Oncolytic Viruses in the Treatment of Cancer: A Review of Current Strategies

Oncolytic viruses are live, replication-competent viruses that replicate selectively in tumor cells leading to the destruction of the tumor cells. Tumor-selective replicating viruses offer appealing advantages over conventional cancer therapy and are promising a new approach for the treatment of human cancer. The development of virotherapeutics is based on several strategies. Virotherapy is not a new concept, but recent technical advances in the genetic modification of oncolytic viruses have improved their tumor specificity, leading to the development of new weapons for the war against cancer. Clinical trials with oncolytic viruses demonstrate the safety and feasibility of an effective virotherapeutic approach. Strategies to overcome potential obstacles and challenges to virotherapy are currently being explored. Systemic administrations of oncolytic viruses will successfully extend novel treatment against a range of tumors. Combination therapy has shown some encouraging antitumor responses by eliciting strong immunity against established cancer.     

Hormonal Resistance in Breast Cancer: Evolving Treatment Strategies

About 70% of breast cancers are hormone receptor (HR) positive, meaning an estrogen receptor (ER) and/or a progesterone receptor (PgR) are present in the tumor. Compounds that modulate ER or PgR signaling, by either competing for estrogen binding to estrogen receptors (synthetic estrogen receptor modulators [eg, tamoxifen]) or opposing the production of estrogen in the body (aromatase inhibitors in postmenopausal women), are dominant among those used to treat HR-positive breast cancer. Although HR-positive tumors are associated with a better prognosis, in the case of advanced disease, most will develop resistance to hormonal treatments over time. Multiple mechanisms of endocrine resistance have been proposed, including ER receptor loss and cross-talk between the ER and HER2/neu (human epidermal growth factor receptor 2; also known as ErbB-2) receptor signaling pathways. The phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homologue deleted on chromosome ten (PTEN)/Akt/mammalian target of rapamycin (mTOR) pathway is often implicated in sensitivity and resistance to therapy. Dysregulated signaling through the PI3K/PTEN/Akt/mTOR pathway may result from genetic alterations in critical components in this pathway. Therapeutic targeting of alternate pathways of growth signaling in ER-positive tumors has the potential to translate into practice-changing therapeutic strategies. This article discusses the concept of primary and secondary endocrine resistance, outlines the proposed mechanisms, and reviews the emerging evidence for interventions designed to overcome resistance and restore ER sensitivity. The recently reported result of the BOLERO-2 study using an mTOR inhibitor (everolimus or RAD001) in combination with an aromatase inhibitor (exemestane) is discussed in some detail.     

Triple-Negative Breast Cancer: A Review of Current Curative Intent Therapies

Breast cancer is the most commonly diagnosed malignancy in women, with triple-negative breast cancer (TNBC) accounting for 10–20% of cases. Historically, fewer treatment options have existed for this subtype of breast cancer, with cytotoxic chemotherapy playing a predominant role. This article aims to review the current treatment paradigm for curative-intent TNBC, while also reviewing potential future developments in this landscape. In addition to chemotherapy, recent advances in the understanding of the molecular biology of TNBC have led to promising new studies of targeted and immune checkpoint inhibitor therapies in the curative-intent setting. The appropriate selection of TNBC patient subgroups with a higher likelihood of benefit from treatment is critical to identify the best treatment approach.     

Genetic Heterogeneity in Breast Cancer Susceptibility

Approximately 20% of breast cancer patients have a family history of the disease, and in one-fourth of these cases breast cancer appears to be inherited as an autosomally dominant trait. Five genes and gene regions involved in breast cancer susceptibility have been uncovered. Germ-line mutations in the recently cloned BRCA1 gene at 17q21 is considered to be responsible for the disease in a majority of the breast-ovarian cancer families and in 40-45% of the site-specific breast cancer families, but appears not to be involved in families with both male and female breast cancer cases. The BRCA2 locus at 13q12-q13 appears to be involved in 40-45% of the site-specific breast cancer families, and in most of the families with affected males. The gene located in this region, however, does not seem to confer susceptibility to ovarian cancer. The TP53 gene is involved in breast cancer development in the Li-Fraumeni syndrome and Li-Fraumeni syndrom-like families, whereas germ-line mutations in the androgen receptor (AR) gene is present in a subset of male breast cancers. Furthermore, females who are obligate carriers of ataxia telangiectasia (AT) have a 4-12 times relative risk of developing breast cancer as compared with the general female population, indicating that germ-line mutations in AT also confer susceptibility to breast cancer.     

