Sheeba Irshad

Genomic scars as biomarkers of homologous recombination deficiency and drug response in breast and ovarian cancers

Poly (ADP-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapies have been found to be particularly effective in tumors that harbor deleterious germline or somatic mutations in the BRCA1 or BRCA2 genes, the products of which contribute to the conservative homologous recombination repair of DNA double-strand breaks. Nonetheless, several setbacks in clinical trial settings have highlighted some of the issues surrounding the investigation of PARP inhibitors, especially the identification of patients who stand to benefit from such drugs. One potential approach to finding this patient subpopulation is to examine the tumor DNA for evidence of a homologous recombination defect. However, although the genomes of many breast and ovarian cancers are replete with aberrations, the presence of numerous factors able to shape the genomic landscape means that only some of the observed DNA abnormalities are the outcome of a cancer cell’s inability to faithfully repair DNA double-strand breaks. Consequently, recently developed methods for comprehensively capturing the diverse ways in which homologous recombination deficiencies may arise beyond BRCA1/2 mutation have used DNA microarray and sequencing data to account for potentially confounding features in the genome. Scores capturing telomeric allelic imbalance, loss of heterozygosity (LOH) and large scale transition score, as well as the total number of coding mutations are measures that summarize the total burden of certain forms of genomic abnormality. By contrast, other studies have comprehensively catalogued different types of mutational pattern and their relative contributions to a given tumor sample. Although at least one study to explore the use of the LOH scar in a prospective clinical trial of a PARP inhibitor in ovarian cancer is under way, limitations that result in a relatively low positive predictive value for these biomarkers remain. Tumors whose genome has undergone one or more events that restore high-fidelity homologous recombination are likely to be misclassified as double-strand break repair-deficient and thereby sensitive to PARP inhibitors and DNA damaging chemotherapies as a result of prior repair deficiency and its genomic scarring. Therefore, we propose that integration of a genomic scar-based biomarker with a marker of resistance in a high genomic scarring burden context may improve the performance of any companion diagnostic for PARP inhibitors.

Molecular heterogeneity of triple-negative breast cancer and its clinical implications.

Purpose of review Triple-negative breast cancer (TNBC) is defined by a lack of expression of hormone receptors, oestrogen and progesterone, as well as human epidermal factor receptor 2. This review focuses on the increasing understanding of the molecular heterogeneity of TNBC subtypes and the therapeutic implications of this subclassification. Recent findings Emerging evidence clearly indicates that TNBC is a heterogeneous disease with varying prognosis according to clinical, pathological and genetic factors. Some distinct histological special types within this clinically defined collection of entities have been shown to have a particularly good prognosis (e.g. medullary carcinomas), and others very poor outcome (e.g. metaplastic carcinomas), whereas the broader immunohistochemically defined ‘core-basal-like’ or gene expression defined ‘basal’ groups generally have a poor prognosis. This molecular subclassification has implicated several biological processes as potential therapeutic targets: the DNA damage response, drivers of deregulated proliferation, angiogenesis, epithelial–mesenchymal transition and immune deregulation. Summary Molecular stratification of these prognostic groups has been critical in identifying novel therapeutic targets for future drug development. The development of poly-(ADP)ribose polymerase inhibitors for BRCA1-mutation carriers with TNBC has led the ongoing efforts to translate fundamental biological insights into improved therapies for a difficult-to-treat breast cancer subgroup.

Therapeutic potential of PARP inhibitors for metastatic breast cancer

Increasing understanding of the cellular aberrations inherent to cancer cells has allowed the development of therapies to target biological pathways, an important step towards individualization of breast cancer therapy. The clinical development of poly(ADP-ribose) polymerase (PARP) inhibitors, with their novel and selective mechanism of action, are an example of this strategy. PARP plays a key role in DNA repair mechanisms, particularly the base excision repair pathway. Initially developed as inhibitors able to enhance the cytotoxicity of radiation and certain DNA-damaging agents, they have more recently been shown to have single-agent activity in certain tumors. Inhibition of PARP in a DNA repair-defective tumor can lead to gross genomic instability and cell death by exploiting the paradigm of synthetic lethality. Several studies have evaluated the role of PARP inhibitors for treatment of breast cancer, particularly in the context of BRCA-mutated and triple-negative breast cancers. In addition, inhibition of PARPs repair functions for chemotherapy-induced DNA lesions has been shown to potentiate the effect of some chemotherapy regimens. This article discusses the current understanding of PARP inhibition as a treatment for metastatic breast cancer, evidence from clinical trials and addresses its future implications.

RORγt+ innate lymphoid cells promote lymph node metastasis of breast cancers

Cancer cells tend to metastasize first to tumor-draining lymph nodes, but the mechanisms mediating cancer cell invasion into the lymphatic vasculature remain little understood. Here, we show that in the human breast tumor microenvironment (TME), the presence of increased numbers of RORγt+ group 3 innate lymphoid cells (ILC3) correlates with an increased likelihood of lymph node metastasis. In a preclinical mouse model of breast cancer, CCL21-mediated recruitment of ILC3 to tumors stimulated the production of the CXCL13 by TME stromal cells, which in turn promoted ILC3-stromal interactions and production of the cancer cell motile factor RANKL. Depleting ILC3 or neutralizing CCL21, CXCL13, or RANKL was sufficient to decrease lymph node metastasis. Our findings establish a role for RORγt+ILC3 in promoting lymphatic metastasis by modulating the local chemokine milieu of cancer cells in the TME. Cancer Res; 77(5); 1083-96. ©2017 AACR.

