Molecular alterations in claudin 18 suppressed and non-suppressed gastric adenocarcinomas to guide targeted therapies.

BACKGROUND: Gastric adenocarcinoma represents an aggressive type of cancer and an important cause of cancer mortality. Progress in gastric cancer therapeutics has resulted from a better understanding of the molecular pathogenesis of the disease and introduction of targeted therapies, but most gastric cancer patients still rely on non-targeted chemotherapy as the mainstay of treatment for advanced disease. METHODS: An analysis of publicly available series from The Cancer Genome Atlas (TCGA) gastric cancer cohort was undertaken to delineate the clinical and genomic landscape of gastric cancers with suppressed expression of claudin 18 compared with cancers with non-suppressed claudin 18. Claudin 18 suppressed cancers were defined as having an mRNA expression z-score relative to normal samples (log RNA Seq V2) of less than -1. Claudin 18 non-suppressed cancers were defined as having an mRNA expression z-score relative to normal samples (log RNA Seq V2) above 0.5. RESULTS: Gastric cancers with claudin 18 mRNA suppression represented 7.7% of the gastric adenocarcinomas of TCGA cohort, while non-suppressed cancers represented 46.6% of the cases. The two groups did not differ in clinical and genomic characteristics, such as mean age, histology, grade, and stage. The mutation landscape of claudin 18 suppressed cases included high mutation rates of TP53, of genes of the WNT/ß-catenin pathway and of ubiquitin ligase FBXW7. Moreover, a subset of both claudin 18 suppressed and non-suppressed cancers displayed mutations in Mismatch Repair (MMR) associated genes or a high tumor mutation burden (TMB). At the mRNA expression level, claudin 18 suppressed gastric cancers showed up-regulation of EMT core transcription factor Snail 2 and down-regulation of genes of HLA cluster. The survival of gastric cancer patients with claudin 18 mRNA suppression was not significantly different compared with patients with non-suppressed claudin 18. CONCLUSION: Sub-sets of gastric cancers with claudin 18 mRNA suppression displayed characteristics of potential therapeutic interest, such as mutations in WNT and PI3K pathways and MMR defects. These may guide the development of alternative targeted therapies, in this sub-set of gastric cancers which are not candidates for claudin 18 targeting therapies.

Mediator kinase module proteins, genetic alterations and expression of super-enhancer regulated genes in colorectal cancer.

BACKGROUND: Genetic alterations are well characterized as contributors to the pathogenesis of cancers. Epigenetic abnormalities can lead to perturbations of the expression of genes in cancer cells without structural defects. Deregulation of proteins of the transcription machinery may result in perturbations of target genes. Mediator, a multiprotein component of the transcription machinery facilitates the function of RNA polymerase II, which transcribes most human genes. A part of the mediator with kinase activity, called the Mediator kinase module shows genetic alterations in a sub-set of colorectal cancers. METHODS: Data from publicly available genomic series of colorectal cancer patients were examined to determine alterations of Mediator kinase module component genes, including MED12, MED12L, MED13, MED13L, CDK8, CDK19, and CCNC. The prevalence of alterations in genomically defined colorectal cancer sub-sets was also interrogated. The effect of Mediator kinase module member gene expression on colorectal cancer relapse-free survival was investigated. RESULTS: Mutations in genes of the Mediator kinase module were present in a small percentage of colorectal cancers, ranging between 2 to 10% for MED12 and MED13 and alternative units MED12L and MED13L and below 2% for kinases CDK8 and CDK19 and cyclin C. Amplifications of the CDK8 gene were observed in 3% to 5% of colorectal cancers. The highest prevalence of mutations was observed in MSI cancers and the equivalent CMS1 group, with other genomic groups showing much lower frequency. An association of higher expression of MED12 with inferior relapse-free survival was observed. In contrast, higher expression of cyclin C was associated with improved survival. Colorectal cancer cell lines with CDK8 amplifications displayed sensitivity to several small molecule inhibitors of the KRAS/PI3K pathway but not to BET inhibitors. CONCLUSION: The Mediator kinase module is deregulated in a sub-set of colorectal cancers with differences observed in genomically defined groups. These variations may result in differences in sensitivity to targeted therapies and may have to be taken into consideration as such therapies are developed.

