Many antihuman epidermal growth factor receptor (anti-HER2)-targeted agents, covering a broad spectrum of mechanisms of action, have been recently developed. The concept of dual anti-HER2 blockade ...has been preclinically and clinically assessed with positive results. In this article, the authors review the biologic rationale for dual HER2 blockade, along with the clinical findings.
Dual anti-HER2 blockade has been assessed in the metastatic setting, including with chemotherapy-free regimens, leading to impressive responses, even in heavily pretreated patients. In the neoadjuvant setting, dual anti-HER2 blockade combinations and chemotherapy have almost doubled the rates of pathologic complete response compared to single anti-HER2 therapy. Similar strategies are now actively being pursued in the adjuvant setting and, it is hoped, will improve the outcome of many patients with HER2-positive breast cancer.
Combining different anti-HER2-targeted agents represents a promising therapeutic strategy, now reaching clinical practice. There are major clinical challenges yet to be resolved, rising from the increasing number of potential combinations and their mechanisms of resistance. Smartly designed clinical trials are required to address these challenges and perhaps to define a subset of patients that can be spared chemotherapy.
The APHINITY (BIG 4-11) study showed that pertuzumab significantly improved the rates of invasive disease-free survival among patients with human epidermal growth factor receptor 2 (HER2)-positive, ...operable breast cancer when added to adjuvant trastuzumab and chemotherapy. Because diarrhea was a common adverse event that could compromise treatment administration, we evaluated the incidence and management of diarrhea in the APHINITY study.
The APHINITY trial is a prospective, randomized, multicenter, multinational, double-blind, placebo-controlled trial. The eligible patients were randomly assigned to receive standard adjuvant chemotherapy and 1 year of trastuzumab combined with pertuzumab or placebo. The diarrhea incidence, severity (National Cancer Institute common terminology criteria for adverse events, version 4.0), onset, and management were analyzed.
A total of 4805 patients were randomized. Diarrhea of any grade was the most common adverse event and occurred in 71% of patients in the pertuzumab arm versus 45% in the placebo arm. Diarrhea grade 3 to 4 was observed in 10% and 4% in the pertuzumab and placebo arms, respectively. The greatest incidence of diarrhea was reported during the concomitant administration of HER2-targeted therapy and taxane (61% vs. 34% of patients experienced an event with pertuzumab vs. placebo, respectively). A marked decrease was observed on chemotherapy cessation. Antidiarrheal agents were commonly used, and diarrhea rarely caused treatment dose modifications or discontinuation.
Diarrhea was a common adverse event in the APHINITY study. Most episodes were low grade and were generally manageable with common antidiarrheal agents. The incidence of diarrhea was greater with the combination of a taxane and HER2-targeted treatment and decreased once chemotherapy was stopped.
In the APHINITY study, a randomized adjuvant trial that included 4805 patients, diarrhea was a common adverse event. The incidence was higher with the combination of a taxane and human epidermal growth factor receptor 2-targeted treatment and decreased after chemotherapy was stopped. Most episodes were low grade and manageable with common antidiarrheal agents.
This is a summary of a paper published in a medical journal that describes the results of a study called CheckMate 274. This study looked at a new treatment for muscle-invasive urothelial cancer, a ...type of cancer found in the urinary tract that has spread from the inner lining of the urinary tract or bladder and into the surrounding muscle wall where it can then spread to other parts of the body. The standard treatment for muscle-invasive urothelial cancer is surgery to remove affected parts of the urinary tract. However, cancer returns in more than half of people after this surgery. Adjuvant therapy is given to people after surgery with muscle-invasive urothelial cancer with a goal to reduce the risk of the cancer coming back; however, at the time this study started, there was no standard adjuvant treatment.
In the CheckMate 274 study, researchers compared nivolumab with a placebo as an adjuvant treatment for people with muscle-invasive urothelial cancer. The aim of the study was to understand how well nivolumab worked to reduce the chance of the cancer returning after surgery. The study also looked at what side effects (unwanted or unexpected results or conditions that are possibly related to the use of a medication) people had with treatment.
The results showed that people who received nivolumab versus placebo: Survived longer before the cancer was detected again, including people who had programmed death ligand-1 (shortened to PD-L1) on their cancer cells. Survived longer before a secondary cancer outside of the urinary tract was detected. Experienced no differences in health-related quality of life (the impact of the treatment on a person's mental and physical health). Had similar side effects to the people who received nivolumab in other studies.
