Giuseppe Curigliano

Pertuzumab and trastuzumab with or without metronomic chemotherapy for older patients with HER2-positive metastatic breast cancer (EORTC 75111-10114): an open-label, randomised, phase 2 trial from the Elderly Task Force/Breast Cancer Group

BACKGROUND Despite the high incidence of metastatic breast cancer and its related mortality in the elderly population, our knowledge about optimal treatment for older patients with cancer is far from adequate. We aimed to evaluate the efficacy of dual anti-HER2 treatment with or without metronomic chemotherapy in older patients with HER2-positive metastatic breast cancer. METHODS We did a multicentre, open-label, randomised, phase 2 trial in 30 centres from eight countries in Europe, in patients with histologically proven, HER2-positive metastatic breast cancer, without previous chemotherapy for metastatic disease, who were 70 years or older, or 60 years or older with confirmed functional restrictions defined by protocol, and had a life expectancy of more than 12 weeks and a performance status according to WHO scale of 0-3. Eligible patients were randomly assigned (1:1) by an online randomisation system based on the minimisation method to receive metronomic oral cyclophosphamide 50 mg per day plus trastuzumab and pertuzumab, or trastuzumab and pertuzumab alone. Trastuzumab was given intravenously with a loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks. Pertuzumab was given intravenously with a loading dose of 840 mg, followed by 420 mg every 3 weeks. Patients were stratified by hormone receptor positivity, previous HER2 treatment, and baseline geriatric screening. The primary endpoint was investigator-assessed progression-free survival at 6 months as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. A difference of 10% or greater between the two groups was sought. Efficacy analyses were by intention to treat; safety was assessed in all patients who received at least one dose of study treatment. In case of progression, all patients were offered trastuzumab emtansine. This trial is registered with ClinicalTrials.gov, number NCT01597414, and is completed. FINDINGS Between July 2, 2013, and May 10, 2016, 80 patients, of whom 56 (70%) had a potential frailty profile according to the geriatric screening G8 score (≤14), were randomly assigned to receive trastuzumab and pertuzumab (n=39) or trastuzumab and pertuzumab plus metronomic oral cyclophosphamide (n=41). Estimated progression-free survival at 6 months was 46·2% (95% CI 30·2-60·7) with trastuzumab and pertuzumab versus 73·4% (56·6-84·6) with trastuzumab and pertuzumab plus metronomic oral cyclophosphamide (hazard ratio [HR] 0·65 [95% CI 0·37-1·12], p=0·12). At a median follow-up of 20·7 months (IQR 12·5-30·4), the median progression-free survival was 5·6 months (95% CI 3·6-16·8) with trastuzumab and pertuzumab versus 12·7 months (6·7-24·8) with the addition of metronomic oral cyclophosphamide. The most frequent grade 3-4 adverse events were hypertension (in six [15%] of 39 patients in the trastuzumab and pertuzumab group vs five [12%] of 41 in the trastuzumab and pertuzumab plus metronomic oral cyclophosphamide group), diarrhoea (four [10%] vs five [12%]), dyspnoea (two [5%] vs four [10%]), fatigue (three [8%] vs two [5%]), pain (two [5%] vs two [5%]), and a thromboembolic event (0 [0%] vs four [10%]). Severe cardiac toxicities were occasionally observed in both groups. In the trastuzumab and pertuzumab group four patients died without progression, due to cardiac arrest during treatment (n=1), peritoneal infection (n=1), respiratory failure (n=1), and sudden death without a specified cause (n=1). In the trastuzumab and pertuzumab plus metronomic oral cyclophosphamide group, one patient died from heart failure. INTERPRETATION Addition of metronomic oral cyclophosphamide to trastuzumab plus pertuzumab in older and frail patients with HER2-positive metastatic breast cancer increased median progression-free survival by 7 months compared with dual HER2 blockade alone, with an acceptable safety profile. Trastuzumab and pertuzumab plus metronomic oral cyclophosphamide, followed by trastuzumab emtansine after disease progression, might delay or supersede the need for taxane chemotherapy in this population. FUNDING F Hoffmann-La Roche.

Immunotherapy of Breast Cancer.

Cancer immunoediting is the process by which the immune system protects the host from tumor development and guides the somatic evolution of tumors by eliminating highly immunogenic tumor cells. A fundamental dogma of tumor immunology and of cancer immunosurveillance in particular is that cancer cells express antigens that differentiate them from their nontransformed counterparts. Molecular studies clearly show that these antigens were often products of mutated cellular genes, aberrantly expressed normal genes, or genes encoding viral proteins. There is a strict correlation between genetic instability and the immune landscape of a breast cancer. Mutational heterogeneity in breast cancer is associated with new cancer-associated genes and new cancer antigens. Frequencies of somatic mutations or mutational burden can be related to the immunogenicity of breast cancer. We believe that molecular subtypes of breast cancer that are triple negative, luminal B-like or HER2-positive have a high mutational burden and can be considered immunogenic. The increasing knowledge of the immune systems capacity to not only recognize and destroy cancer, but also to shape cancer immunogenicity will develop more informed attempts to control cancer via immunological approaches. To be effective in breast cancer, immunotherapies will have to increase the quality or quantity of immune effector cells, reveal additional protective tumor antigens, and/or eliminate cancer-induced immunosuppressive mechanisms. Multiple immunotherapy approaches are under investigation in patients with breast cancer. These include vaccine approaches to elicit strong specific immune responses to tumor antigens such as WT-1, HER2 and NY-ESO-1, approaches involving adoptive transfer of in vitro-expanded, naturally arising or genetically engineered tumor-specific lymphocytes, therapeutic administration of monoclonal antibodies to target and eliminate tumor cells, and approaches that inhibit or destroy the molecular or cellular mediators of cancer-induced immunosuppression, such as CTLA-4, PD-1 or Treg cells. Here we provide a concise and comprehensive review on the role and utility of promising immunotherapeutics for the treatment of patients with breast cancer.