Targeting super-enhancer activity for colorectal cancer therapy.

In addition to genetic variants and copy number alterations, epigenetic deregulation of oncogenes and tumor suppressors is a major contributor in cancer development and propagation. Regulatory elements for gene transcription regulation can be found in promoters which are located in the vicinity of transcription start sites but also at a distance, in enhancer sites, brought to interact with proximal sites when occupied by enhancer protein complexes. These sites provide most of the specific regulatory sequences recognized by transcription factors. A sub-set of enhancers characterized by a longer structure and stronger activity, called super-enhancers, are critical for the expression of specific genes, usually associated with individual cell type identity and function. Super-enhancers show deregulation in cancer, which may have profound repercussions for cancer cell survival and response to therapy. Dysfunction of super-enhancers may result from multiple mechanisms that include changes in their sequence, alterations in the topological neighborhoods where they belong, and alterations in the proteins that mediate their function, such as transcription factors and epigenetic modifiers. These can become potential targets for therapeutic interventions. Genes that are targets of super-enhancers are cell and cancer type specific and could also be of interest for therapeutic targeting. In colorectal cancer, a super-enhancer regulated and over-expressed oncogene is MYC, under the influence of the WNT/ß-catenin pathway. Identification and targeting of additional oncogenes regulated by super-enhancers in colorectal cancer may pave the way for combination therapies targeting the super-enhancer machinery and signal transduction pathways that regulate the specific transcription factors operative on them.

Neo-adjuvant therapies for ER positive/HER2 negative breast cancers: from chemotherapy to hormonal therapy, CDK inhibitors, and beyond.

INTRODUCTION: Chemotherapy has been traditionally used as neo-adjuvant therapy in breast cancer for down-staging of locally advanced disease in all sub-types. In the adjuvant setting, genomic assays have shown that a significant proportion of ER positive/HER2 negative patients do not derive benefit from the addition of chemotherapy to adjuvant endocrine therapy. An interest in hormonal treatments as neo-adjuvant therapies in ER positive/HER2 negative cancers has been borne by their documented success in the adjuvant setting. Moreover, cytotoxic chemotherapy is less effective in ER positive/HER2 negative disease compared with other breast cancer subtypes in obtaining pathologic complete responses. AREAS COVERED: Neo-adjuvant therapies for ER positive/HER2 negative breast cancers and associated biomarkers are reviewed, using a Medline survey. A focus of discussion is the prediction of patients that are unlikely to derive extra benefit from chemotherapy and have the highest probabilities of benefiting from hormonal and other targeted therapies. EXPERT OPINION: Predictive biomarkers of response to neo-adjuvant chemotherapy and hormonal therapies are instrumental for selecting ER positive/HER2 negative breast cancer patients for each treatment. Chemotherapy remains the standard of care for many of those patients requiring neo-adjuvant treatment, but other neo-adjuvant therapies are increasingly used.

Tight Junction Claudins and Occludin Are Differentially Regulated and Expressed in Genomically Defined Subsets of Colon Cancer.

Metastatic colon cancer remains incurable despite improvements in survival outcomes. New therapies based on the discovery of colon cancer genomic subsets could improve outcomes. Colon cancers from genomic studies with publicly available data were examined to define the expression and regulation of the major tight junction proteins claudins and occludin in genomic groups. Putative regulations of the promoters of tight junction genes by colon-cancer-deregulated pathways were evaluated in silico. The effect of claudin mRNA expression levels on survival of colon cancer patients was examined. Common mutations in colon-cancer-related genes showed variable prevalence in genomically identified groups. Claudin genes were rarely mutated in colon cancer patients. Genomically identified groups of colon cancer displayed distinct regulation of claudins and occludin at the mRNA level. Claudin gene promoters possessed clustered sites of binding sequences for transcription factors TCF4 and SMADs, consistent with a key regulatory role of the WNT and TGFß pathways in their expression. Although an effect of claudin mRNA expression on survival of colon cancer patients as a whole was not prominent, survival of genomic subsets was significantly influenced by claudin mRNA expression. mRNA expression of the main tight junction genes showed differential regulation in various genomically defined subgroups of colon cancer. These data pinpoint a distinct role of claudins and pathways that regulate them in these subgroups and suggest that subgroups of colon cancer should be considered in future efforts to therapeutically target claudins.

