Immune approaches to the treatment of breast cancer, around the corner?

Immunotherapy for the treatment of breast cancer can be categorized as either (a) specific stimulation of the immune system by active immunization, with cancer vaccines, or (b) passive immunization, such as tumor-specific antibodies (including immune modulators) or adoptive cell therapy that inhibit the function of, or directly kill, tumor cells. We will present the current information and the future perspectives of immunotherapy in patients with breast cancer, including the prognostic role of tumor infiltrating lymphocytes, immune signatures, targeted therapies modulating the immune system, and tumor antigen cancer vaccines. Active immunotherapy in breast cancer and its implementation into clinical trials have been largely a frustrating experience in the last decades. The concept that the immune system regulates cancer development is experiencing a new era of interest. It is clear that the cancer immunosurveillance process indeed exists and potentially acts as an extrinsic tumor suppressor. Also, the immune system can facilitate tumor progression by sculpting the immunogenic phenotype of tumors as they develop. Cancer immunoediting represents a refinement of the cancer immunosurveillance hypothesis and resumes the complex interaction between tumor and immune system into three phases: elimination, equilibrium, and escape. Major topics in the field of immunology deserve a response: what do we know about tumor immunogenicity, and how might we therapeutically improve tumor immunogenicity? How can we modulate response of the immune system? Is there any gene signature predictive of response to immune modulators? The success of future immunotherapy strategies will depend on the identification of additional immunogenic antigens that can serve as the best tumor-rejection targets. Therapeutic success will depend on developing the best antigen delivery systems and on the elucidation of the entire network of immune signaling pathways that regulate immune responses in the tumor microenvironment.

Biopsy confirmation of metastatic sites in breast cancer patients: clinical impact and future perspectives.

Determination of hormone receptor (estrogen receptor and progesterone receptor) and human epidermal growth factor receptor 2 status in the primary tumor is clinically relevant to define breast cancer subtypes, clinical outcome,and the choice of therapy. Retrospective and prospective studies suggest that there is substantial discordance in receptor status between primary and recurrent breast cancer. Despite this evidence and current recommendations,the acquisition of tissue from metastatic deposits is not routine practice. As a consequence, therapeutic decisions for treatment in the metastatic setting are based on the features of the primary tumor. Reasons for this attitude include the invasiveness of the procedure and the unreliable outcome of biopsy, in particular for biopsies of lesions at complex visceral sites. Improvements in interventional radiology techniques mean that most metastatic sites are now accessible by minimally invasive methods, including surgery. In our opinion, since biopsies are diagnostic and changes in biological features between the primary and secondary tumors can occur, the routine biopsy of metastatic disease needs to be performed. In this review, we discuss the rationale for biopsy of suspected breast cancer metastases, review issues and caveats surrounding discordance of biomarker status between primary and metastatic tumors, and provide insights for deciding when to perform biopsy of suspected metastases and which one (s) to biopsy. We also speculate on the future translational implications for biopsy of suspected metastatic lesions in the context of clinical trials and the establishment of bio-banks of biopsy material taken from metastatic sites. We believe that such bio-banks will be important for exploring mechanisms of metastasis. In the future,advances in targeted therapy will depend on the availability of metastatic tissue.

Impact of autoimmune diseases on outcome of patients with early breast cancer.

Our aim was to analyze the impact of a concurrent autoimmune disease on outcome of patients with early breast cancer. We reviewed medical charts of patients with a diagnosis of autoimmune diseases (AD) among a population of 17.153 cases. We categorized ADs as endocrine, rheumatic, systemic, neurological diseases and vasculitis. For each patient in the study group, we matched 2 patients. The events to determine overall survival (OS) and disease free survival (DFS) were identified from follow-up data. We identified 279 (1.62%) patients with early breast cancer and concurrent ADs. The median follow-up was 7.0 years. The 10-year OS rate was 86% (95% CI, 80% to 91%) in the study group and 90% (95% CI, 86% to 93%) for the control group (p = 0.011). In patients with ER positive/HER2 negative subtype a worse OS was observed in the study group when compared to the control group (p = 0.0046); this difference remained statistically significant when the analysis was restricted to breast cancer mortality (p = 0.045). The 10-year DFS rate was 69% (95% CI, 61% to 76%) in the study group and 72% (95% CI, 66% to 77%) for the control group (p = 0.22). Autoimmunity at diagnosis of early breast cancer is associated with worse survival.

Mechanisms of anorexia-cachexia syndrome and rational for treatment with selective ghrelin receptor agonist.

