.54-0.93), PFS (HR 0.69; 95% CI, 0.45-1.06), SAE (OR, 0.37; 95% CI, 0.24-0.56); nivolumab, OS (HR 0.77; 95% CI, 0.58-1.02), PFS (HR 1.08; 95% CI, 0.77-1.66), SAE (OR, 0.13; 95% CI, 0.08-0.2) pembrolizumab, OS (HR 0.86; 95% CI, 0.72-1.04), PFS (HR 1.28; 95% CI, 0.96-1.71), SAE (OR, 0.4; 95% CI, 0.30-0.53). Conclusions: the combination of PD-1 inhibitors with chemotherapy improves OS and PFS in previously untreated gastroesophageal cancers. Single-agent anti-PD-1 drugs improve safety in refractory disease, with no significant change in OS and PFS.

Integrated whole-exome and transcriptome analysis of 250 treatment-refractory or relapsed (R/R) childhood solid tumors.

10006 Background: The major genomic profiling studies that have helped define the molecular landscapes of pediatric cancers have typically focused on untreated pediatric cancers at diagnosis. Despite improvements in overall survival for childhood cancers, patients with treatment-refractory or relapsed (R/R) solid tumors face a poor prognosis. The genomic underpinnings of R/R disease are less well-characterized. Here, we describe the integrated genomic and transcriptomic analysis of 250 R/R solid tumors from 202 children profiled within precision medicine studies (NCT01355679, NCT01802567, NCT02162732) conducted by the Beat Childhood Cancer Consortium. Methods: Tumor-normal whole-exome and tumor mRNA sequencing was performed by Ashion Analytics (Phoenix, Arizona), a CAP-accredited, CLIA-certified laboratory, or within the research setting at TGen. Longitudinal tumor samples were sequenced for 20 patients. Variant calling included single nucleotide variants, indels, copy number alterations, and fusions. Integrated genomic and transcriptomic research analysis included microsatellite instability assessment, immunogenomic profiling, and functional gene set enrichment analysis. Results: Forty-six tumor types were represented, grouped into four general categories: sarcomas (36.1%; n = 73), neuroblastomas (29.2%; n = 59), CNS tumors (23.3%; n = 47), and other rare tumors (11.4%; n = 23). For patients with whole exome sequencing data, 78.3% (n = 144/184) of tumors bore a somatic alteration in at least one known cancer gene. Over one-third (39.1%; 72/184) of the cohort bore oncogenic fusions and/or oncogenic/likely-oncogenic hotspot mutations in a known cancer gene. Pathognomonic fusions were identified in 25% (46/184) of tumors, occurring most frequently in sarcomas. Pathogenic or likely pathogenic germline variants were identified in 8.7% (16/184) of patients. Microsatellite instability was detected in five different tumor types. Despite nearly all tumors (94%, 173/184) having at least one predicted strong binding neoantigen, over a quarter of tumors lacked transcript expression of these neoantigens or exhibited low MHC class I expression. Further, a subset of tumors showed elevated expression of the co-inhibitory immune checkpoint molecule PDL1. Transcriptional analysis and functional gene set enrichment analysis identified cross-pathology tumor clusters associated with immune signaling, development, and cellular signaling pathways. Longitudinal analysis revealed temporal heterogeneity pointing to the importance of re-biopsy at relapse for targeted treatment planning. Conclusions: Together, these data suggest R/R childhood solid tumors exhibit shared molecular features that are reflective of underlying biology, demonstrating the importance of comprehensive profiling to inform molecularly-guided treatment of R/R disease.

Prognostic Significance of Glucocorticoid Receptor Expression in Cancer: A Systematic Review and Meta-Analysis.