Molecular Heterogeneity of Triple-Negative Breast Cancer

Triple-negative breast cancers (TNBCs) are a group of aggressive breast cancers with a greater incidence of relapse, stage-for-stage, than ER/PR-positive and HER2-positive breast cancers, despite optimum loco-regional and systemic therapy. To date, no single targeted therapy has been approved for treatment of TNBC, and cytotoxic chemotherapy remains the standard systemic treatment. Recently, gene expression analysis identified six distinct TNBC subtypes, each with unique biology. In this review we discuss current and forthcoming therapeutic strategies and novel approaches to targeted treatment of these TNBC subtypes.     

Current and Emerging Treatment Strategies for Anal Cancer

Concurrent radiotherapy and chemotherapy (5-fluorouracil and mitomycin-C) is established as a sphincter-preserving treatment for squamous cell carcinoma of the anal canal. However, there is room for improvement in rates of tumor control as well as a need to reduce treatment-induced toxicity. Efforts are underway to test the value of newer radiosensitizing chemotherapeutic and molecular targeted agents, as well as to establish the value of advances in radiation therapy planning and delivery. This review discusses the evolution of therapy for anal cancer, from early clinical trials establishing the current standard to more recent studies evaluating cisplatin, capecitabine, oxaliplatin, and cetuximab. Early clinical results from studies incorporating intensity-modulated radiation therapy are also discussed.     

Heterogeneity of Triple-Negative Breast Cancer: Histologic Subtyping to Inform the Outcome

BackgroundThis study assesses outcome in terms of disease-free survival (DFS) and overall survival (OS) of special types of triple-negative breast cancer (TNBC).Patients and MethodsWe identified 8801 women with first primary nonmetastatic breast cancer operated on at the European Institute of Oncology between 1997 and 2005. Of these patients, 781 consecutive patients with immunohistochemically defined TNBC were selected for the analyses. We explored patterns of recurrence by histologic type. Median follow-up was 5.7 years (range 0-13 years).ResultsThe 5-year DFS was 77% for TNBC, 68% for human epidermal growth factor receptor 2 (HER2)-positive breast cancer, and 84% and 95% for luminal B and luminal A breast cancer, respectively. From 781 TNBC subtypes, 693 cases (89%) were classified as ductal not otherwise specified (NOS) (invasive ductal carcinoma [IDC]), 29 were classified as apocrine (3.7%), 18 (2.3%) were classified as lobular, 10 (1.2%) were classified as adenoid cystic, and 10 (1.2%) were classified as metaplastic. Five-year DFS and OS were 77% and 84% for patients with ductal carcinoma, 56% and 89% for patients with metaplastic carcinoma, and both 5-year DFS and OS were 100% for patients with adenoid cystic and medullary carcinomas, respectively.ConclusionDistinct prognostic implications may derive from the specific histotype of TNBC. The identification of these special types has a significant clinical utility and should be considered in therapeutic algorithms.     

Early-stage Triple-negative Breast Cancer: Time to Optimize Personalized Strategies

Triple-negative breast cancer (TNBC) accounts for approximately 15%-20% of breast cancers diagnosed worldwide, which amounts to almost 200 000 cases each year. Although historically TNBC is considered difficult to treat with a poor prognosis, there is emerging evidence showing excellent response rates in a subset of TNBC patients. Attempts to de-escalate chemotherapy in hormone-receptor-positive (HR+) and HER2-neu amplified breast cancer subtypes have been successful. At present, robust strategies to personalize therapy in early-stage TNBC do not exist, and despite excellent response rates in a subset of patients, all patients are exposed to the same several cycles of cytotoxic chemotherapy. Personalizing therapy in TNBC represents a challenge due to the scarcity of treatment options outside of cytotoxic chemotherapy and limited predictive and prognostic biomarkers to tailor treatment. Recent developments in understanding TNBC biology have sparked interest in exploring treatment optimization and personalization with the goal of achieving excellent response rates and long-term clinical outcomes, while simultaneously reducing physical, psychological, and financial toxicities for select patients. Here, we provide an update on the current evidence to support future studies examining de-escalating chemotherapy in patients with low-risk TNBC and adjuvant intensification strategies to improve outcomes for patients who are at high risk for systemic failure despite current standard-of-care treatments.     