Molecular Characteristics and Therapeutic Vulnerabilities of Claudin-low Breast Cancers Derived from Cell Line Models.

BACKGROUND/AIM: Breast cancers constitute heterogeneous tumor groups and their categorization in subtypes based on the expression of the estrogen (ER), progesterone (PR) and HER2 receptors has advanced therapeutics. Claudin-low breast cancer has been proposed as an additional subtype which is mostly ER, PR and HER2 negative, but its identification has not led to corresponding specific treatments yet. MATERIALS AND METHODS: Breast cancer cell lines from the Cancer Cell Line Encyclopedia (CCLE) were assessed for mRNA suppression of claudins and mRNA expression of ER and ERBB2 (the gene encoding HER2). The set of identified claudin-low cell lines were compared with representative ER-/ERBB2- cell lines for associated molecular alterations, gene dependencies through CRISPR and microRNA arrays and in vitro drug sensitivities using the Genomics of Drug Sensitivity in Cancer (GDSC) project. RESULTS: Claudin-low cell lines display up-regulation of mRNA expression of epithelial to mesenchymal transition (EMT) regulators. Methylation sensitive genes are down-regulated in claudin-low lines compared with other cell lines, without associated up-regulation of DNA methyltransferases. Dependency screen microarrays reveal dependencies of claudin-low cell lines on components of the cytoskeleton but no consistent dependencies in known oncogenes or tumor suppressors. Potential drug sensitivities revealed in the drug screens included sensitivities to WNT pathway modulators, tyrosine kinase cascade inhibitors and BET inhibitors. On the other hand, claudin-low cell lines showed resistance to deacetylase inhibitors. CONCLUSION: Claudin-low cell line models duplicate features of claudin-low breast cancers and may serve as guides for identification of drugs worth exploring for further development.

Presentation, Molecular Characteristics, Treatment, and Outcomes of Colorectal Cancer in Patients Older than 80 Years Old.

Background: An increasing proportion of the population of patients with cancer presents at an advanced age, increasing the challenges of successful and well-tolerated treatments. In the older spectrum of the geriatric cancer patients, those older than 80 years old, challenges are even higher because of increasing comorbidities and decreasing organ function reserves. Methods: Studies regarding colorectal cancer presentation, treatment, and prognosis in patients older than 80 years old available in the literature were evaluated and were compiled within a narrative review. Molecular attributes of colorectal cancer in the subset of patients older than 80 years old in published genomic cohorts were also reviewed and were compared with similar attributes in younger patients. Results: Characteristics of colorectal cancer in octogenarians are in many aspects similar to younger patients, but patients older than 80 years old present more often with right colon cancers. Surgical treatment of colorectal cancer in selected patients over 80 years old is feasible and should be pursued. Adjuvant chemotherapy is under-utilized in this population. Although combination chemotherapy is in most cases not advisable, monotherapy with fluoropyrimidine derivatives is feasible and efficacious. Conclusions: Outcomes of colorectal cancer patients over the age of 80 years old may be optimized with a combination of standard treatments adjusted to the individual patient's functional status and organ reserves. Increased support for the older age group during their colorectal cancer treatment modalities would improve oncologic outcomes with decreasing adverse outcomes of therapies.

EMT Features in Claudin-Low versus Claudin-Non-Suppressed Breast Cancers and the Role of Epigenetic Modifications.