Simple SummaryIn solid tumours, emerging evidence indicates that signalling through the glucocorticoid receptor (GR) can encourage the growth and spread of tumours and so drugs targeting this receptor are in development for use in cancer treatment. For these reasons, GR may be useful in anticipating a patient’s outcome upon their cancer diagnosis or to predict their tumours response to drugs targeting this receptor. In this review we aim to ascertain whether GR expression in tumours affects cancer patient survival. Overall, GR expression did not affect patient survival when assessing all cancer types. However, we found that in certain cancer subtypes such as gynaecological cancers (endometrial and ovarian) and early stage, untreated triple negative breast cancers, high GR expression is linked with cancer progression and therefore a poorer patient prognosis. Further studies are needed to uncover the exact role of GR in specific tumour (sub)types in order to provide the correct patients with GR targeting therapies.In solid malignancies, the glucocorticoid receptor (GR) signalling axis is associated with tumour progression and GR antagonists are in clinical development. Therefore, GR expression may be a useful potential prognostic or predictive biomarker for GR antagonist therapy in cancer. The aim of this review is to investigate if GR expression in tumours is predictive of overall survival or progression free survival. Twenty-five studies were identified through systematic searches of three databases and a meta-analysis conducted using a random effects model, quantifying statistical heterogeneity. Subgroup analysis was conducted for cancer types and publication bias was assessed via funnel plots. There was high heterogeneity in meta-analysis of the studies in all cancer types, which found no association between high GR expression with overall survival (pooled unadjusted HR 1.16, 95% CI (0.89–1.50), n = 2814; pooled adjusted HR 1.02, 95% CI (0.77–1.37), n = 2355) or progression-free survival (pooled unadjusted HR 1.12, 95% CI (0.88–1.42), n = 3365; pooled adjusted HR 1.04, 95% CI (0.6–1.81), n = 582) across all cancer types. However, subgroup meta-analyses showed that high GR expression in gynaecological cancers (endometrial and ovarian) (unadjusted HR 1.83, 95% CI (1.31–2.56), n = 664) and early stage, untreated triple negative breast cancers (TNBCs) (unadjusted HR 1.73, 95% CI (1.35–2.23), n = 687) is associated with disease progression. GR expression in late stage, chemotherapy treated TNBC was not prognostic (unadjusted HR 0.76, 95% CI (0.44, 1.32), n = 287). In conclusion, high GR expression is associated with an increased risk of disease progression in gynaecological and early stage, untreated TNBC. Additional studies are required to elucidate the tumour specific function of the GR receptor in order to ensure GR antagonists target the correct patient groups.

Abstract PD9-07: Genomic landscape of metastatic breast cancer (MBC): Comprehensive cell-free DNA analysis from over 10,000 patients and comparison with primary breast cancer

Abstract Background: Current tissue-based genomic sequencing datasets typically reflect early stage, mostly treatment-naïve cohorts, and fail to capture the genomic landscape of advanced disease, including mutations conferring acquired resistance to therapy. Plasma cell-free DNA (cfDNA) can provide information on somatic alterations non-invasively and can capture spatial tumor heterogeneity. Here, we studied cfDNA from 15,564 blood samples from 12, 827 patients (11.5% of patients had serial samples) with MBC, and analyzed the differences in mutational landscape between cohorts of heavily pre-treated and primary untreated breast cancers. Materials and methods: Deidentified aggregate genomic data from stage III/IV breast cancer clinical samples submitted for cfDNA next-generation sequencing (NGS) analysis with Guardant360 (Guardant Health, Inc; Redwood City, CA, USA) assay between 11/25/16 and 5/26/20. This clinical assay detects somatic single nucleotide variants (SNVs), indels, copy number gains, and fusions in either all or a subset of exons in up to 74 genes. We compare the observed alterations to events detected from whole-exome sequencing data representing ~1,000 untreated primary breast cancers from The Cancer Genome Atlas (TCGA) project. Results: In the overall cohort (N = 12, 827), the average patient age was 61 (range 18-100); 99% were female. Of the 11,290 pts with at least one samples with a non-synonymous alteration, the most frequently mutated genes were TP53 (53%), PIK3CA (38%), ESR1 (28%), ATM (13%), GATA3 (10%), and ARID1A (10%) at varying allelic frequencies with dynamic changes over time (in pts with serial specimens) highlighting clonal heterogeneity and temporal evolution. Copy-number gains were most frequent in FGFR1 (13%), CCND1 (11%), EGFR (9%) and PIK3CA (9%), but fusions were infrequent (below 1%), with fusions involving FGFR3 (n=22), FGFR2 (n=12), ALK (n=7), NTRK1 (n=6), RET (n=4), and ROS1 (n=1). Overall, patients had significantly higher frequency of actionable alterations based on ctDNA analysis, as compared to that observed in TCGA. Similarly, non-synonymous mutations were identified in genes associated with acquired resistance, including ESR1 (28%), ERBB2 (9%), PTEN (8.1%), RB1 (7.7%), NF1 (6.2%), and AKT1 (4%), mutated at frequencies significantly exceeding those observed in TCGA. Finally, we developed a novel classifier to identify the breast cancer receptor subtypes based on differential genomic profile, which was further validated in an independent genomic dataset. Conclusions: In the largest dataset to date, we provide the comparative genomic landscape of the various SNVs, indels, copy-number gains, and fusions identified by next generation sequencing of cfDNA in patients with MBC, compared to primary breast cancer. Interestingly, both targetable genomic alterations and resistance mutations occur at frequencies much higher than observed in primary breast cancer, highlighting the genomic complexity of MBC and potential need for combinatorial therapy. Finally, we describe a novel classifier for detection of HR+ and HER2+ tumors, which could be particularly valuable clinically given the receptor switch with tumor evolution and practical difficulty with serial tissue biopsies in MBC. Comparison of genomic signature profiles between MBC and primary breast cancer will be presented at the meeting. Citation Format: Aditya Bardia, Massimo Cristofanilli, Justin Cha, Lesli Kiedrowski, Dejan Juric, Ben H Park, Adam Brufsky, Joyce O’Shaughnessy, Becky Nagy, Leif Ellisen, Ignaty Leshchiner, Gaddy Getz. Genomic landscape of metastatic breast cancer (MBC): Comprehensive cell-free DNA analysis from over 10,000 patients and comparison with primary breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD9-07.

