Characteristics Of Individual Cancers Research Articles

High-confidence calling of normal epithelial cells allows identification of a novel stem-like cell state in the colorectal cancer microenvironment.

Single-cell analyses can be confounded by assigning unrelated groups of cells to common developmental trajectories. For instance, cancer cells and admixed normal epithelial cells could adopt similar cell states thus complicating analyses of their developmental potential. Here, we develop and benchmark CCISM (for Cancer Cell Identification using Somatic Mutations) to exploit genomic single nucleotide variants for the disambiguation of cancer cells from genomically normal non-cancer cells in single-cell data. We find that our method and others based on gene expression or allelic imbalances identify overlapping sets of colorectal cancer versus normal colon epithelial cells, depending on molecular characteristics of individual cancers. Further, we define consensus cell identities of normal and cancer epithelial cells with higher transcriptome cluster homogeneity than those derived using existing tools. Using the consensus identities, we identify significant shifts of cell state distributions in genomically normal epithelial cells developing in the cancer microenvironment, with immature states increased at the expense of terminal differentiation throughout the colon, and a novel stem-like cell state arising in the left colon. Trajectory analyses show that the new cell state extends the pseudo-time range of normal colon stem-like cells in a cancer context. We identify cancer-associated fibroblasts as sources of WNT and BMP ligands potentially contributing to increased plasticity of stem cells in the cancer microenvironment. Our analyses advocate careful interpretation of cell heterogeneity and plasticity in the cancer context and the consideration of genomic information in addition to gene expression data when possible.

Abstract 10: Precision medicine strategy to elucidate and target Bcl-2 prosurvival proteins in a wide spectrum of cancers

Abstract Effective practice of precision medicine in oncology relies on identifying and targeting unique characteristics of individual cancers. Coupling functional analysis with genomic screening will further enhance the selection of efficacious cancer therapies. Cancer is a heterogeneous disease that is defined by distinct capabilities, one of which is the evasion of apoptosis, controlled by the antiapoptotic protein members, Bcl-2, Bcl-xL, Mcl-1, and Bfl-1. These antiapoptotic proteins have become validated therapeutic targets, as manifested by the FDA-approved venetoclax, a selective Bcl-2 inhibitor, and several other molecules in clinical trials that target Mcl-1 and Bcl-xL. One of the translational challenges lies in predicting functional antiapoptotic dependence in a patient’s cancer and discriminating responders from nonresponders to Bcl-2 family targeted therapy. We have successfully characterized an updated array of Bcl-2 family antagonists, consisting of peptides and selective small-molecule BH3-mimetics via in vitro binding assays and functional analysis using model cell lymphoma cell lines. With this selective set of chemical tools, we employed the BH3 profiling assay across a wide spectrum of hematologic and solid tumor cell lines in order to functionally dissect survival dependence. To validate the results of BH3 profiling, we performed treatments with BH3-mimetics and analyzed their ability to induce apoptosis, which further demonstrated how cancers can be differentiated and targeted based on antiapoptotic dependence. The obtained data suggest that hematologic cancer cell lines mainly rely on Mcl-1 and Bcl-2 for survival and commonly undergo apoptosis in response to single-agent inhibitors of these proteins. Solid tumor cell lines are more dependent upon Bcl-xL and Mcl-1 and certain cell lines display increased involvement of Bfl-1. These cell lines undergo apoptosis when exposed to a combination of Bcl-xL/Mcl-1 inhibitors. Single agent-responsive solid tumor cell lines are less common but can be identified by BH3 profiling. This approach was successfully applied to primary patient samples to validate clinical utility. Further applications of dynamic BH3 profiling were explored to demonstrate how various FDA-approved therapies can alter antiapoptotic dependencies and aid in the design of rational combination therapies with BH3-mimetics. This work lays a translational foundation in the field of precision medicine by incorporating Bcl-2 protein family targeting into potential personalized cancer treatments. Citation Format: Karson J. Kump, Matthew Lieberman, Rita A. Avelar, Charles Foucar, Malathi Kandarpa, Antonio Di Cristofano, Russell J. Ryan, Sami N. Malek, Ryan A. Wilcox, Dale L. Bixby, Tycel J. Phillips, Moshe Talpaz, Analisa DiFeo, Zaneta Nikolovska-Coleska. Precision medicine strategy to elucidate and target Bcl-2 prosurvival proteins in a wide spectrum of cancers [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr 10.