The use of molecular imaging combined with genomic techniques to understand the heterogeneity in cancer metastasis

Tumour heterogeneity has, in recent times, come to play a vital role in how we understand and treat cancers; however, the clinical translation of this has lagged behind advances in research. Although significant advancements in oncological management have been made, personalized care remains an elusive goal. Inter- and intratumour heterogeneity, particularly in the clinical setting, has been difficult to quantify and therefore to treat. The histological quantification of heterogeneity of tumours can be a logistical and clinical challenge. The ability to examine not just the whole tumour but also all the molecular variations of metastatic disease in a patient is obviously difficult with current histological techniques. Advances in imaging techniques and novel applications, alongside our understanding of tumour heterogeneity, have opened up a plethora of non-invasive biomarker potential to examine tumours, their heterogeneity and the clinical translation. This review will focus on how various imaging methods that allow for quantification of metastatic tumour heterogeneity, along with the potential of developing imaging, integrated with other in vitro diagnostic approaches such as genomics and exosome analyses, have the potential role as a non-invasive biomarker for guiding the treatment algorithm.

Unilateral Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia and Multiple Carcinoids Treated with Surgical Resection

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare pulmonary disorder with less than 50 reported cases in the literature. DIPNECH belongs to the group of preinvasive lesions defined by the 1999 World Health Organization classification, including atypical adematous hyperplasia and squamous dysplasia–carcinoma in situ.1 DIPNECH refers to collections of scattered single cells, small nodules, or linear proliferations of neuroendocrine cells, without invasion beyond the basement membrane, sometimes accompanied by chronic inflammation or fibrosis1. It is reserved only for cases in which the hyperplasia is diffuse and primary in nature. DIPNECH has a predilection for nonsmoking middle-aged females and is associated with a predominantly obstructive ventilatory defect, typically in association with obliterative bronchiolar fibrosis2. The most common symptoms include nonproductive cough and exertional dyspnea, and patients are commonly misdiagnosed as bronchial asthma or chronic bronchitis.

Profiling the immune stromal interface in breast cancer and its potential for clinical impact.

Advances in DNA sequencing technologies, as well as refined bioinformatics methods for interpretation of complex datasets, have provided the opportunity to comprehensively assess gene expression in tumours and their surrounding microenvironment. More recently, these advances have highlighted the interplay between the immune effector mechanisms and breast cancer cell biology, emphasizing the long-recognized link between immunity and cancer. Studying immune-associated genes has not only resulted in further stratification within the broad pathological types of breast cancers, but also provided further biological insights into the complex heterogeneity within breast cancer subgroups. On the basis that anti-cancer therapies can modify the host-tumour interaction, investigators have focused their attention on the predictive value of immune parameters as markers of therapeutic anti-tumour response. We discuss the current status of immune signatures in breast cancer and some of the fundamental limitations that need to be overcome to move these discoveries into clinic.

Imaging tumour heterogeneity of the consequences of a PKCα-substrate interaction in breast cancer patients.

Breast cancer heterogeneity demands that prognostic models must be biologically driven and recent clinical evidence indicates that future prognostic signatures need evaluation in the context of early compared with late metastatic risk prediction. In pre-clinical studies, we and others have shown that various protein-protein interactions, pertaining to the actin microfilament-associated proteins, ezrin and cofilin, mediate breast cancer cell migration, a prerequisite for cancer metastasis. Moreover, as a direct substrate for protein kinase Cα, ezrin has been shown to be a determinant of cancer metastasis for a variety of tumour types, besides breast cancer; and has been described as a pivotal regulator of metastasis by linking the plasma membrane to the actin cytoskeleton. In the present article, we demonstrate that our tissue imaging-derived parameters that pertain to or are a consequence of the PKC-ezrin interaction can be used for breast cancer prognostication, with inter-cohort reproducibility. The application of fluorescence lifetime imaging microscopy (FLIM) in formalin-fixed paraffin-embedded patient samples to probe protein proximity within the typically <10 nm range to address the oncological challenge of tumour heterogeneity, is discussed.

AllergoOncology: Opposite outcomes of immune tolerance in allergy and cancer

While desired for the cure of allergy, regulatory immune cell subsets and nonclassical Th2‐biased inflammatory mediators in the tumour microenvironment can contribute to immune suppression and escape of tumours from immunological detection and clearance. A key aim in the cancer field is therefore to design interventions that can break immunological tolerance and halt cancer progression, whereas on the contrary allergen immunotherapy exactly aims to induce tolerance. In this position paper, we review insights on immune tolerance derived from allergy and from cancer inflammation, focusing on what is known about the roles of key immune cells and mediators. We propose that research in the field of AllergoOncology that aims to delineate these immunological mechanisms with juxtaposed clinical consequences in allergy and cancer may point to novel avenues for therapeutic interventions that stand to benefit both disciplines.

Crosstalk between Innate Lymphoid Cells and Other Immune Cells in the Tumor Microenvironment

Our knowledge and understanding of the tumor microenvironment (TME) have been recently expanded with the recognition of the important role of innate lymphoid cells (ILC). Three different groups of ILC have been described based on their ability to produce cytokines that mediate the interactions between innate and adaptive immune cells in a variety of immune responses in infection, allergy, and autoimmunity. However, recent evidence from experimental models and clinical studies has demonstrated that ILC contribute to the mechanisms that generate suppressive or tolerant environments that allow tumor regression or progression. Defining the complex network of interactions and crosstalk of ILC with other immune cells and understanding the specific contributions of each type of ILC leading to tumor development will allow the manipulation of their function and will be important to develop new interventions and therapeutic strategies.