21P Germline and somatic variants in DNA DMAGE repair (DDR) genes in patients with untreated, early-stage triple negative breast cancers (TNBC)

Mutations in DDR genes, most notably BRCA1/2 and have been predictive to respond to PARP inhibitors and other DNA-damaging systemic therapies. However, the reports of detected germline and somatic variants in other DDR-related genes in early-stage, untreated breast cancers is limited. Here we report variants identified in multiple DDR-related genes in patients with untreated TNBC and association with pathologic complete response (pCR).

Inside the USCAP Journals

Inside the USCAP Journals

Inside the USCAP Journals

Inside the USCAP Journals

The Emerging Role of ESR1 Mutations in Luminal Breast Cancer as a Prognostic and Predictive Biomarker of Response to Endocrine Therapy.

Mutations in the hotspot ligand-binding domain of the estrogen receptor (ER) gene ESR1 have recently been recognized as mechanisms of endocrine resistance in endocrine receptor-positive metastatic breast cancer (MBC). Accumulating data suggest these mutations develop under the selective pressure of endocrine treatments, and are infrequent in untreated ER-positive breast cancers. In vitro studies show that these mutations confer ligand-independent activity, resistance to estrogen deprivation, and relative resistance to tamoxifen and fulvestrant. Post-hoc retrospective and prospective analyses of ESR1 mutations in patients with MBC have consistently found that these mutations are markers of poor prognosis and predict resistance to aromatase inhibitors (AIs). These results warrant further investigation and prospective validation in dedicated studies. Moreover, studies are ongoing to clarify the activity of novel drugs in the context of metastatic endocrine resistant luminal breast cancer harboring ESR1 mutations. In this review, we summarize the pre-clinical and clinical findings defining the characteristics of ESR1 mutant breast cancer, and highlight the potential clinical developments in this field.

Lack of detectable neoantigen depletion signals in the untreated cancer genome.

Somatic mutations can result in the formation of neoantigens, immunogenic peptides that are presented on the tumor cell surface via HLA molecules. These mutations are expected to be under negative selection pressure, but the extent of the resulting neoantigen depletion remains unclear. Based on HLA affinity predictions, we annotated the human genome for its translatability to HLA binding peptides and screened for reduced single nucleotide substitution rates in large genomic datasets from untreated cancers. Apparent neoantigen depletion signals became negligible when considering trinucleotide-based mutational signatures, either due to lack of power or efficient immune evasion mechanisms active early during tumor evolution.