Cancer cachexia is a multi-organ, multifactorial and often irreversible syndrome affecting many patients with cancer. Cancer cachexia is invariably associated with weight loss, mainly from loss of skeletal muscle and body fat, conditioning a reduced quality of life due to asthenia, anorexia, anaemia and fatigue. Treatment options for treating cancer cachexia are limited. The approach is multimodal and may include: treatment of secondary gastrointestinal symptoms, nutritional treatments, drug, and non-drug treatments. Nutritional counselling and physical training may be beneficial in delaying or preventing the development of anorexia-cachexia. However, these interventions are limited in their effect, and no definitive pharmacological treatment is available to address the relevant components of the syndrome. Anamorelin is a first-in-class, orally active ghrelin receptor agonist that binds and stimulates the growth hormone secretagogue receptor centrally, thereby mimicking the appetite-enhancing and anabolic effects of ghrelin. It represents a new class of drug and an additional treatment option for this patient group, whose therapeutic options are currently limited. In this review we examine the mechanisms of anamorelin by which it contrasts catabolic states, its role in regulation of metabolism and energy homeostasis, the data of recent trials in the setting of cancer cachexia and its safety profile.

Crosstalk between bone niche and immune system: osteoimmunology signaling as a potential target for cancer treatment.

There is a well recognized link between the bone and the immune system and in recent years there has been a major effort to elucidate the multiple functions of the molecules expressed in both bone and immune cells. Several molecules that were initially identified and studied in the immune system have been shown to have essential functions also in the bone. An interdisciplinary field embracing immune and bone biology has been brought together and called "osteoimmunology". The co-regulation of the skeletal and immune systems strikingly exemplifies the extreme complexity of such an interaction. Their interdependency must be considered in designing therapeutic approaches for either of the two systems. In other words, it is necessary to think of the osteoimmune system as a complex physiological unit. Denosumab was originally introduced to specifically target bone resorption, but it is now under evaluation for its effect on the long term immune response. Similarly, our current and still growing knowledge of the intimate link between the immune system and bone will be beneficial for the safety of drugs targeting either of these integrated systems. Given the large number of molecules exerting functions on both the skeletal and immune systems, osteoimmunological understanding is becoming increasingly important. Both bone and immune systems are frequently disrupted in cancer; and they may be crucial in regulating tumor growth and progression. Some therapies - such as bisphosphonates and receptor activator of NF-κB ligand (RANKL) targeted drugs - that aim at reducing pathologic osteolysis in cancer may interact with the immune system, thus providing potential favorable effects on survival.

Investigational platelet-derived growth factor receptor kinase inhibitors in breast cancer therapy.

INTRODUCTION: Aberrant regulation of platelet-derived growth factors (PDGFs) and their receptors (PDGFR) has been shown to be involved in many solid tumors, including breast cancer. PDGFR-α and PDGFR-ß expressions were documented in breast cancer and are correlated with tumor aggressiveness and metastasis. Preclinical evidence further suggests tumor stimulatory roles of PDGFRs expressed by tumor stroma cells and indicates a deleterious effect of stromal PDGFRs on intratumoral drug uptake. AREAS COVERED: This review summarizes the present understanding of PDGF signaling in breast cancer based on experimental studies and available clinical trials. It also provides a critical discussion of selected ongoing clinical trials in patients with breast cancer involving PDGFR inhibition with tyrosine kinase inhibitors, specifically in endocrine responsive breast cancer. EXPERT OPINION: An increased molecular understanding of response and resistance mechanisms to endocrine therapy will be essential for therapeutic advances in PDGFR-directed cancer therapy. Future developments in the field will rely on clinical studies where prospective analyses of target expression in breast cancer cells and in the tumor stroma are included. More selective PDGFR inhibitors with reduced side effects will be crucial for combinatorial therapies. Development of sensitive diagnostics is of critical importance for patient selection and monitoring of therapeutic effects.

Immune checkpoint blockade in cancer treatment: a double-edged sword cross-targeting the host as an "innocent bystander".

Targeted immune checkpoint blockade augments anti-tumor immunity and induces durable responses in patients with melanoma and other solid tumors. It also induces specific "immune-related adverse events" (irAEs). IrAEs mainly include gastrointestinal, dermatological, hepatic and endocrinological toxicities. Off-target effects that arise appear to account for much of the toxicity of the immune checkpoint blockade. These unique "innocent bystander" effects are likely a direct result of breaking immune tolerance upon immune check point blockade and require specific treatment guidelines that include symptomatic therapies or systemic corticosteroids. What do we need going forward to limit immune checkpoint blockade-induced toxicity? Most importantly, we need a better understanding of the roles played by these agents in normal tissues, so that we can begin to predict potentially problematic side effects on the basis of their selectivity profile. Second, we need to focus on the predictive factors of the response and toxicity of the host rather than serially focusing on individual agents. Third, rigorous biomarker-driven clinical trials are needed to further elucidate the mechanisms of both the benefit and toxicity. We will summarize the double-edged sword effect of immunotherapeutics in cancer treatment.