Toward Personalized Computer Simulation of Breast Cancer Treatment: A Multiscale Pharmacokinetic and Pharmacodynamic Model Informed by Multitype Patient Data

The usefulness of mechanistic models to disentangle complex multiscale cancer processes, such as treatment response, has been widely acknowledged. However, a major barrier for multiscale models to predict treatment outcomes in individual patients lies in their initialization and parametrization, which needs to reflect individual cancer characteristics accurately. In this study, we use multitype measurements acquired routinely on a single breast tumor, including histopathology, MRI, and molecular profiling, to personalize parts of a complex multiscale model of breast cancer treated with chemotherapeutic and antiangiogenic agents. The model accounts for drug pharmacokinetics and pharmacodynamics. We developed an open-source computer program that simulates cross-sections of tumors under 12-week therapy regimens and used it to individually reproduce and elucidate treatment outcomes of 4 patients. Two of the tumors did not respond to therapy, and model simulations were used to suggest alternative regimens with improved outcomes dependent on the tumor's individual characteristics. It was determined that more frequent and lower doses of chemotherapy reduce tumor burden in a low proliferative tumor while lower doses of antiangiogenic agents improve drug penetration in a poorly perfused tumor. Furthermore, using this model, we were able to correctly predict the outcome in another patient after 12 weeks of treatment. In summary, our model bridges multitype clinical data to shed light on individual treatment outcomes. SIGNIFICANCE: Mathematical modeling is used to validate possible mechanisms of tumor growth, resistance, and treatment outcome.

Recent advances in arsenic trioxide encapsulated nanoparticles as drug delivery agents to solid cancers.

Since arsenic trioxide was first approved as the front line therapy for acute promyelocytic leukemia 25 years ago, its anti-cancer properties for various malignancies have been under intense investigation. However, the clinical successes of arsenic trioxide in treating hematological cancers have not been translated to solid cancers. This is due to arsenic's rapid clearance by the body's immune system before reaching the tumor site. Several attempts have henceforth been made to increase its bioavailability toward solid cancers without increasing its dosage albeit without much success. This review summarizes the past and current utilization of arsenic trioxide in the medical field with primary focus on the implementation of nanotechnology for arsenic trioxide delivery to solid cancer cells. Different approaches that have been employed to increase arsenic's efficacy, specificity and bioavailability to solid cancer cells were evaluated and compared. The potential of combining different approaches or tailoring delivery vehicles to target specific types of solid cancers according to individual cancer characteristics and arsenic chemistry is proposed and discussed.

ESPEN guidelines on nutrition in cancer patients

Cancers are among the leading causes of morbidity and mortality worldwide, and the number of new cases is expected to rise significantly over the next decades. At the same time, all types of cancer treatment, such as surgery, radiation therapy, and pharmacological therapies are improving in sophistication, precision and in the power to target specific characteristics of individual cancers. Thus, while many cancers may still not be cured they may be converted to chronic diseases. All of these treatments, however, are impeded or precluded by the frequent development of malnutrition and metabolic derangements in cancer patients, induced by the tumor or by its treatment. These evidence-based guidelines were developed to translate current best evidence and expert opinion into recommendations for multi-disciplinary teams responsible for identification, prevention, and treatment of reversible elements of malnutrition in adult cancer patients. The guidelines were commissioned and financially supported by ESPEN and by the European Partnership for Action Against Cancer (EPAAC), an EU level initiative. Members of the guideline group were selected by ESPEN to include a range of professions and fields of expertise. We searched for meta-analyses, systematic reviews and comparative studies based on clinical questions according to the PICO format. The evidence was evaluated and merged to develop clinical recommendations using the GRADE method. Due to the deficits in the available evidence, relevant still open questions were listed and should be addressed by future studies. Malnutrition and a loss of muscle mass are frequent in cancer patients and have a negative effect on clinical outcome. They may be driven by inadequate food intake, decreased physical activity and catabolic metabolic derangements. To screen for, prevent, assess in detail, monitor and treat malnutrition standard operating procedures, responsibilities and a quality control process should be established at each institution involved in treating cancer patients. All cancer patients should be screened regularly for the risk or the presence of malnutrition. In all patients - with the exception of end of life care - energy and substrate requirements should be met by offering in a step-wise manner nutritional interventions from counseling to parenteral nutrition. However, benefits and risks of nutritional interventions have to be balanced with special consideration in patients with advanced disease. Nutritional care should always be accompanied by exercise training. To counter malnutrition in patients with advanced cancer there are few pharmacological agents and pharmaconutrients with only limited effects. Cancer survivors should engage in regular physical activity and adopt a prudent diet.

