: Despite dramatic improvements in survival achieved with currently available anti-HER2 agents, HER2-positive metastatic breast cancer remains an almost invariably deadly disease, with primary or ...acquired resistance to HER2-directed agents developing during treatment. Many efforts are focused on identifying new agents that may more effectively inhibit HER2 signaling and on possible combination strategies.
: This review summarizes the landscape of drugs under development for HER2-positive metastatic breast cancer, as antibody-drug conjugates, monoclonal anti-HER2 antibodies, bispecific antibodies, or novel tyrosine kinase inhibitors. Moreover, available data for possible combination of anti-HER2 drugs and different agents, as immunotherapy, PI3K/mTOR inhibitors, CDK4/6 inhibitors currently under evaluation are reviewed. These strategies may overcome mechanisms of resistance and further improve patient outcomes.
: Identification of valuable predictive biomarkers is needed to better inform choice of treatment sequence for the individual patient and limit the financial toxicity of these agents.
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-β 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.
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.
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.
Alteration of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin signaling pathway is key for the growth and survival of several cancers, including breast cancer. In addition, ...dysregulation of PI3K signaling may contribute to resistance to several anticancer agents. PI3K inhibitors may, therefore, be effective as antineoplastic therapy. Buparlisib is a potent and highly specific oral inhibitor of the pan-class I PI3K family. Buparlisib specifically inhibits class I PIK3 in the PI3K/AKT kinase signaling pathway in an ATP-competitive manner, thus inhibiting the production of the secondary messenger phosphatidylinositol (3,4,5)-trisphosphate and activation of the PI3K signaling pathway. This may induce inhibition of tumor cell growth and survival in susceptible tumor cell populations. Buparlisib is currently under investigation in patients with a variety of solid tumors, including breast cancer. Buparlisib has been validated as a promising anticancer agent, and tremendous efforts have been taken to develop it. However, buparlisib monotherapy has resulted in humble benefit so far. Results from studies combining buparlisib with different anticancer agents - namely, endocrine therapy, anti-HER2 therapy, and chemotherapy - have showed variable efficacy with consistent substantial toxicity.
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Background: Peripheral blood parameters, such as neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (dNLR), platelet-to-lymphocyte ratio (PLR), ...lymphocyte-to-monocyte ratio (LMR) and LDH level, have been correlated to immunotherapy (IO) benefit in melanoma and lung cancer. We investigated if peripheral blood parameters could have the same predictive role in a variety of solid tumors treated with either single-agent IO or IO combinations. Methods: Baseline (0 to 14 days from treatment start) blood parameters, including NLR, dNLR, PLR, LMR and LDH, were collected in patients (pts) with metastatic solid tumors treated in phase I trials testing anti-PD-1/PD-L1 single agent (N = 59) and anti-PD-1/PD-L1-based combinations (N = 94), including combinations with immune checkpoint inhibitors/agonists or other agents. IO benefit was assessed for overall survival (OS), progression free survival (PFS), overall response rate (ORR), disease control rate (DCR), and 90-day mortality rate. Logistic regression, Kaplan-Meier method, and Cox regression were carried out to evaluate the impact of clinical and baseline blood parameters on IO efficacy. Results: From Aug2014 to May2019, 153 pts were included median age 58 (32-80). Female/male ratio was 1.47:1 (91 females/62 males). The most common tumors were gastrointestinal, breast, and gynecological cancers (22.9%, 22.2%, and 15.0%, respectively). Sixty pts (39.2%) had received more than two lines of therapy. Overall, ORR, DCR, and 90-day mortality were 11.8%, 34.9%, and 15.7%, respectively. At multivariate analysis, LDH higher than upper limit of normal (ULN) was associated with reduced DCR (LDH ≤ULN vs > ULN: 50.8% vs 20.8%, OR 0.25, 95%CI 0.1-0.62, p = .003) and increased 90-day mortality (LDH ≤ULN vs > ULN: 7.9% vs 24.5%, OR 3.59, 95%CI 1.18-10.9, p = .025). At a median follow-up of 25.9 months (22.3-29.6), 138 pts (90.2%) experienced tumor progression and 117 (77.0%) had died. At multivariate Cox regression analysis, LDH > ULN and dNLR > 3 were independently associated with reduced PFS (LDH > ULN: HR 1.97, 95%CI 1.30-2.99, p < .001; dNLR > 3: HR 2.29, 95%CI 1.39-3.77, p < .001) and reduced OS (LDH > ULN: HR 2.04, 95%CI 1.26-3.28, p = .004; dNLR > 3: HR 2.06, 95%CI 1.12-3.79, p = .02). Conclusions: Our analysis confirms that baseline LDH > ULN and dNLR > 3 are predictive biomarkers for IO efficacy, regardless of tumor type and combinations with other drugs, representing an easy tool that deserves prospective validation in IO-based clinical trials.
Abstract The main rationale for neoadjuvant therapy for breast cancer is to provide effective systemic treatment while surgically down-staging the cancer. This down-staging was initially to convert ...inoperable patients to operable and later to increase rates of breast conservation in patients initially deemed mastectomy only candidates. Unexpectedly, in recent neoadjuvant trials lower rates of breast conservation have been observed than in past decades, despite remarkable advances in systemic therapies, which have increased pathologic complete response rates. These results point to factors aside from response and eligibility for breast conservation that may lead surgeons and/or patients to recommend and choose mastectomy. Here, we aim to examine the surgical benefits offered by the modern era neoadjuvant therapy and explore factors that have contributed to this decrease in breast conservation rates. If the main benefit of neoadjuvant therapy is to increase the opportunity for breast conservation, then our review suggests that to optimize less invasive surgical approaches, we will need to address both surgeon and patient-level variables and biases that may be limiting our ability to identify patients appropriate for less aggressive options. As an oncology community, we must be aware of the surgical overtreatment of breast cancer, especially in a time where systemic therapies have remarkably improved outcomes and responses.
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.
Breast cancer (BC) remains the most frequently diagnosed cancer and the most common cause of cancer death among women of all races worldwide. Over 80% of BC cases are hormone receptor (HR)-positive, ...comprised of luminal A and luminal B per molecular subtypes, imposing an urgent need to fully understand the mechanisms behind progression. Ribociclib is a selective cycline-dependent kinase 4 and 6 inhibitor. A phase 1 and a phase 3 trial have established a definitive role of ribociclib as frontline in the treatment of endocrine-sensitive advanced BC. Areas covered: Herein, the authors provide an overview of the data on ribociclib covering all aspects of the drug from its pharmacokinetics to efficacy and safety. The authors also provide their perspectives for the future. Expert opinion: Ribociclib is offering an opportunity to explore a new compound at the crossroads of different molecular activity and cell targets, which focus on endocrine-resistance reversal in multiple settings including early BC. Moreover, its activity against different subtypes of BC is being studied as is its immune-modulating effect. One cautionary note is that, in a market of concomitant similar competitors, a financial discussion will be mandatory.
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