Monitoring tumor-derived cell-free DNA in patients with solid tumors: clinical perspectives and research opportunities.

Circulating cell-free DNA represents a non-invasive biomarker, as it can be isolated from human plasma, serum and other body fluids. Circulating tumor DNA shed from primary and metastatic cancers may allow the non-invasive analysis of the evolution of tumor genomes during treatment and disease progression through 'liquid biopsies'. The serial monitoring of tumor genotypes, which are instable and prone to changes under selection pressure, is becoming increasingly possible. The "liquid biopsy" provide novel biological insights into the process of metastasis and may elucidate signaling pathways involved in cell invasiveness and metastatic competence. This review will focus on the clinical utility of circulating cell free DNA in main solid tumors, including genetic and epigenetic alterations that can be detected.

Dendritic cell-based vaccines: clinical applications in breast cancer.

Recent evidence suggests that the immune system is involved in the carcinogenesis process and the antitumor immune responses impact the clinical outcome, thus emphasizing the concept of cancer immune surveillance. In this context, dendritic cells (DCs) seem to play a crucial role, as they are the most potent antigen-presenting cells (APCs) and are able to stimulate naive T lymphocytes and to generate memory T lymphocytes. Immunotherapy with DC-based vaccines is a very attractive approach to treat cancer, offering the potential for high tumor-specific cytotoxicity. Although breast cancer (BC) is traditionally considered a poorly immunogenic tumor, increasing numbers of both preclinical and clinical studies demonstrate that vaccination with DCs is capable of inducing an antitumor-specific response, while being well tolerated and safe. However, clinical objective responses are still disappointing and many reasons may explain the difficulty of developing effective DC-based therapies for BC. In this review, we discuss the characteristics of DCs, and the major clinical indications for DC-based immunotherapy in BC with related drawbacks.

High Ki-67 score is indicative of a greater benefit from adjuvant chemotherapy when added to endocrine therapy in luminal B HER2 negative and node-positive breast cancer.

BACKGROUND: The indication of adjuvant chemotherapy for patients with highly proliferative estrogen receptor-positive breast cancer is controversial. We analyzed the predictive value of Ki67 for the efficacy of adjuvant chemotherapy in patients with estrogen receptor-positive, node-positive breast cancer. PATIENTS AND METHODS: We identified 1241 patients with Luminal B early stage breast cancer with 1-3 axillary positive nodes who underwent surgery between 1995 and 2005 at the European Institute of Oncology and received adjuvant hormonotherapy and/or chemotherapy. Differences in the distribution of characteristics according to treatment were evaluated by the Chi-square test. To evaluate the effect of adding chemotherapy to hormonotherapy, the propensity score method was used to match patients' characteristics minimizing bias related to the non-random assignment of treatment. RESULTS: The probability of receiving chemotherapy was significantly associated with age, tumor grade, degree of hormone responsiveness, tumor size and peripheral vascular invasion. The propensity score distribution was statistically different between the two treatment groups (p < 0.0001). The 5-year OS percentages were 95.8% (95% CI, 93.5-97.2) in the hormonotherapy group and 96.2% (95%CI, 94.4-97.4%) in the hormonotherapy/chemotherapy group (log-rank test p-value 0.663). The 5-year DFS percentages were 84.6% (95% CI, 81.0-87.6%) in the hormonotherapy group and 84.2% (95% CI, 81.3-86.7%) in the hormonotherapy/chemotherapy group (log-rank test p-value 0.388). However, when analyzing the 5-year DFS by Ki-67 distribution, Subpopulation Treatment Effect Pattern Plot (STEPP) analysis showed a beneficial effect of chemotherapy in patients with highly proliferative tumor (Ki-67 ≥ 32%). The interaction between Ki-67 and treatment was statistically significant (p = 0.027). CONCLUSIONS: Ki67 expression identifies a subset of patients with Luminal B and node-positive breast cancer who could benefit from addition of adjuvant chemotherapy to hormonotherapy. Dichotomy was observed for Ki67 at 32% level.

Molecular pathways: human leukocyte antigen G (HLA-G).

