Andrew A. Davis

Metabolic Syndrome and Triple-Negative Breast Cancer: A New Paradigm

Triple-negative breast cancers (TNBCs) are aggressive tumors with poor prognosis compared to other breast cancer subtypes. The evidence linking TNBC with the metabolic syndrome, which consists of central obesity, insulin resistance, impaired glucose tolerance, dyslipidemia, and hypertension, has emerged from clinical studies and experiments using cell lines and mouse models. Epidemiological studies have associated abdominal obesity with increased incidence of TNBC. Additionally, insulin resistance, dyslipidemia, and hypertension are associated with increased incidence of breast cancer across all subtypes. The insulin-leptin-adiponectin axis has been implicated mechanistically in breast cancer tumorigenesis. Specifically, increased leptin and decreased adiponectin levels disrupt homeostatic signaling pathways involved in cell proliferation, survival, cell-cycle regulation, and angiogenesis. Insulin, insulin-like growth factor I (IGF-I), and epidermal growth factor receptor (EGFR) may mediate interactions between these two hormones. Further research will facilitate the development of targeted therapeutics and programs to modify lifestyle factors to modulate the insulin-leptin-adiponectin axis for TNBC.

Immunotherapy for cancer in the central nervous system: Current and future directions

ABSTRACT Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults and still remains incurable. Although immunotherapeutic vaccination against GBM has demonstrated immune-stimulating activity with some promising survival benefits, tumor relapse is common, highlighting the need for additional and/or combinatorial approaches. Recently, antibodies targeting immune checkpoints were demonstrated to generate impressive clinical responses against advanced melanoma and other malignancies, in addition to showing potential for enhancing vaccination and radiotherapy (RT). Here, we summarize the current knowledge of central nervous system (CNS) immunosuppression, evaluate past and current immunotherapeutic trials and discuss promising future immunotherapeutic directions to treat CNS-localized malignancies.

Biomarkers for PD-1/PD-L1 Blockade Therapy in Non–Small-cell Lung Cancer: Is PD-L1 Expression a Good Marker for Patient Selection?

Immunotherapy has emerged as a promising treatment modality in cancer therapy. With improved understanding of how to tip the balance of immune homeostasis, novel therapeutics targeting immune checkpoints have been developed, with durable responses observed in multiple solid tumors, including melanoma, renal cell carcinoma, and non-small-cell lung cancer. Clinical trials have reported favorable responses using programmed cell death-1 protein receptor (PD-1)/programmed cell death-1 protein ligand (PD-L1) blockade as monotherapy and most impressively in combinatorial trials with cytotoxic T-lymphocyte antigen-4 protein blockade. Nonetheless, a clinical benefit has not been observed in all patients. Therefore, identifying the ideal biomarkers for patient selection would be of great value in optimizing and personalizing immunotherapy. The utility of PD-L1 expression as a biomarker has varied in different clinical trials and immunohistochemistry assays. In addition, the response to immune checkpoint inhibition has been complicated by PD-L1 expression as a marker influenced by the dynamic tumor microenvironment. No consensus has yet been reached on whether PD-L1 expression is an ideal marker for patient selection. Recent research has shown promise for alternative markers, including T-cell immunohistochemistry, other immunologic markers, T-cell receptor clonality, and somatic mutational burden. However, additional studies are needed to assess the value of these as practical predictive biomarkers for patient selection and treatment response.

Concordance between genomic alterations assessed by next-generation sequencing in tumor tissue or circulating cell-free DNA