Adjunctive imprint cytology of core needle biopsy specimens improved diagnostic accuracy for breast cancer

ObjectiveRecently, therapies targeting the biological characteristics of individual cancers according to markers indicating underlying molecular biological mechanisms have become available. Core needle biopsy (CNB) is widely used, not only to diagnose, but also to determine therapeutic strategies, in patients with breast cancer. Although the diagnostic accuracy of CNB is acceptably high, false-negative results have occasionally been encountered.MethodsThe results of adjunctive imprint cytology (AIC) coinciding with CNB in 2,820 patients suspected to have breast cancer were retrospectively reviewed. The feasibility and clinical usefulness of AIC-assisted diagnosis were analyzed.ResultsFourteen-hundred and sixty-four cases were diagnosed as not malignant using CNB alone. Forty-seven of 1464 cases were suspected to be malignant on a cytological review of AIC, and 42 were confirmed to be breast cancer on additional biopsies. The combination of CNB and AIC achieved a sensitivity of 100% (1398/1398) and a specificity of 99.6% (1417/1422). Small lesions and large noninvasive- or scirrhous-type carcinomas were the common features of the CNB-negative/AIC-positive cases.ConclusionsAdjunctive imprint cytodiagnosis is a simple and easy procedure that assists the pathological diagnosis of breast cancer using CNB and therefore serves as a possible novel standard application.

P3-07-30: Applying the Findings of the Z11 Trial to a UK Practice.

Abstract Introduction: The finding of a positive sentinel node is currently managed by further Level III axillary lymph node clearance (ALNC). The rationale behind this approach is that of local disease control, but there is little evidence that axillary lymph node clearance results in a reduction in axillary recurrence or in mortality. ALNC is however associated with increased morbidity (lymphoedema, nerve damage, reduced shoulder function) and significantly prolongs hospital stay. The Z11 trial suggests that ALNC following positive sentinel node biopsy does not result in lower axillary recurrence rates compared to the group in whom clearance was not undertaken and has obvious implications for evidence-based practice. The Z11 trial has strict inclusion criteria (T1/T2 tumour, breast conservation surgery) with all patients receiving adjuvant whole breast radiotherapy and systemic chemotherapy or endocrine therapy. For patients who do not meet the patient population of Z11, such as women undergoing mastectomy, the Sloane-Kettering predictive normogram provides an estimate of risk for residual axillary disease after positive sentinel node biopsy and the estimate of this risk may inform the clinical decision to clear the axilla based on individual cancer characteristics. Methods: Our population comprises both symptomatic and screening patients, with an axillary positivity rate of approximately a third. This study was undertaken to assess the impact that Z11 would have on our practice. Our prospectively maintained records were searched for ALNC patients treated between 2003 and 2011. We assessed the number of node-positive patients conforming to Z11 criteria and the number who demonstrated residual axillary positivity at clearance after a positive sentinel node. The axillary recurrence rate for this group after ALNC was recorded. We calculated the number of clearances that could have been avoided, and extrapolated the reduction in morbidity in lymphodema and nerve damage using the audited incidence of these complications in our institution. We calculated the financial cost saving in terms of theatre usage and hospital stay. In addition, we assessed whether the Memorial Sloane Kettering predictive normogram is useful in the prediction of residual axillary disease for the group of patients excluded from the Z11 cohort. Results: 1601 patients underwent axillary staging. 65% of our patients with node-positive disease were identified pre-operatively with ultrasound and biopsy and proceeded directly to ALNC. Our overall axillary recurrence rate was low (<1% at 5 years). 26% of our patients would not meet the criteria for Z11, predominantly due to the requirement for mastectomy. Of those that met the Z11 criteria, 60% had no further axillary disease at clearance and a further 25% demonstrated low volume (1-3 positive nodes) residual disease only. The Memorail Sloane Kettering normogram can be used in estimating risk of residual axillary disease in patients undergoing mastectomy. Discussion: Using these criteria nearly 25% of axillary clearances in our population of breast cancer patients could be avoided with obvious cost savings both in terms of morbidity and finance, considerations that are important in planning our service for the future. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-07-30.