BACKGROUND: Breast cancers are heterogeneous and are classified according to the expression of ER, PR and HER2 receptors to distinct groups with prognostic and therapeutic implications. Within the triple-negative group, with no expression of these three receptors, molecular heterogeneity exists but is currently not exploited in the clinic. The claudin-low phenotype is present in a subset of triple-negative breast cancers and constitutes together with basal-like cancers the most extensive groups within triple-negative breast cancers. Suppression of epithelial cell adhesion molecules in claudin-low cancers is also a hallmark of Epithelial Mesenchymal Transition (EMT). METHODS: The groups of claudin-low and claudin-non-suppressed breast cancers from the extensive publicly available genomic cohorts of the METABRIC study were examined to delineate and compare their molecular landscape. Genetic and epigenetic alterations of key factors involved in EMT and potentially associated with the pathogenesis of the claudin-low phenotype were analyzed in the two groups. RESULTS: Claudin-low cancers displayed up-regulation of several core transcription factors of EMT at the mRNA level, compared with claudin-non-suppressed breast cancers. Global promoter DNA methylation was increased in both groups of triple-negative cancers and in claudin-low ER-positive cancers compared with the rest of ER-positive cancers. Histone modifier enzymes, including methyltransferases, demethylases, acetyltransferases and deacetylases displayed amplifications more frequently in claudin-non-suppressed triple-negative cancers than in claudin-low counterparts and the expression of some of these enzymes differed significantly between the two groups. CONCLUSION: Claudin-low and claudin-non-suppressed triple-negative breast cancers differ in their landscape of EMT core regulators and epigenetic regulators. These differences may be explored as targets for therapeutic interventions specific to the two groups of triple-negative breast cancers.

High tumor mutation burden (TMB) in microsatellite stable (MSS) colorectal cancers: Diverse molecular associations point to variable pathophysiology.

BACKGROUND: Colorectal cancers with defects in the Mismatch Repair (MMR) system represent a minority of the disease. MMR defective cancers are characterized by high Tumor Mutation Burden (TMB) and are sensitive to immunotherapy with immune checkpoint inhibitors. In contrast, the majority of colorectal cancers are MMR proficient (Microsatellite Stable, MSS) and display a low TMB. However, a few of these MSS cancers have high TMB. METHODS: Published genomic studies of colorectal cancers were examined to identify cases profiled as MSS and having a TMB above 10 mutations / Mb. Data from four studies detailed in the cBioportal for cancer genomics site and providing data on MSI status were examined. RESULTS: In the MSK study of metastatic colorectal cancers, 7.5% of patients with MSS tumors had a high TMB of more than 10 mutations/ Mb. The MSK study of localized rectal cancers showed that 9.5% of patients with MSS tumors had a high TMB. The DFCI cohort included 10 patients with TMB above 10 mutations/ Mb characterized as MSS and not having MMR or proofreading polymerases mutations. Mutations in genes encoding for proteins of the KRAS pathways were more frequent in MSS tumors with high TMB than in counterparts with low TMB. Moreover, genes involved in DNA damage response and in epigenetic regulations were more frequently mutated in MSS colorectal cancers with high TMB. CONCLUSION: Alterations of the KRAS signal transduction pathways, DDR gene mutations and epigenetic modifier mutations may contribute to increase mutation burden in subsets of MSS colorectal cancers.

Comparison of Clinical Subtypes of Breast Cancer within the Claudin-Low Molecular Cluster Reveals Distinct Phenotypes.

BACKGROUND: Molecular subtyping of breast cancer has provided a new perspective on the pathogenesis of the disease and a foundation for building a clinical classification for this heterogeneous disease. The initial classification categorizing breast cancers into five groups, luminal A, luminal B, ERBB2-overexpressing, basal-like and normal-like, was later supplemented by an additional group, claudin-low tumors. However, the claudin-low group has been more difficult to align with clinically used immunohistochemical categories. The identity of this group among clinical cases remains ill defined. METHODS: The METABRIC cohort comprising more than 1700 breast cancers and providing information for classifying them in both clinical groups and the genomic PAM50/claudin-low groups was analyzed to derive relationships and clarify potential pathogenic ramifications. Comparisons of the claudin-low cases bearing different clinical group classifications and of the respective cases with the same clinical non-claudin-low classifications were performed. RESULTS: ER-negative/HER2-negative breast cancers are predominantly (88.4%) basal-like and claudin low. Conversely, most basal-like cancers (83.6%) are ER negative/HER2 negative. However, claudin-low breast cancers are only in 68.4% of cases ER negative/HER2 negative and the other clinical phenotypes, mostly ER positive/HER2 negative/low proliferation, are also represented in more than 30% of claudin-low cancers. These claudin-low non-ER-negative/HER2-negative breast cancers differ from claudin-low ER-negative/HER2-negative cases in grade, prevalence of integrative clusters, and prevalence of common mutations and common amplifications. Differences also exist between the two groups classified clinically as ER negative/HER2 negative, that are genomically basal-like or claudin-low, including in menopause status, grade, histology, prevalence of high tumor mutation burden, distribution of integrative clusters, prevalence of TP53 mutations and of amplifications in the MYC and MCL1 loci. Furthermore, distinct characteristics are observed between the luminal A and claudin-low groups within the clinical ER-positive/HER2-negative/low proliferation group. CONCLUSION: Within genomically claudin-low breast cancers, the ER-negative/HER2-negative group is distinct from the group with either ER or HER2 positivity. Conversely, within clinical phenotypes, claudin-low and non-claudin-low breast cancers differ in clinical characteristics and molecular attributes.