An analysis of genetic heterogeneity in untreated cancers.

Genetic intratumoural heterogeneity is a natural consequence of imperfect DNA replication. Any two randomly selected cells, whether normal or cancerous, are therefore genetically different. Here, we review the different forms of genetic heterogeneity in cancer and re-analyse the extent of genetic heterogeneity within seven types of untreated epithelial cancers, with particular regard to its clinical relevance. We find that the homogeneity of predicted functional mutations indriver genes is the rule rather than the exception. In primary tumours with multiple samples, 97% of driver-gene mutations in 38 patients were homogeneous. Moreover, among metastases from the same primary tumour, 100% of the driver mutations in 17 patients were homogeneous. With a single biopsy of a primary tumour in 14 patients, the likelihood of missing a functional driver-gene mutation that was present in all metastases was 2.6%. Furthermore, all functional driver-gene mutations detected in these 14 primary tumours were present among all their metastases. Finally, we found that individual metastatic lesions responded concordantly to targeted therapies in 91% of 44patients. These analyses indicate that the cells within the primary tumours that gave rise to metastases are genetically homogeneous with respect to functional driver-gene mutations, and we suggest that future efforts to develop combination therapies have the potential to be curative.

Immune Cytolytic Activity Is Associated With Genetic and Clinical Properties of Glioma.

Background: Immunotherapy provided unprecedented advances in the treatment of several previously untreated cancers. However, these immunomodulatory maneuvers showed limited response to patients with glioma in clinical trials. Our aim was to depict the immune characteristics of glioma with immune cytolytic activity at genetic and transcriptome levels.Methods: In total, 325 gliomas from CGGA dataset as training cohort and 699 gliomas from TCGA dataset as validation cohort were enrolled in our analysis. We calculated the immune cytolytic activity for 1,000 of gliomas. The characteristics of immune cytolytic activity in gliomas were interpreted by the corresponding clinical, molecular genetics and radiological information.Results: We found that immune cytolytic activity was highly associated with molecular, clinical, and edema extent. High cytolytic activity gliomas were more likely to be diagnosed as glioblastoma and might be a potential marker of mesenchymal subtype. Moreover, those gliomas exhibited significantly increased copy number alterations including recurrent focal amplifications of PDGFA and EGFR, as well as recurrent deletions of CDKN2A/B. Subsequent biological function analysis revealed that the immune response and immune checkpoints expression were significantly correlated with the cytolytic activity of gliomas. Immune cytolytic activity was significantly positively associated with the extent of peri-tumor edema and was independently correlated with reduced survival time.Conclusion: Our results highlighted the immunoregulatory mechanism heterogeneity of gliomas. Cytolytic activity, indirectly reflected by the extent of peri-tumor edema, may provide a potential index to evaluate the status of immune microenvironment and immune checkpoints in glioma, which should be fully valued for precision classification and immunotherapy.