Treatment of Early Breast Cancer with Conservation of the Breast a Review

This paper reviews the current status of conservative treatment for early breast cancer. While the first patients were treated with such techniques more than 60 years ago, it is during the last decade that randomized trials have confirmed that such treatment is comparable to mastectomy in preventing breast cancer death. Radiotherapy to the breast after local tumour excision is important to prevent local breast relapse, but it is not clear whether it has any influence on the risk of distant metastases. Several questions remain to be answered. While most investigators agree that the breast should receive a radiation dose of about 50 Gy in 5 weeks, there is no general agreement about the need for a tumour bed booster dose. Considering patients with tumour infiltration at the surgical resection line for whom it is not possible for cosmetic reasons to perform re-resection, it is not clear whether an acceptable local control rate can be achieved through application of a high booster dose in the tumour bed. More trials are needed to show whether certain patients with small invasive carcinomas should be treated with wide local excision without radiotherapy. The need for radiotherapy after local excision for small intraductal (ductal carcinoma in situ) cancers is being addressed in ongoing trials.     

Breast Cancer Heterogeneity: Roles in Tumorigenesis and Therapeutic Implications

Purpose of review

Breast cancer heterogeneity constitutes a significant investigational and therapeutic challenge. Here we review recent findings on breast cancer heterogeneity, focusing on its extent across the distinct molecular subtypes, the degree of spatial and temporal intra-tumor heterogeneity, and possible approaches to dissect and counteract it.

Recent findings

Recent massively parallel sequencing studies have solidified the notion that estrogen receptor (ER)-positive and ER-negative breast cancers have divergent genetic landscapes. Numerous studies have addressed the origins of heterogeneity and the challenges it poses for patient management; however, its dynamic evolution in the light of novel targeted therapies is yet to be fully understood.

Summary

Tumor heterogeneity poses diagnostic and therapeutic challenges. Implementation of novel methodologies, such as single cell sequencing and analysis of cell-free DNA, might afford us the means to comprehend intra-tumor heterogeneity with greater precision, and to overcome the diagnostic and therapeutic challenges posed by it.

     

Current Status and Problems of Breast Cancer Treatment with Schizophrenia

BackgroundSchizophrenia is a devastating mental disease that affects approximately 1% of the world's population. Breast cancer is the second most common type of cancer in the world that causes death in women. It is often unclear whether patients with schizophrenia receive recommended cancer treatment that met the guideline. This study characterized breast cancer treatment disruptions in schizophrenia patients and sought to identify and resolve correctable predictors of those disruptions.Materials and methodsA retrospective cohort study was conducted on 55 primary breast cancer patients diagnosed with schizophrenia and treated for breast cancer. We evaluated the characteristics of the breast cancer patients with schizophrenia compared to those of 610 breast cancer patients without schizophrenia.ResultsCompared to the control group, the schizophrenia group had significantly advanced T and N factors and disease stage. Significantly fewer patients in the schizophrenia group than in the control group received chemotherapy (P < .0001) or recommended cancer treatment (P = .0004). Within the schizophrenia group, the patients in need of ADL support were significantly less likely to receive recommended cancer treatment.ConclusionPatients with schizophrenia are often diagnosed with breast cancer in advanced stages. In addition, patients with schizophrenia with reduced ADL are less likely to receive chemotherapy or recommended cancer treatment. It is highly recommended that patients with schizophrenia undergo breast cancer screening so that they can be diagnosed early and treated adequately.     