A Systematic Review and Meta-Analysis of Trifluridine/Tipiracil plus Bevacizumab for the Treatment of Metastatic Colorectal Cancer: Evidence from Real-World Series.

BACKGROUND: Colorectal cancer is the most prevalent gastrointestinal neoplasm. When metastatic, the disease has limited systemic treatment options. Novel targeted therapies have expanded these options for subsets with specific molecular alterations, such as microsatellite instability (MSI)-high cancers, but additional treatments and combinations are in urgent need to improve outcomes and improve survival of this incurable disease. The fluoropyrimidine-derivative trifluridine, in combination with tipiracil, has been introduced as a third-line treatment, and more recently, it was studied in combination with bevacizumab. This meta-analysis reports on studies with this combination in clinical practice outside clinical trials. METHODS: A literature search in the Medline/PubMed and Embase databases was executed for finding series of trifluridine/tipiracil with bevacizumab in metastatic colorectal cancer. Criteria for inclusion in the meta-analysis were English or French language of the report, inclusion of twenty or more patients with metastatic colorectal cancer treated with trifluridine/tipiracil in combination with bevacizumab outside of a trial and containing information regarding response rates, progression-free survival (PFS), and overall survival (OS). Information on the demographics of the patients and on adverse effects of treatment was also collected. RESULTS: Eight series with a total of 437 patients were eligible for the meta-analysis. The performed meta-analysis discovered a summary response rate (RR) of 2.71% (95% confidence interval (CI): 1.11-4.32%) and a disease control rate (DCR) of 59.63% (95% CI: 52.06-67.21%). Summary PFS was 4.56 months (95% CI: 3.57-5.55 months), and summary OS was 11.17 months (95% CI: 10.15-12.19 months). Common adverse effects identified mirrored the adverse-effect profile of the two components of the combination. CONCLUSION: The current systematic review and meta-analysis reports the efficacy of trifluridine/tipiracil with bevacizumab in advanced lines of therapy for metastatic colorectal cancer in the setting of clinical practice outside clinical trials. Discovery of predictive biomarkers of response to trifluridine/tipiracil with bevacizumab will promote the tailoring of this treatment to individual patients to maximize clinical benefit.

KRAS mutated colorectal cancers with or without PIK3CA mutations: Clinical and molecular profiles inform current and future therapeutics.

BACKGROUND: Colorectal cancer is one of the most prevalent malignancies and its molecular pathogenesis has been intensely investigated for several decades. As a result, great progress has been made and targeted therapies have been introduced in the clinic. This paper examines colorectal cancers based on two of the most common molecular alterations, KRAS and PIK3CA mutations as a basis for therapeutic targeting. METHODS: Two publicly available genomic series with clinical data were evaluated for prevalence and characteristics of cases with and without KRAS and PIK3CA mutations and the literature was reviewed for relevant information on the therapeutic implication of these alterations as well as other coincident alterations to derive therapeutic individualized options of targeted treatments. RESULTS: Colorectal cancers without KRAS and PIK3CA mutations represent the most prevalent group (48-58 % of patients) and present therapeutic targeted opportunities with BRAF inhibitors and immune checkpoint inhibitors in the subsets with BRAF mutations (15-22 %) and Microsatellite Instability (MSI, 14-16 %), respectively. The second most prevalent sub-set, with KRAS mutations and PIK3CA wild type, representing 20-25 % of patients, has currently few targeted options, besides specific KRAS G12C inhibitors for the small percentage of cases (9-10 %) that bear this mutation. Cancers with KRAS wild type and PIK3CA mutations are observed in 12-14 % of colorectal cancer patients, harbor the highest percentage of cases with BRAF mutations and Microsatellite Instability (MSI), and are candidates for the respective targeted therapies. New targeted therapies in development, such as ATR inhibitors could be effective in cases with ATM mutations and ARID1A mutations that are also most prevalent in this sub-group (14-22 % and 30 %, respectively). KRAS and PIK3CA double mutant cancers have also few targeted options currently and could benefit from combination therapies with PI3K inhibitors and new KRAS inhibitors in development. CONCLUSION: The backbone of common KRAS and PIK3CA mutations is a rational frame for development of therapeutic algorithms in colorectal cancer and can help guide new drug therapies development. In addition, the prevalence of different molecular groups presented here may help with planning of combination clinical trials by providing estimations of sub-sets with more than one alteration.