Developmental pathways in breast cancer and breast tumor-initiating cells: Therapeutic implications

The recognition of breast cancer as a molecularly heterogeneous disease where individual tumors display cellular hierarchy containing “primitive” stem-like tumor-initiating cells (TICs) and their derivatives, has directed efforts towards the development of personalized targeted therapies based on the characteristics of individual cancers. Targeted therapies are designed to attack processes that uniquely support cancer progression, including maintenance of TICs, invasion, metastasis, cell survival and tumor-related angiogenesis and thereby result in less collateral damage than conventional chemotherapy. Recently, it has been demonstrated that pathways such as Hedgehog (Hh), Wnt and Notch, which regulate development during embryonic life and somatic stem cells (SCs) in the adult organism, can be reactivated in malignancies and support the TIC compartment. Herein, we review the role of developmental pathways in stem cell biology and provide an up-to-date survey of pre-clinical and clinical trials of novel strategies to target them.

Direct evidence that heterogeneity necessitates and limits the use of multidrug chemotherapy in colon cancer

Considerable progress in the form of multidrug chemotherapy has recently been made in chemotherapy for the prolongation of survival in advanced colon cancer. It is generally accepted that colon cancer is biologically heterogeneous for multiple properties, including sensitivity to chemotherapeutic agents and metastasis. Although this partly explains the success of multidrug chemotherapy, there has been no direct evidence that multidrug regimens affect individual heterogenous cancer characteristics in colon cancer. Here, we present a case of metachronous ovarian metastasis in a colon cancer patient with dissemination who underwent irinotecan-based followed by oxaliplatin-based chemotherapy. We were able to obtain three samples from the patient, one of primary cancer and two of metastatic tumors from secondary surgery. Of note, both chemoresistant and chemosensitive tumors were present in the patient at the same time. To understand the influence of multidrugs on individual cancer characteristics, we examined differences in the molecular characteristics of the three samples using RT-PCR, focusing in particular on alterations in chemoresistant genes. In shrunken peritoneal metastasis, we found a significant increase in the mRNA levels of an irinotecan-sensitive gene, although other molecular factors were resistant to both 5-FU and oxaliplatin. We also confirmed that the recurrent ovarian tumor showed significant resistance to all three drugs: 5-FU, irinotecan and oxaliplatin. These results suggest that the heterogeneity of colon cancer necessitates and limits the use of multidrug chemotherapy.

Difficult beginnings—Cancer in infancy

The incidence of cancer in the first year of life, reported in the United States at greater than 230 per million 1, is more than 50% higher than in childhood (0–14 years of age) as a whole 2. Caution has been advised, for numerous reasons, in interpreting successive incidence rates that indicate a recent rise in frequency 1. The distribution of diseases in infancy by incidence differs substantially from that in later childhood; the commonest cancers in infants in the United States (in descending rank order) being neuroblastoma, leukemias, brain tumors and retinoblastoma. It should be recognized that there are notable differences in the racial distribution of these diseases. In the United States for example, neuroblastoma occurs more frequently in whites than in blacks. Moreover, such disparities are described in other parts of the world, as in the lower rank order of neuroblastoma in Taiwan 3. Within developing countries other distributions have been reported, such as the top ranking of retinoblastoma in some areas of India and Pakistan 4. Furthermore, there are also important differences in the biologic characteristics of individual cancers in infants by comparison with older children, as exemplified by the clinical and molecular phenotypes of acute lymphoblastic leukaemia 5. In this symposium the topics of neuroblastoma, leukemias, brain tumors and retinoblastoma were addressed respectively by Dr. Robert Castleberry, Dr. Johann Hitzler and Dr. Lewis Silverman, Dr. Eric Bouffet and Dr. Brenda Gallie. The management of chemotherapy in the very young can be particularly challenging as emphasized by Dr. Gideon Koren. Supportive care of infants with cancer poses additional problems. The issues of nutrition, pain and immunization were discussed by Dr. Paul Pencharz with Mary Barron, Dr. Bonnie Stevens and Dr. Upton Allen, respectively. While the survival prospects overall for children with cancer in the first year of life are poor by comparison with those of older children, one notable exception is that of neuroblastoma 1. But what of other outcome measures? Very little information exists on the health status and health-related quality of life in survivors of cancer in infancy. Given the developmental status of these children and the intensity of therapy to which they are commonly exposed, it is likely that the burden of morbidity in survivors will be high. In addition, the journey from diagnosis through the treatment experience to survivorship can have major adverse effects on families, as described by Dr. Anne Kazak. The occurrence of cancer early in life has provided remarkable insights to the pathogenesis of malignant disease, likely linked to antenatal etiologies as exemplified by tumor suppressor genes 6. The hardship experienced by infants with cancer and their families may be offset somewhat if clinical and laboratory-based investigators take advantage of the learning opportunities provided by these disorders to devise more effective interventions with better therapeutic outcomes based on enhanced understanding of cancers in the very young.