A rude awakening from tumour cells

In women who have had breast cancer, drug treatments are often stopped five years after removal of the primary tumour. A meta-analysis shows that these individuals are still at risk of relapse. In women who have had breast cancer, drug treatments are often stopped five years after removal of the primary tumour. A meta-analysis shows that these individuals are still at risk of relapse.

Gyneco-oncological genomics and emerging biomarkers for cancer treatment with immune-checkpoint inhibitors

In gynecological cancers tumor infiltrating lymphocytes and upregulation of immune-related gene signatures have been associated with a better prognosis. Knowledge of tumor immunogenicity and associated gene signatures suggests that the tumor immune landscape is a key determinant to define patient prognosis and potentially to predict response to immune-checkpoint inhibitors. The aim of this review is to give an overview of immune gene signatures across gynecology histological cancer types, defining their prognostic and potential predictive role. In the current review we will present data on these gene signatures, on immunohistochemical features and their potential importance to select patients potentially eligible to trials with immune-checkpoint inhibitors.

Precision Trial Drawer, a Computational Tool to Assist Planning of Genomics-Driven Trials in Oncology

PurposeTrials that accrue participants on the basis of genetic biomarkers are a powerful means of testing targeted drugs, but they are often complicated by the rarity of the biomarker-positive population. Umbrella trials circumvent this by testing multiple hypotheses to maximize accrual. However, bigger trials have higher chances of conflicting treatment allocations because of the coexistence of multiple actionable alterations; allocation strategies greatly affect the efficiency of enrollment and should be carefully planned on the basis of relative mutation frequencies, leveraging information from large sequencing projects.MethodsWe developed software named Precision Trial Drawer (PTD) to estimate parameters that are useful for designing precision trials, most importantly, the number of patients needed to molecularly screen (NNMS) and the allocation rule that maximizes patient accrual on the basis of mutation frequency, systematically assigning patients with conflicting allocations to the drug associated ...

Clinical efficacy of ribociclib as a first-line therapy for HR-positive, advanced breast cancer

ABSTRACT Introduction: 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.

Inflammatory breast cancer and chest wall disease: The oncologist perspective

Chest wall inflammatory and lymphangitic breast cancer represents a clinical spectrum and a model disease. Inflammation and the immune response have a role in the natural history of this special clinical presentation. Preclinical models and biomarker studies suggest that inflammatory breast cancer comprises a more important role for the tumour microenvironment, including immune cell infiltration and vasculogenesis, especially lympho-angiogenesis. Across this clinical continuum of the chest wall disease there is an important role of the inflammation cascade. The activation of mature dendritic cells (DCs) through toll like receptors (TLRs) or by inflammatory cytokines converts immature DCs into mature DCs that present specific antigen to T cells, thereby activating them. Maturation of DCs is accompanied by co-stimulatory molecules and secretion of inflammatory cytokines polarizing lymphocytic, macrophages and fibroblast infiltration. It is unknown whether immune cells associated to the IBC microenvironment play a role in this scenario to transiently promote epithelial to mesenchymal transition (EMT) in these cells. Immune and microenvirnment factors can induce phenotypic, morphological, and functional changes in breast cancer cells. We can hypothesize that similar inflammatory conditions in vivo may support both the rapid metastasis and tight tumor emboli that are characteristic of chest wall disease and that targeted anti-inflammatory therapy may play a role in this patient population. The current review will review biological and clinical data of this special condition.

Profile of buparlisib and its potential in the treatment of breast cancer: evidence to date [Corrigendum]

[This corrects the article on p. 23 in vol. 10, PMID: 29430197.].

Profile of buparlisib and its potential in the treatment of breast cancer: evidence to date

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.

Targeting Immune Checkpoint

Tumor cell transformation prompts to activation of adaptive and innate immune responses, which had a crucial role in eliminating and controlling early cancer growth. Over the past 10 years, there has been a greater understanding of the immune response to tumors which has led to the development of a huge number of immunotherapeutic strategies [1, 2]. The immune system plays a dual role in cancer: it not only can suppress tumor growth by destroying cancer cells or inhibiting their outgrowth but also promotes tumor progression either by selecting for tumor cells that are more fit to survive in an immunocompetent host or by establishing conditions within the tumor microenvironment that facilitate tumor outgrowth. The conceptual framework called “cancer immunoediting” integrates the immune system’s dual host-protective and tumor-promoting roles. Nonetheless, numerous studies have shown that tumors can be recognized and contained for extended periods of time by the immune response through the concerted action of the innate and adaptive immune responses [3]. Agents such as the immune checkpoint inhibitors have demonstrated to induce a response in a number of solid malignancies [4], but their therapeutic benefit has not been seen in all cancer types. The initial enthusiasm for immune checkpoint inhibitors is mainly based on results obtained in melanoma, lung cancer, bladder cancer, and renal cell carcinoma [5]. But also in breast cancer (BC), preliminary data from the first clinical studies is encouraging.