The Landscape and Therapeutic Targeting of BRCA1, BRCA2 and Other DNA Damage Response Genes in Pancreatic Cancer.

Genes participating in the cellular response to damaged DNA have an important function to protect genetic information from alterations due to extrinsic and intrinsic cellular insults. In cancer cells, alterations in these genes are a source of genetic instability, which is advantageous for cancer progression by providing background for adaptation to adverse environments and attack by the immune system. Mutations in BRCA1 and BRCA2 genes have been known for decades to predispose to familial breast and ovarian cancers, and, more recently, prostate and pancreatic cancers have been added to the constellation of cancers that show increased prevalence in these families. Cancers associated with these genetic syndromes are currently treated with PARP inhibitors based on the exquisite sensitivity of cells lacking BRCA1 or BRCA2 function to inhibition of the PARP enzyme. In contrast, the sensitivity of pancreatic cancers with somatic BRCA1 and BRCA2 mutations and with mutations in other homologous recombination (HR) repair genes to PARP inhibitors is less established and the subject of ongoing investigations. This paper reviews the prevalence of pancreatic cancers with HR gene defects and treatment of pancreatic cancer patients with defects in HR with PARP inhibitors and other drugs in development that target these molecular defects.

Pancreatic adenocarcinomas without KRAS, TP53, CDKN2A and SMAD4 mutations and CDKN2A/CDKN2B copy number alterations: a review of the genomic landscape to unveil therapeutic avenues.

BACKGROUND: Pancreatic adenocarcinoma is one of the cancers with the worst prognosis. The current treatment paradigm based on combination chemotherapy has improved survival over the last decade, but the disease is still fatal in most cases. New therapies exploiting the increasing understanding of the molecular pathology of the disease are needed. Although the disease presents with few recurrent molecular alterations, these represent opportunities for targeted treatments to be developed. However, a minority of cases are devoid of these common alterations. A description of the molecular landscape of this sub-set of pancreatic adenocarcinoma could uncover other molecular lesions present in them that could serve as therapeutic targets. METHODS: The sub-set of pancreatic cancers without the common alterations in KRAS, TP53, CDKN2A and SMAD4 has been examined from published and publicly available pancreatic cancer cohorts for determination of their clinical and molecular characteristics. The cBioportal platform was used for this evaluation and the OncoKB knowledgebase was used for determination of the functional significance of discovered mutations. RESULTS: About 5% to 10% of pancreatic adenocarcinomas present without the usual molecular alterations that characterize the disease. These cases tend to be genomically stable and have low prevalence of microsatellite or chromosome instability. Molecular alterations that are observed in pancreatic cancers in lower frequencies than the four most prevalent alterations, such as DNA Damage Response and epigenetic modifier mutations, are still observed in the sub-set without the common alterations and may be pathogenically relevant. CONCLUSIONS: Despite the absence of most frequent pancreatic cancer alterations in a sub-set of pancreatic adenocarcinomas, this sub-set possesses other alterations in frequencies similar to the rest of pancreatic cancers. Putative targeting of alterations present is discussed and can serve as the basis for targeted therapies development.

Characteristics and Prognosis of 8p11.23-Amplified Squamous Lung Carcinomas.