Molecular-pathological prognostic factors of gastric cancer: a review

Invasion and metastasis are critical determinants of cancer morbidity. Genes and molecules participating in these steps must be regarded as potential prognostic factors. Growth factors and their receptors, cell-cycle regulators, cell-adhesion molecules and matrix-degrading enzymes are those to be used as prognostic factors, including epidermal growth factor (EGF), EGF receptor, K-sam, HER-2, interleukin (IL)-8, vascular endothelial growth factor (VEGF), cyclin E, p27, E-cadherin, CD44v6, matrix metalloproteinase-1 (MMP-1), and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1). Alterations in epigenetics, such as aberrant DNA methylation and histone modification that are, in part, associated with the tumor progression of gastric cancer, can be candidate prognostic factors. The number of methylated genes may serve as a marker of tumor progression. Genetic polymorphism not only affects cancer susceptibility but also influences malignant phenotype; examples include single-nucleotide polymorphism in the HER-2 and MMP-9 genes. Comprehensive gene expression analyses are useful to search for novel genes related to invasion and metastasis and potential prognostic factors. Serial analysis of gene expression (SAGE) has identified several these genes, such as CDH17, APOE, FUS, COL1A1, COL1A2, GW112, and MIA. Overexpression of MIA is found to be associated with poor prognosis. Microarray analysis has great potential for identifying the characteristics of individual cancers, from the view point of gene expression profiles. A combination of these examinations can not only foretell a patient's prognosis but can also give information directly connected with personalized cancer medicine and prevention.

Causes of physician delay in the diagnosis of breast cancer.

Understanding sources of physician delay in diagnosis of breast cancer will assist efforts to expedite diagnosis. To test whether increased reliance on screening mammography has affected causes of physician delay in diagnosis of breast cancer. Survey of delays in a case series. Practice specializing in breast diseases in a region with high use of screening mammography. Four hundred thirty-five consecutive patients treated for 454 breast cancers of any stage. Customary patient care. Whether delay was related to how cancer was identified, patient age, individual cancer characteristics (such as tumor type), mammography reports, or physician expertise. Twenty-one women (5%) were inappropriately reassured that a malignant lump was benign without biopsy, 14 women (3%) had a misread mammogram, 4 women (1%) had a misread pathologic finding, and 5 women (1%) had cancer missed by a poorly performed fine-needle aspiration biopsy. Delay was associated with a benign mammography report (relative risk, 10.8; 95% confidence interval, 5.1-22.8), a woman finding her own mass (relative risk, 3.3; 95% confidence interval, 1.8-6.2), and current hormone replacement therapy (relative risk, 3.1; 95% confidence interval, 1.2-8.5). The leading cause of physician delay in diagnosis of breast cancer continues to be inappropriate reassurance that a mass is benign without biopsy. Reducing delay in diagnosis will require less willingness to rely on clinical examination to decide that a mass is benign, less reliance on benign mammography reports to decide not to biopsy a mass, and a requirement that fine-needle aspiration biopsy be done by persons with demonstrated competence for the procedure.

Molecular diagnosis of gastric cancer: present and future.

Although histopathological diagnosis is extremely useful for the definitive as well as the supportive diagnosis of gastric cancer in clinical practice, it is limited in certain respects. Over the past 15 years, integrated research in molecular pathology has clarified the details of genetic and epigenetic abnormalities of cancer-related genes in the course of the development and progression of gastric cancer. These abnormalities, which include telomerase activation, genetic instability, and abnormalities in oncogenes, tumor suppressor genes, cell-cycle regulators, cell adhesion molecules, and DNA repair genes, could be effective markers in the molecular diagnosis of gastric cancer. It is possible that the molecular analysis of these alterations in histopathology specimens may overcome deficiencies in diagnoses that depend only on histomorphology, and, consequently, we may be able to improve the differential diagnosis of cancer, obtain information on the grade of malignancy, and identify patients at high risk of developing multiple primary cancers. In Hiroshima, we have established a system of molecular-pathological diagnosis as a routine service; about 5,000 lesions of the stomach have been subjected to this diagnosis, and much useful information has been obtained. In the near future, genetic analysis by means of DNA microarray may become routine in the diagnosis of gastric cancer. Genetic analysis of histopathology specimens may make clear the characteristics of individual cancers; indicating the common and specific features of molecular pathogenesis that may be directly connected with gene therapy or molecular-targeted therapy. By analyzing the relationship between single-nucleotide polymorphisms and cancer susceptibility, we will be able to obtain information on cancer prevention from histopathology samples.