Human leukocyte antigen G (HLA-G) is a nonclassical MHC class I molecule that exerts important tolerogenic functions. Its main physiologic expression occurs in the placenta, where it participates in the maternal tolerance toward the fetus. HLA-G expression was found in embryonic tissues, in adult immune privileged organs, and in cells of the hematopoietic lineage. It is expressed in various types of primary solid (melanoma, head and neck, lung, urogenital, gastrointestinal, and breast cancers) and hematologic malignancies (acute leukemia, lymphomas) and metastases. HLA-G ectopic expression is observed in cancer, suggesting that its expression is one strategy used by tumor cells to escape immune surveillance. In this review, we will focus on HLA-G expression in cancers and its association with the prognosis. We will highlight the underlying molecular mechanisms of impaired HLA-G expression, the immune tolerant function of HLA-G in tumors, and the potential diagnostic use of membrane-bound and soluble HLA-G as a biomarker to identify tumors and to monitor disease stage. As HLA-G is a potent immunoinhibitory molecule, its blockade remains an attractive therapeutic strategy against cancer. Elimination of HLA-G-expressing cancer cells would be important in the efficacy of anticancer therapies.

Developing an effective breast cancer vaccine: challenges to achieving sterile immunity versus resetting equilibrium.

INTRODUCTION: Evading immune destruction is an emerging hallmark of cancer. Immunotherapy of cancer is categorized as either specific stimulation of the immune system by active immunization, with cancer vaccines, or passive transfer of humor or cellular materials, such as, tumor specific antibodies (including immunomodulators) or adoptive cell therapy that inhibit the function of- or directly kill tumor cells. Modulation of immune response in cancer patients is the result of a balanced activity of T regulators and T effector cells. METHODS AND RESULTS: We will present the current information and the prospects for the future of immunotherapy in patients with breast cancer including tumor antigens for vaccines and targets for monoclonal antibodies and adoptive T-cell therapy. DISCUSSION: Active immunotherapy in breast cancer and its implementation into clinical trials has largely been a frustrating experience in the last decades. After many years of controversy, the concept that the immune system regulates cancer development is experiencing a new resurgence. It is clear that the cancer immunosurveillance process indeed exists and potentially acts as an extrinsic tumor suppressor. It has been also clear that the immune system can facilitate tumor progression by sculpting the immunogenic phenotype of tumors as they develop. Cancer immunoediting represents a refinement of the cancer immunosurveillance hypothesis and resumes the complex interaction between tumor and immune system into three phases: elimination, equilibrium, and escape. CONCLUSION: What do we know about tumor immunogenicity and how might we therapeutically improve tumor immunogenicity? The first vaccine and the first immunomodulating agent were recently approved by the US Food and Drug Administration (FDA) for the treatment of prostate cancer (sipuleucel-T) and melanoma (ipilimumab), respectively. The success of future immunotherapy strategies will depend on the identification of additional immunogenic antigens that can serve as the best tumor-rejection targets. Therapeutic success will depend on developing the best antigen delivery systems and on the elucidation of the entire network of immune signalingsignaling pathways that regulate immune responses in the tumor microenvironment.

Induction therapy and stem cell mobilization in patients with newly diagnosed multiple myeloma.

Autologous stem cell transplantation (ASCT) is considered the standard therapy for younger patients with newly diagnosed symptomatic multiple myeloma (MM). The introduction into clinical practice of novel agents, such as the proteasome inhibitor bortezomib and the immunomodulatory derivatives (IMiDs) thalidomide and lenalidomide, has significantly contributed to major advances in MM therapy and prognosis. These novel agents are incorporated into induction regimens to enhance the depth of response before ASCT and further improve post-ASCT outcomes. Between January 2000 and November 2011, 65 patients with MM were transplanted in the Department of Biomedical Science and Clinical Oncology at the University of Bari. According to Durie-Salmon, 60 patients had stage III of disease and 5 stage II. Only 7 patients were in stage B (renal failure). Induction regimens that were administered in two or more cycles were VAD (vincristine, adriamycin, and dexamethasone), Thal-Dex (thalidomide, dexamethasone), Len-Dex (lenalidomide, dexamethasone), Vel-Dex (bortezomib, dexamethasone), VTD (bortezomib, thalidomide, and dexamethasone), and PAD (bortezomib, pegylated liposomal doxorubicin, and dexamethasone). In mobilization procedure, the patients received cyclophosphamide and granulocyte colony-stimulating factor (G-CSF). The number of cells collected through two or more leukapheresess, response after induction, and toxicity were evaluated to define the more adequate up-front induction regimen in transplantation-eligible MM patients.