BACKGROUND: Copy number alterations are common genetic lesions in cancer. In squamous non-small cell lung carcinomas, the most common copy-number-altered loci are at chromosomes 3q26-27 and 8p11.23. The genes that may be drivers in squamous lung cancers with 8p11.23 amplifications are unclear. METHODS: Data pertaining to copy number alterations, mRNA expression and protein expression of genes located in the 8p11.23 amplified region were extracted from various sources including The Cancer Genome Atlas, the Human Protein Atlas and the Kaplan Meier Plotter. Genomic data were analyzed using the cBioportal platform. Survival analysis of cases with amplifications compared to nonamplified cases was performed using the Kaplan Meier Plotter platform. RESULTS: The 8p11.23 locus is amplified in 11.5% to 17.7% of squamous lung carcinomas. The most frequently amplified genes include NSD3, FGFR1 and LETM2. Only some of the amplified genes present concomitant overexpression at the mRNA level. These include NSD3, PLPP5, DDHD2, LSM1 and ASH2L, while other genes display lower levels of correlation, and still, some genes in the locus show no mRNA overexpression compared with copy-neutral samples. The protein products of most locus genes are expressed in squamous lung cancers. No significant difference in overall survival in 8p11.23-amplified squamous cell lung cancers versus nonamplified cancers is observed. In addition, there is no adverse effect of mRNA overexpression for relapse-free survival of any of the amplified genes. CONCLUSION: Several genes that are part of the commonly amplified locus 8p11.23 in squamous lung carcinomas are putative oncogenic candidates. A subset of genes of the centromeric part of the locus, which is amplified more commonly than the telomeric part, show high concomitant mRNA expression.

Homologous Recombination Defects and Mutations in DNA Damage Response (DDR) Genes Besides BRCA1 and BRCA2 as Breast Cancer Biomarkers for PARP Inhibitors and Other DDR Targeting Therapies.

Homologous recombination repair (HRR) is the cellular mechanism for error-free repair of double strand DNA (dsDNA) breaks. Cancer cells with mutations in both alleles of genes encoding for proteins involved in HRR, such as BRCA1 and BRCA2, have defects in the repair process. As a result, these cells repair dsDNA breaks with alternative mechanisms, such as non-homologous end joining. In breast cancers with germline mutations in BRCA1 and BRCA2 genes, HRR defects result in sensitivity to PARP inhibitors, drugs that interfere with the function of PARP enzyme and promote trapping of the enzyme on DNA and stalling of the process of repairing single strand breaks. HRR defects also lead to sensitivity to DNA damaging chemotherapy due to the inability of cells to repair chemotherapy induced DNA lesions. Besides germline mutations in BRCA1 and BRCA2, somatic mutations in these genes or germline and somatic mutations or other genetic and epigenetic alterations of other genes involved in homologous recombination (HR) may produce HRR defects leading to sensitivity to PARP inhibitors. However, studies are less conclusive, a fact that may relate to the common lack of bi-allelic loss of function in these cases, as opposed to cancers with germline BRCA1 or BRCA2 defects that usually acquire bi-allelic loss of function. In addition, there is heterogeneity between the different HRR genes and the severity of the resulting HRR defects, as measured by HR defect assays. This review article examines the landscape of HRR gene mutations in breast cancer and the possible therapeutic implications of HRR defects other than germline BRCA1 and BRCA2 mutations for targeted therapies. Identification of a wider range of breast cancers with HRR defects may expand the subset of patients that derive benefit from PARP inhibitors and other DDR-targeting drugs in the clinic.

An evaluation of the Index4 tool for chemotherapy toxicity prediction in cancer patients older than 70 years old.

Chemotherapy, although beneficial for improving outcomes in both localized and metastatic cancers, may be associated with significant adverse effects, especially for patients with decreased functional reserves. Prediction of patients who will not tolerate well chemotherapy treatment may help in modifying treatment plans and in reallocating resources to vulnerable patients. One hundred seventeen consecutive cancer patients over the age of 70 scheduled for chemotherapy treatment in a single cancer center were included in the study. Prediction of adverse chemotherapy outcomes were calculated using a prediction tool proposed and validated from the Cancer and Aging Research Group (CARG) and a prediction tool proposed by us, called Index4. The 2 tools were compared for their ability to predict grade 3 and 4 toxicities, Emergency Department (ED) and hospital admissions and chemotherapy discontinuation. The accuracy of both predictive tools was suboptimal. A high CARG score had a sensitivity of 46.3% and a specificity of 82% and an Index4 of 1 or above had a sensitivity of 53.7% and a specificity of 60% in predicting grade 3-4 adverse effects. The performance of the 2 tools in predicting ED and hospital admissions and chemotherapy discontinuation was comparable. An Index4 score of 0 was superior in predicting absence of grade 3-4 toxicities than a low CARG score (p = 0.002, McNemar's test). The CARG tool for chemotherapy adverse effect prediction in geriatric cancer patients and the Index4 were able to predict adverse outcomes with moderate accuracy. Given its ease of calculation Index4 may be an alternative to CARG tool, suitable for a busy oncology practice.