Abstract 1698: A million years of precision oncology knowledge for the world

Abstract Introduction: The most valuable information for someone with the diagnosis of cancer is the ability to predict which treatment will be most effective for them, and their prognosis. The most effective way to generate the knowledge required to do this for all people affected by cancer is to amass large datasets of deep molecular and detailed phenotypic data through health systems as part of routine care. However, the pathways and processes are not in place and require development, with the paramount challenge being the acquisition and application of rich, reliable clinical data including treatment and response parameters. Although multiple regional platforms have been established to generate cancer genomics data, no platform exists that can capture, aggregate, harmonize and appropriately share data globally to enable analysis of pooled individual participant data. Method: The International Cancer Genome Consortium1, established in 2007, aimed to define the genomes of 25,000 primary untreated cancers. The ICGC solved numerous data governance, ethical and logistical challenges and provided the international community with comprehensive genomic data for many cancer types. The ICGC’s next Initiative -ARGO aims to Accelerate Research in Genomic Oncology to provide a million patient-years of precision oncology knowledge to the world. To achieve this, ICGC-ARGO will acquire detailed treatment and response information mostly from participants in clinical trials along with genomic, transcriptomic and proteomic data from their tumors and healthy tissues. Results: ICGC membership already spans 28 countries, with new commitments to ARGO from 10 programmes investigating a range cancer types, comprising an estimate of 200,000 patient years of data. Regional Data Processing Centres are in operation in 4 countries to coordinate ICGC-ARGO data and to validate and process sequencing data through a standardized series of data analysis pipelines. A central site will integrate the various ICGC-ARGO data sets and disseminate to the community through the ICGC Data Portal. Policies and guidelines have been established that address the global challenges of clinical cancer genomics such as standardisation of clinical data parameters, data access structures, data composition and management and jurisdictional issues that impact global data sharing. Conclusion: The data generated by ICGC ARGO member programmes will allow for precise correlation of molecular attributes with clinical features, allowing for the discovery of molecular markers of response, resistance and adverse events, as well as novel therapeutic targets. This knowledge will translate into new approaches to improve outcomes for people affected by cancer. The ICGC ARGO project will also address the challenges of generating and sharing genomic data matched with clinical and patient information on a global scale. Citation Format: Amber Johns, International Cancer Genome Consortium (ARGO Initiative). A million years of precision oncology knowledge for the world [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1698.

Application of a Neural Network Whole Transcriptome–Based Pan-Cancer Method for Diagnosis of Primary and Metastatic Cancers

A molecular diagnostic method that incorporates information about the transcriptional status of all genes across multiple tissue types can strengthen confidence in cancer diagnosis. To determine the practical use of a whole transcriptome-based pan-cancer method in diagnosing primary and metastatic cancers and resolving complex diagnoses. This cross-sectional diagnostic study assessed Supervised Cancer Origin Prediction Using Expression (SCOPE), a machine learning method using whole-transcriptome RNA sequencing data. Training was performed on publicly available primary cancer data sets, including The Cancer Genome Atlas. Testing was performed retrospectively on untreated primary cancers and treated metastases from volunteer adult patients at BC Cancer in Vancouver, British Columbia, from January 1, 2013, to March 31, 2016, and testing spanned 10 822 samples and 66 output classes representing untreated primary cancers (n = 40) and adjacent normal tissues (n = 26). SCOPE's performance was demonstrated on 211 untreated primary mesothelioma cancers and 201 treatment-resistant metastatic cancers. Finally, SCOPE was used to identify the putative site of origin in 15 cases with initial presentation as cancers with unknown primary of origin. A total of 10 688 adult patient samples representing 40 untreated primary tumor types and 26 adjacent-normal tissues were used for training. Demographic data were not available for all data sets. Among the training data set, 5157 of 10 244 (50.3%) were male and the mean (SD) age was 58.9 (14.5) years. Testing was performed on 211 patients with untreated primary mesothelioma (173 [82.0%] male; mean [SD] age, 64.5 [11.3] years); 201 patients with treatment-resistant cancers (141 [70.1%] female; mean [SD] age, 55.6 [12.9] years); and 15 patients with cancers of unknown primary of origin; among the treatment-resistant cancers, 168 were metastatic, and 33 were the primary presentation. An accuracy rate of 99% was obtained for primary epithelioid mesotheliomas tested (125 of 126). The remaining 85 mesotheliomas had a mixed etiology (sarcomatoid mesotheliomas) and were correctly identified as a mixture of their primary components, with potential implications in resolving subtypes and incidences of mixed histology. SCOPE achieved an overall mean (SD) accuracy rate of 86% (11%) and F1 score of 0.79 (0.12) on the 201 treatment-resistant cancers and matched 12 of 15 of the putative diagnoses for cancers with indeterminate diagnosis from conventional pathology. These results suggest that machine learning approaches incorporating multiple tumor profiles can more accurately identify the cancerous state and discriminate it from normal cells. SCOPE uses the whole transcriptomes from normal and tumor tissues, and results of this study suggest that it performs well for rare cancer types, primary cancers, treatment-resistant metastatic cancers, and cancers of unknown primary of origin. Genes most relevant in SCOPE's decision making were examined, and several are known biological markers of respective cancers. SCOPE may be applied as an orthogonal diagnostic method in cases where the site of origin of a cancer is unknown, or when standard pathology assessment is inconclusive.