Current Approach to Breast Cancer Risk Reduction for Women with Hereditary Predispositions to Breast Cancer

Risk reduction strategies for women at an increased risk for breast cancer include prophylactic mastectomy, prophylactic salpingo-oophorectomy, and chemoprevention. These techniques have been well studied in certain high-risk populations such as women with significant family histories of breast cancer and women with BRCA1 and BRCA2 mutations. Rapid evolution in genetic testing technology has enabled increased access and ability to analyze genes associated with an increased risk for breast cancer. These genes include but are not limited to BRCA1 and BRCA2. This technological progress has expanded the definition and number of women classified as having a genetic predisposition to breast cancer; however, literature specifically evaluating efficacy of breast cancer risk reduction strategies in this expanded population does not yet exist. In order to appreciate the effectiveness of risk-reducing strategies for women with a hereditary predisposition to breast cancer, we provide an overview of current literature and recommendations for risk-reducing mastectomy, risk-reducing salpingo-oophorectomy, and chemoprevention in the high-risk breast cancer population.     

Anti-Angiogenic Strategies in Breast Cancer: An Update

Angiogenesis plays a role in primary tumor growth and metastatic potential of breast cancer, and within the past decade, the development of angiogenesis inhibitors has been a significant focus of clinical research efforts. Multiple studies to date have confirmed a role for bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), in combination with chemotherapy in the treatment of metastatic breast cancer. Efforts to determine the efficacy of second-generation VEGF receptor antagonists in breast cancer patients are ongoing. In addition, trials are underway to investigate potential synergy between anti-angiogenic agents and other classes of breast cancer therapeutics and to examine the efficacy of angiogenesis inhibition in nonmetastatic disease. Preliminary work evaluating predictors of response to therapy, including serologic biomarkers, class-effect toxicity, or dynamic radiologic change, and pharmacogenetics, has been promising; however, future study is critical to best identify the patient population most likely to benefit from anti-angiogenic therapy.     

Intratumoral Heterogeneity in Breast Cancer: A Comparison of Primary and Metastatic Breast Cancers

Intratumoral heterogeneity presents challenges in the management of cancer. To gain deeper insight in intratumoral heterogeneity at different levels and tumor sites for common biomarkers in breast cancers, this report examines seven cases of invasive breast cancer with multiple axillary nodal metastases and/or recurrences for immunohistochemical expression of estrogen receptors, progesterone receptors, human epidermal growth receptor 2, and Ki67 on all tissue blocks in both primary and metastatic tumors.     

Breast Cancer Classification to Select Patients for Cancer Treatment

Gene expression arrays have shown that breast cancer is comprised of at least four different molecular diseases. These are 1) basal-like breast cancer, 2) human epidermal growth factor receptor 2 (Her2)-positive/estrogen receptor (ER)-negative breast cancer; 3) luminal A breast cancer; and 4) luminal breast B cancer. Basal-like cancer is characterized by ER-negative, progesterone receptor–negative, and Her2-negative expressions. Luminal breast cancer is characterized by ER-positive expression, with the luminal B subtype exhibiting a higher expression of proliferation genes. Several studies have shown that luminal A breast cancer exhibits a better outcome compared with other classes. Also, recent studies have shown that the same subclass is less chemosensitive. These data suggest that some selected luminal A breast cancer cases could be spared adjuvant chemotherapy given their better outcome and lesser chemosensitivity compared with other subtypes of breast cancer. Although other subtypes are more chemosensitive, there is debate about whether some drugs could be active in specific subtypes. Anthracyclines have been reported to be more effective in Her2-overexpressing breast cancer, and cisplatin is currently under investigation in basal-like breast cancer. Finally, some data suggest that luminal B breast cancer exhibits higher sensitivity to aromatase inhibitors. Overall, molecular classes exhibit different sensitivity to conventional drugs. To what extent these data obtained in retrospective biomarker studies could be implemented in daily practice is a matter of debate given the heterogeneity of findings in different studies.     