Molecular Alterations and Putative Therapeutic Targeting of Planar Cell Polarity Proteins in Breast Cancer.

BACKGROUND: Treatment and outcomes of breast cancer, one of the most prevalent female cancers, have improved in recent decades. However, metastatic breast cancer remains incurable in most cases, and new therapies are needed to ameliorate prognosis. Planar cell polarity (PCP) is a characteristic of epithelial cells that form layers and is integral to the communication of these cells with neighboring cells. Dysfunction of PCP is observed in cancers and may confer a targetable vulnerability. METHODS: The breast cancer cohorts from The Cancer Genome Atlas (TCGA) and the METABRIC study were interrogated for molecular alterations in genes of the PCP pathway. The groups with the most prevalent alterations were characterized, and survival was compared with counterparts not possessing PCP alterations. Breast cancer cell lines with PCP alterations from the Cancer Cell Line Encyclopedia (CCLE) were interrogated for sensitivity to drugs affecting PCP. RESULTS: Among genes of the PCP pathway, VANGL2, NOS1AP and SCRIB display amplifications in a sizable minority of breast cancers. Concomitant up-regulation at the mRNA level can be observed mostly in basal cancers, but it does not correlate well with the amplification status of the genes, as it can also be observed in non-amplified cases. In an exploration of cell line models, two of the four breast cancer cell line models with amplifications in VANGL2, NOS1AP and SCRIB display sensitivity to drugs inhibiting acyl-transferase porcupine interfering with the WNT pathway. This sensitivity suggests a possible therapeutic role of these inhibitors in cancers bearing the amplifications. CONCLUSION: Molecular alterations in PCP genes can be observed in breast cancers with a predilection for the basal sub-type. An imperfect correlation of copy number alterations with mRNA expression suggests that post-translational modifications are important in PCP regulation. Inhibitors of acyl-transferase porcupine may be rational candidates for combination therapy development in PCP-altered breast cancers.

Breast cancer sub-types display heterogeneity in gene amplification and mRNA expression of the anti-apoptotic members of BCL2 family.

BACKGROUND: Progress in therapies and improved outcomes in recent decades have followed a better understanding of breast cancers pathogenesis and their heterogeneity but new treatments are needed especially for metastatic disease which remains incurable. Inhibition of apoptosis is a hallmark characteristic of cancer and can be targeted for therapy. METHODS: The five anti-apoptotic members of the BCL2 family are at the core of apoptosis execution and are involved in apoptosis evasion of transformed cells. Genetic lesions as well as mRNA regulation of these members in breast cancer and its sub-types and implications for survival outcomes were investigated using data from various publicly available databases. RESULTS: Genes encoding for anti-apoptotic BCL2 proteins are rarely mutated in breast cancer and copy number alterations are observed only in MCL1 gene which is amplified in a minority of breast cancer ranging from 1.6% to 18.7% in breast cancers. Over-expression of BCL2, BCL-X and MCL1 is observed in luminal A cancers, while cases of luminal B and basal breast cancers display mRNA up-regulation of BCL-X and MCL1, respectively. Basal cancers possess also more frequently than other sub-sets MCL1 amplifications. Survival outcomes are not significantly different in cancers with higher expression of anti-apoptotic BCL2 mRNAs. CONCLUSION: Therapeutic targeting of the apoptotic process in breast cancer sub-types will be improved by a detailed understanding of the core players in the process, including anti-apoptotic BCL2 family proteins. A sub-set of breast cancers harbor amplifications of MCL1 and dysregulations of expression of most family members that could affect the sensitivity to their inhibition by altering the cell's apoptotic threshold.