Abstract P3-08-07: Distinct biological signatures describe differences in BRCA mutated subgroups

Abstract Background: BRCA mutated (BRCA+) breast cancers are expected to have increased activation of Homologous Recombination Deficiency (HRD) and altered DNA damage repair pathways when compared to BRCA wildtype (BRCA-). To better understand differences in these populations, biological patterns and immune responses to BRCA+ breast cancers were evaluated. The primary aim of our study was to use novel gene expression tools to assess early stage breast cancers with and without germline BRCA mutations, and within distinct BRCA+ subgroups. Methods: We identified 124 early stage untreated breast cancers with and without BRCA mutations (n = 62 and 62, respectively). Our BRCA- group was matched by hormone receptor (HR) status, age, and stage to the BRCA+ group. The NanoString Breast Cancer 360 panel was applied to RNA isolated from 80 breast tumors (BRCA+ = 39; BRCA- = 41). The BRCA+ group had a BRCA1+ subgroup (n=17) and a BRCA2+ subgroup (n=22). Results: There was a significant increase in two BC360 signatures in both the BRCA1+ and BRCA2+ tumors compared with the BRCA- population: Prosigna™Risk of Recurrence (ROR) score [BRCA1+: HR: 1.142 (95% CI 1.019, 1.279), p=0.02; BRCA2+: HR: 1.321 (95% CI 1.190, 1.466), p<0.001] and HRD [BRCA1+: HR: 3.576 (95% CI 2.174, 5.880), p=0.02; BRCA2+: HR: 1.801 (95% CI 1.142, 2.840), p<0.001]. BRCA1+ tumors had lower expression of ESR1 [p=0.03], PGR [p=0.02], ER signaling [p<0.001], and differentiation [p=0.005]; while BRCA2+ tumors had lower expression of stroma markers [p=0.02] and inflammatory chemokines [p=0.001]. The two BRCA+ subgroups had distinct molecular subtype correlation trends that were highly significant. BRCA1+ tumors were positively associated with a basal subtype [p<0.001], whereas this association was not significant for BRCA2+ tumors. BRCA2+ tumors were associated with an increase in luminal B subtype [p=0.05]. All BRCA+ tumors had a decrease in luminal A subtype correlation [BRCA1+: p<0.001; BRCA2+: p=0.002]. In addition to the BC360 signatures, a differential analysis of all genes in the BC360 panel revealed more single gene differences in BRCA2+ than BRCA1+ tumors when compared to BRCA- tumors. Conclusions: In early stage BRCA+ breast cancer, tumors have higher ROR and increased HRD signature scores compared to BRCA- tumors. Furthermore, BRCA1+ and BRCA2+ tumors have both signature and single gene expression differences when compared to BRCA- tumors, indicating distinct subgroup-related biology. The greater correlation of BRCA1+ tumors with basal-like biology and BRCA2+ tumors with aggressive hormonal biology confirms these trends. Distinctions in hormone receptor signaling, DNA-damage pathways, and microenvironment/inflammatory features between BRCA1 and BRCA2 associated cancers suggest a need for different prevention and therapeutic strategies for each of these breast cancer subtypes. The unique biological patterns identified here should be further evaluated as predictive or prognostic tools that could be translated into clinical care for early stage BRCA+ patients. Citation Format: Force J, Plichta J, Stashko I, Kimmick G, Westbrook K, Sammons S, Hwang S, Hyslop T, Kauff N, Castellar E, Nair S, Weinhold K, Davis S, Mashadi-Hossein A, Brauer HA, Marcom PK. Distinct biological signatures describe differences in BRCA mutated subgroups [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-08-07.

Non-Invasive Imaging of Normalized Solid Stress in Cancers in Vivo.

The solid stress (SSg) that develops inside a cancer is an important marker of cancer’s growth, invasion and metastasis. Currently, there are no non-invasive methods to image SSg inside tumors. In this paper, we develop a new, non-invasive and cost-effective imaging method to assess SSg inside tumors that uses ultrasound poroelastography. Center to the proposed method is a novel analytical model, which demonstrates that SSg and the compression-induced stress (SSc) that generates inside the cancer in a poroelastography experiment have the same spatial distribution. To show the clinical feasibility of the proposed technique, we imaged and analyzed the normalized SSg inside treated and untreated human breast cancers in a small animal model. Given the clinical significance of assessing SSg in cancers and the advantages of the proposed ultrasonic methods, our technique could have a great impact on cancer diagnosis, prognosis and treatment methods.