Coping Strategies Among Couples Adjusting to Primary Breast Cancer

Abstract

In psychosocial oncology social support is a recognized factor in facilitating adaptation to cancer. Spouses are often the first source of support for each other. However, the adaptation process of couples dealing with cancer has been little explored. This article presents the results of a qualitative study carried out with 16 couples, in each of which the woman had breast cancer. The goal of this study was to better understand the manner in which the couple as a dyad deals with the disruptions and demands related to the disease and its treatments. This report highlights the principal issues that confront couples in the first year after diagnosis and the adjustment strategies they use to deal with these issues. A theoretical understanding of the adjustment process of couples dealing with breast cancer emerges as a result of this study.     

First-Line Treatment for Endocrine-Sensitive Bone-Only Metastatic Breast Cancer: Systematic Review and Meta-analysis

In the last decade, several clinical trials have investigated novel endocrine combinations for the first-line treatment of hormone receptor–positive metastatic breast cancer. Nevertheless, the use of combinations for the first-line treatment of bone-only disease is widely discussed as a result of its indolent natural history. We performed a comprehensive search of phase 3 randomized clinical trials published in the literature through September 2018. Our aim was to explore the role of the new endocrine approaches in bone-only metastatic breast cancer, suggesting a possible strategy for their selection. In particular, we evaluated the comparative risk of adverse event occurrence during these treatments. A total of 6 studies were deemed suitable for meta-analysis: the Monaleesa-2, Monaleesa-7, Monarch-3, Paloma-2, SWOG, and Alliance trials. Overall, the novel strategies were shown to improve progression-free survival in bone-only disease (hazard ratio = 0.65; 95% confidence interval, 0.49-0.86; P = .003). Combinations with cyclin-dependent kinase inhibitors improved progression-free survival (hazard ratio = 0.54; 95% confidence interval, 0.39-0.75; P < .001) with an acceptable toxicity profile. Abemaciclib was associated with increased anemia and gastrointestinal toxicity (especially diarrhea), whereas palbociclib was associated with increased leukopenia (but not neutropenia) compared to the other compounds. Increased aspartate aminotransferase levels were reported for both ribociclib and abemaciclib. The combination of cyclin-dependent kinase 4/6 inhibitors and endocrine therapy represents an effective and well-tolerated approach for first-line treatment in bone-only disease settings. Because no direct comparison between the 3 cyclin-dependent kinase 4/6 inhibitors is available, the selection of the most appropriate treatment should be based on toxicity profile as well as patient preference and copathologies.     

Characterization of Weakly Hormone Receptor (HR)-Positive,HER2-Negative Breast Cancer and Current Treatment Strategies

BackgroundHormone receptor (HR) and human epidermal growth factor receptor-2 (HER2) status is critical for determining management of breast cancer. Previous reports of small cohorts with weak HR-positive (HR+)/HER2-negative (HER2-) disease showed similar rates of pathologic complete response (pCR) following neoadjuvant chemotherapy (NAC) as triple negative breast cancer (TNBC). This study aims to further characterize this group, focusing on pCR rates following NAC.Patients and MethodsPatients with stage I-III, HR+/HER2- breast cancer were identified using the University of Wisconsin Hospital Cancer Registry. Medical records were reviewed for demographics, tumor characteristics with quantification level of estrogen and progesterone receptor (≤33%), treatment, and follow-up data.ResultsData was reviewed from 2,900 patients and a total of 64 patients met inclusion criteria. Eighty percent received chemotherapy, about half with NAC (n = 30, 48%). Of 28 patients who received NAC followed by breast and axillary surgery, 12 (43%; 95% CI 25%-63%) had pCR (ypT0/Tis/ypN0). Of the 11 patients who had biopsyproven nodal disease at diagnosis and NAC followed by axillary surgery, 7 (64%, 95% CI 31%-89%) patients had pCR at the axilla. Only one patient with pCR developed recurrent disease. For those that recurred, median time to recurrence was 13.6 (5.6-48.7) months.ConclusionsBreast cancers that are HER2- and weakly HR+ treated with NAC demonstrated pCR rate more similar to TNBC than breast cancers that are strong HR+. Neoadjuvant approaches may improve pCR rates, which provides important prognostic information. Clinical trials should be developed to focus on this unique patient cohort.