Genomic analysis of tumor tissue is the standard technique for identifying DNA alterations in malignancies. Genomic analysis of circulating tumor cell-free DNA (cfDNA) represents a relatively non-invasive method of assessing genomic alterations using peripheral blood. We compared the concordance of genomic alterations between cfDNA and tissue biopsies in this retrospective study. Twenty-eight patients with advanced solid tumors with paired next-generation sequencing tissue and cfDNA biopsies were identified. Sixty-five genes were common to both assays. Concordance was defined as the presence or absence of the identical genomic alteration(s) in a single gene on both molecular platforms. Including all aberrations, the average number of alterations per patient for tissue and cfDNA analysis was 4.82 and 2.96, respectively. When eliminating alterations not detectable in the cfDNA assay, mean number of alterations for tissue and cfDNA was 3.21 and 2.96, respectively. Overall, concordance was 91.9–93.9%. However, the concordance rate decreased to 11.8–17.1% when considering only genes with reported genomic alterations in either assay. Over 50% of mutations detected in either technique were not detected using the other biopsy technique, indicating a potential complementary role of each assay. Across 5 genes (TP53, EGFR, KRAS, APC, CDKN2A), sensitivity and specificity were 59.1% and 94.8%, respectively. Potential explanations for the lack of concordance include differences in assay platform, spatial and temporal factors, tumor heterogeneity, interval treatment, subclones, and potential germline DNA contamination. These results highlight the importance of prospective studies to evaluate concordance of genomic findings between distinct platforms that ultimately may inform treatment decisions.

Adenoid cystic carcinoma: current therapy and potential therapeutic advances based on genomic profiling

Adenoid cystic carcinoma (ACC) is a rare cancer with high potential for recurrence and metastasis. Efficacy of current treatment options, particularly for advanced disease, is very limited. Recent whole genome and exome sequencing has dramatically improved our understanding of ACC pathogenesis. A balanced translocation resulting in the MYB-NFIB fusion gene appears to be a fundamental signature of ACC. In addition, sequencing has identified a number of other driver genes mutated in downstream pathways common to other well-studied cancers. Overexpression of oncogenic proteins involved in cell growth, adhesion, cell cycle regulation, and angiogenesis are also present in ACC. Collectively, studies have identified genes and proteins for targeted, mechanism-based, therapies based on tumor phenotypes, as opposed to nonspecific cytotoxic agents. In addition, although few studies in ACC currently exist, immunotherapy may also hold promise. Better genetic understanding will enable treatment with novel targeted agents and initial exploration of immune-based therapies with the goal of improving outcomes for patients with ACC.

Concordance of Genomic Alterations by Next-Generation Sequencing in Tumor Tissue versus Circulating Tumor DNA in Breast Cancer

While identifying genomic alterations in tumor tissue is the current gold-standard technique for molecular profiling, circulating tumor DNA (ctDNA) represents a noninvasive method of assessing genomic alterations using peripheral blood. The concordance of genomic alterations between two commercially available ctDNA and tissue biopsies was compared in 45 patients with breast cancer using paired next-generation sequencing tissue and ctDNA biopsies. Across all genes, concordance between the two platforms was 91.0% to 94.2%. When only considering genomic alterations in either assay (e.g., excluding wild type/wild type genes), concordance was 10.8% to 15.1% with full plus partial concordance of 13.8% to 19.3%. Concordant mutations were associated with significantly higher variant allele frequency. Over half of mutations detected in either technique were not detected using the other biopsy technique. Including variants of unknown significance, the average number of alterations per patient was significantly higher for tissue (4.56) compared with ctDNA (2.16). When eliminating alterations not detectable in the ctDNA assay, mean number of alterations for tissue and ctDNA was similar (2.67 for tissue, 2.16 for ctDNA). Across five representative genes (TP53, PIK3CA, ERBB2, BRCA1, and BRCA2), sensitivity and specificity were 35.7% and 95.0%, respectively. Concordance when genomic alterations was detected in either tissue or ctDNA was low with each technique detecting a significant amount of nonoverlapping mutations. Potential explanations for the lack of concordance include tumor heterogeneity, different sequencing techniques, spatial and temporal factors, and potential germline DNA contamination. The study indicates that both tissue and blood-based NGS may be necessary to describe the complex biology of breast cancer. Mol Cancer Ther; 16(7); 1412–20. ©2017 AACR.