Clinico- pathological correlation of pattern of cervical lymph node metastases in oral cavity cancers

Introduction: The Oral Squamous cell carcinoma spreads by lymphatics. Hence it is the important prognostic factor in oral carcinoma. The involvement of lymph nodes guides in the treatment of oral carcinoma and neck dissection. By knowing the level of involvement of oral carcinoma, the staging can be done and the type of neck dissection can be planned accordingly and decrease the morbidity of the radical neck dissection.Aim: To determine the clinico pathological correlation of pattern of cervical lymph nodes metastases in oral cavity cancers. Methodology: It is a prospective study of histologically proven oral carcinoma of 50 patients. Data for the study collected from the patients coming to the General Surgery OPD at SS Institute of Medical sciences and Research Centre, Davangere, over a period of two years from October 2016 to August 2018. Inclusion Criteria included are patients with clinical suspicion of oral cancer with positive/negative lymph nodes, previously untreated oral cancers, histologically proven oral carcinoma cases. Exclusion Criteria are patients not willing to give informed consent, patients who are unfit for general anaesthesia, prior treatment of other head and neck cancers by surgery, chemotherapy and radiotherapy, previous surgery in the neck, presence of distant metastasis. Clinical neck examination done along with other necessary radiological investigations. The neck examination is compared with histological examination. The analysis done by Sensitivity, Specificity and Accuracy of the neck examination.Results: In our study, Pathologically level II (56.3%) was the most commonly involved lymph node station in patients with oral cancer. Most of the patients presented in an advanced stage clinically. Stage IV was the commonest with 20(40%) patients. The Sensitivity and Specificity of the clinical neck examination were 76.9% and 61.8% respectively in patients with oral cancer. The accuracy of clinical examination is 78%. In our study, tumour stage had a positive correlation (r=0.987) with the pathological nodal status, that was significant (p=

Gastric Cancer With Leptomeningeal Carcinomatosis

Leptomeningeal carcinomatosis (LC) is an extremely rare complication of all cancer which involves metastases of the primary tumor to the central nervous system, predominantly the meninges of the brain and spinal cord. It is estimated to occur in as little as 5% of cancers and is predominantly terminal. Adenocarcinomas are the most common type of cancer seen with this condition and both breast and lung adenocarcinomas are the most common cancers associated with LC. The most common tumor mechanism of metastases consists of hematogenous spread to the vessels of the arachnoid or choroid plexus. Estimated time of survival is 4-6 weeks without treatment. Presenting significant symptoms that manifest including headaches, nausea, vomiting, ataxia, incontinence, and focal neurological deficits. Diagnosis can be made with analysis of CSF from a lumbar puncture or with an MRI showing enhancement of the leptomeninges of the brain and spinal cord. Because of the terminal prognosis, treatment is mainly for control of neurological symptoms and quality of life. Patients can undergo surgery to relieve CSF flow obstruction, radiation to affected sites, and/or intra-thecal chemotherapy. If a patient is not a candidate for any of the above, supportive treatments such as opioids for analgesia, anticonvulsants for seizures, antidepressants, and anxiolytics are utilized. We report a case of a patient with known stage 4 gastric cancer who presented to our hospital with altered mental status (AMS). He had an MRI of the brain 2 weeks prior to admission which was read as negative and his AMS was originally attributed to sepsis from a urinary tract infection (UTI). He was found to be on a “drug holiday” from his palliative chemotherapy. During his hospital course, the patient developed seizures and was transferred to the intensive care unit (ICU). Repeat MRI of the brain revealed leptomeningeal carcinomatosis. The patient was not a candidate for any intervention and was treated supportively with anxiolytics, anticonvulsants, and opioids. We concluded that LC can manifest in a matter of weeks in patients with untreated primary cancers. Patients typically present with AMS, confusion, or headaches and prompt diagnosis should be made to prevent neurological complications. Once diagnosed, the focus should be on reduction of neurological symptoms and supportive measures.