: NCT02632409 (ClinicalTrials.gov).
This study sought to determine whether an autoimmune background could identify patients with HER2-positive early breast cancer (EBC) who derive differential benefit from primary adjuvant ...trastuzumab-based therapy.
HERA is an international randomized trial of 5,102 women with HER2-positive EBC, who were enrolled to either receive adjuvant trastuzumab or not. In this exploratory analysis, the interaction between autoimmune history and the magnitude of trastuzumab benefit was evaluated.
A total of 5,099 patients were included in the current analysis. Among them, 325 patients (6.4%) had autoimmune disease history, 295 of whom had active disease. Patients were randomly assigned to trastuzumab or no-trastuzumab groups. Similar reductions in the risk of events in patients with and without autoimmune history were observed (interaction p=0.95 for disease-free survival, and p=0.62 for overall survival).
No evidence of a differential benefit from trastuzumab in patients with a medical history of autoimmune disease was found.
HER2-positive breast cancer (BC) constitutes a molecular subtype of the disease with an aggressive biologic behavior. Trastuzumab revolutionized the treatment of this disease, changing its natural ...history. Lapatinib is active in the metastatic setting, approved for patients who were pretreated with trastuzumab. However, resistance to anti-HER2 agents is a major clinical issue, occurring in both early-stage and advanced disease, and new treatment options are clearly needed. An abundance of HER2-targeted agents are being clinically developed: monoclonal antibodies, small molecule inhibitors, and antibody drug conjugates (ADC). Combining HER2-targeted agents in regimens of dual HER2 blockade has already reached clinical practice in the metastatic setting, confirming the preclinical efficacy of enhanced HER2 inhibition. Promising results have been generated in the neoadjuvant setting, and large randomized trials are seeking evidence for dual HER2 blockade in the adjuvant setting. ADC represent another hope for improved treatment outcomes of HER2-positive BC, as exemplified by the positive results of clinical trials employing trastuzumab-DM1 (trastuzumab emtansine, T-DM1). Moreover, an understanding of the molecular mechanisms mediating resistance to HER2 blockade has opened new therapeutic avenues, with several targeted agents entering clinical trials. This paper presents the clinical data of the HER2-targeted agents under development, as well as an overview of the biologic rationale for the development of agents aimed at circumventing anti-HER2 resistance.
The National Cancer Institute of the United States defines personalized medicine (PM) as “a form of medicine that uses information about a person’s genes, proteins and environment to prevent, ...diagnose and treat disease” (National Cancer Institute, Dictionary of Cancer Terms)
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. Consequently, the ultimate dream is the generation of a “molecular fingerprint” via a simple blood test or tumor sample that allows the physician to refine an individual patient’s prognosis, select the best possible therapeutic option, and minimize the toxicity from therapies by identification of distinct genetic markers. The enormous gains to patients and ultimately health care systems are unmistakable.
Abstract Background/aims Considerable evidence has indicated that apoptosis plays an important role in hepatocyte death in chronic liver disease. However, the cellular and molecular mechanisms ...underlying liver regeneration in these diseases are largely unknown. Plausibly, certain molecules expressed to counteract apoptosis might provide survival advantage of certain liver cells. Therefore, we investigated a possible expression of decoy receptor 3 of the tumour necrosis factor receptor family in chronic liver diseases since decoy receptor 3 is known to inhibit apoptosis mediated by pro-apoptotic tumour necrosis factor family ligands including Fas ligand. Methods A series of liver biopsies from patients with different stages of fibrosis were subjected to immunohistochemistry and in situ hybridization. Results Both decoy receptor 3 protein and mRNA were mainly expressed in biliary epithelial cells and infiltrating lymphocytes in the diseased livers. Most noticeably, intense decoy receptor 3 expression was observed in newly developing biliary ductules in regenerative nodules as well as dysplastic nodules of cirrhotic livers. In addition, decoy receptor 3 secretion in hepatocellular carcinoma cells in culture was via the activation of mitogen-activated protein kinases. Conclusion Decoy receptor 3 was specifically expressed in chronic liver diseases and hepatocellular carcinoma cells, and decoy receptor 3 might facilitate the survival of liver cells by exerting its anti-apoptotic activity during the progression of liver cirrhosis and hepatocarcinogenesis.
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