Recent Advances and Future Strategies for Immune-Checkpoint Inhibition in Small-Cell Lung Cancer

Abstract Small‐cell lung cancer (SCLC) is distinguished from non–small‐cell lung cancer by its rapid growth and more frequent metastases. Although patients with SCLC are highly responsive to chemotherapy and radiation therapy, long‐term prognosis remains poor, with relapse and disease recurrence occurring in almost all cases. Whereas combination chemotherapies continue to be the standard of care in extensive‐stage SCLC, there is value in exploring whether immune‐checkpoint inhibition is an effective treatment strategy, given the durable responses in non–small‐cell lung cancer. Data from SCLC trials have shown clinical activity and response to cytotoxic T‐lymphocyte antigen‐4 protein and programmed cell death‐1 blockade, suggesting that antibodies targeting these pathways may be effective in improving survival outcome. However, data on clinical activity by programmed cell death‐1 ligand expression in SCLC are not widely available. Limited data indicate that programmed cell death‐1 ligand expression may not be an ideal biomarker for patient selection. Continued research is necessary to better optimize patient selection and response to therapy.

Characteristics of individuals with breast cancer rearrangements in BRCA1 and BRCA2

Large rearrangements in BRCA1 and BRCA2 occur in a small percentage (< 1%) of patients tested for hereditary breast (BC) and ovarian cancer. It is unclear what factors predict BRACAnalysis Large Rearrangement Test (BART) positivity.

Path toward precision oncology: Review of targeted therapy studies and tools to aid in defining "actionability" of a molecular lesion and patient management support

Precision medicine trials and targeted therapies have shifted to the forefront of oncology. Although targeted therapies have shown initial promise, implementation across the broad landscape of oncology has many challenges. These limitations include an incomplete understanding of the functional significance of variant alleles as well as the need for clinical research and practice models that are more patient-centered and account for the complexity of individual patient tumors. Furthermore, successful implementation of targeted therapies will also be predicated on efforts to standardize the framework for patient management support. Here, we review current implementations of targeted therapies in precision oncology and discuss how “actionability” is defined for molecular targets in cancer therapeutics. We also comment on the growing need for bioinformatics tools and data platforms to complement advances in precision oncology. Finally, we discuss current frameworks for integrating precision oncology into patient management and propose an integrated model that combines features of molecular tumor boards and decision support systems. Mol Cancer Ther; 16(12); 2645–55. ©2017 AACR. See related article by Pilié et al., p. 2641

Abstract 658: Association of tumor mutational burden (TMB) with DNA repair mutations and response to anti-PD-1/PD-L1 therapy in non-small cell lung cancer (NSCLC)

Background: Identifying optimal biomarkers for response to anti-PD-1/PD-L1 therapies in non-small cell lung cancer (NSCLC) is critical. Tumor mutational burden (TMB) is a potential biomarker of genomic instability and neoantigen binding sites to activated effector T cells. The goal of this study was to examine the association of TMB with overall survival for patients treated with checkpoint blockade and to correlate TMB with mutational status, including DNA repair mutations. Methods: We retrospectively examined TMB using next-generation sequencing (FoundationOne) for 82 patients with NSCLC in our institution. TMB included coding base substitutions and indel alterations, but excluded potentially functional mutations. TMB high versus low was stratified based on 15 mutations per megabase pair. We correlated TMB with DNA repair mutations, mutational status, and smoking history. In addition, survival data were obtained for 35 patients who were treated with anti-PD-1/PD-L1 therapy. Results: TMB was associated with significantly longer overall survival for patients treated with checkpoint blockade (Table 1, p Conclusions: Higher TMB was associated with improved survival for patients treated with anti-PD-1/PD-L1 therapies. In addition, TMB was correlated with DNA repair mutations, number of coding mutations, prior treatment, and smoking. Our results indicate that TMB can be used as a biomarker for response to checkpoint blockade in NSCLC. Citation Format: Andrew A. Davis, Young Kwang Chae, Sarita Agte, Alan Pan, Nisha Mohindra, Victoria Villaflor, Kirtee Raparia, Francis J. Giles. Association of tumor mutational burden (TMB) with DNA repair mutations and response to anti-PD-1/PD-L1 therapy in non-small cell lung cancer (NSCLC) [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 658. doi:10.1158/1538-7445.AM2017-658