Abstract 4749: VISTA immune checkpoint deregulation in human triple-negative breast cancer

Abstract Immunotherapy for breast cancer has lagged behind the advances in other tumor types, suggesting the need for novel immune targets. VISTA/PD-1H is a checkpoint receptor expressed on immune cells that is an effective anti-cancer target in mouse models and now in early human clinical trials. We utilized an in vitro system to examine epigenetic changes arising early after depletion of breast cancer tumor suppressor proteins. This demonstrates that epigenetic alterations occur in normal human mammary cell lines lacking BRCA2 and result in regulation of VISTA through an NF-kB-dependent pathway. VISTA is strongly induced by growth factor limitation, an effect that is blunted by BRCA2-induced NF-kB activation and binding to a kB site in the VISTA promoter. This suggests that repression of VISTA may be an early consequence of BRCA2 depletion in pre-neoplastic tissues leading to immune infiltration. In contrast, in primary, untreated human triple-negative breast cancers, VISTA is over-expressed on tumor cells, independent of its presence on immune cells. VISTA positive TNBCs (14%) have significantly increased tumor infiltrating lymphocytes (TILs) whereas VISTA strong positive TNBCs (6%) have significantly decreased TILs and tumor PD-L1 staining, suggesting a higher level of immunosuppression. Gene expression and tumor genomics in TNBCs suggests that transcriptional networks to regulate physiologic immunoreceptor levels are corrupted during malignant transformation. In summary, this work identifies a BRCA2-loss-of-function signaling pathway that regulates an important immune checkpoint molecule via NF-kB activation in pre-neoplastic tissues and triple-negative breast cancers with important consequences for the immune microenvironment. We expect these observations to enhance immunotherapeutics for breast cancer. Citation Format: Joshua J. Gruber, Marisa M. Juntilla, Soo-Ryum Yang, Benjamin Geller, Natalie Jager, Chien-Yu Lin, Andrew M. Lipchik, Justin Chen, Ashwin Ram, Shaveta Vinayak, Melinda L. Telli, Robert B. West, James M. Ford, Michael P. Snyder. VISTA immune checkpoint deregulation in human triple-negative breast cancer [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 4749.

Avoiding chemotherapy for advanced nononcogene addicted NSCLC overexpressing PD-L1: Rule or option?

Patients with nonsmall-cell lung cancers expressing high levels of PD-L1 present a therapeutic dilemma for clinicians who have to choose between pembrolizumab as a single agent or in combination with chemotherapy. In order to help them as they ponder over this decision we performed a meta-analysis using the data available from randomized clinical trials that enrolled patients with untreated advanced nonsmall-cell lung cancers with PD-L1 expression level ≥50%. We evaluated interactions according to type of treatment–add-on strategy: pembrolizumab plus chemotherapy versus chemotherapy or head-to-head strategy: pembrolizumab alone versus chemotherapy. Hazard and Odds Ratios (HR/OR) for primary (overall survival, OS) and secondary endpoints (progression-free survival, PFS and objective response rate, ORR) were extracted and cumulated by adopting a random-effect model with 95% confidence interval. Four clinical trials that enrolled 2,754 patients including 1,252 with PD-L1 expression in ≥50% of cells were examined. We did not find a significant interaction (P = 0.16) between an add-on strategy and head-to-head comparisons with pembrolizumab for OS (HRs in favor of immunotherapy of 0.50 and 0.67, respectively). A significant quantitative interaction favoring the add-on strategy was found for PFS and ORR (P < 0.001), with a HR for PFS of 0.36 with the add-on strategy and 0.65 in head-to head comparisons, and an OR for ORR of 5.35 and 1.58, respectively. In absence of planned prospective noninferiority trials addressing this issue, addition of chemotherapy to pembrolizumab appears to decrease tumor size and delay disease progression significantly more than pembrolizumab alone, but has no impact on OS. We conclude that the data support deciding between both treatment options on an individual basis by considering a patients’ clinical status and disease characteristics.