abstract: Researchers find discordance between standard human epidermal growth factor receptor 2 (HER2) testing and HER2 status reported on Oncotype DX - CA: A Cancer Journal for Clinicians

Researchers find discordance between standard human epidermal growth factor receptor 2 (HER2) testing and HER2 status reported on Oncotype DX -  2012 - CA: A Cancer Journal for Clinicians

Activity and resistance of trastuzumab according to different clinical settings

Activity and resistance of trastuzumab according to different clinical settings: Publication year: 2012


Trastuzumab, a humanized monoclonal antibody directed against HER2, has shown efficacy in breast cancers; however many patients do not respond to this reagent. Here, we discuss the potential mechanisms of trastuzumab efficacy and resistance in different clinical settings as a step toward optimizing the appropriate application of this antibody. The three major antitumor mechanisms of trastuzumab, i.e., inhibition of proliferation, antibody-dependent cell cytotoxicity (ADCC) and inhibition of DNA repair, appear to be differentially operative in different clinical settings. ADCC appears to be the prevalent mechanism in trastuzumab neoadjuvant monotherapy, whereas in neoadjuvant, adjuvant or metastatic settings in which trastuzumab is combined with chemotherapy, the relative role of ADCC is probably small, considering the compromising effects of chemotherapy on the immune cells that mediate this mechanism. In neoadjuvant and adjuvant settings involving concomitant use of trastuzumab and chemotherapy, the primary mechanism at play is presumably inhibition of DNA repair by the antibody, while in sequential protocols, the antibody acts mostly by exerting cytostatic activity through inhibition of HER2-mediated tumor cell proliferation. According to the ability of the antibody to induce cytotoxic or cytostatic antitumor effects depending on the clinical setting, different criteria, i.e., RECIST for cytotoxic effect, OS, and DFS for cytostatic, must be considered in accurately estimating antibody efficacy. Moreover, since trastuzumab resistance likely depends directly on the mechanisms responsible for its antitumor activity, resistance mechanisms must also be considered with respect to the different clinical settings.

not yet recruiting: A Phase I Study To Evaluate The Antitumor Activity And Safety Of AVX901 - Full Text View - ClinicalTrials.gov

A Phase I Study To Evaluate The Antitumor Activity And Safety Of AVX901

This study is not yet open for participant recruitment.

Verified February 2012 by Duke University

First Received on January 24, 2012. Last Updated on February 1, 2012 History of Changes

Sponsor:	Duke University
Collaborator:	Department of Defense
Information provided by (Responsible Party):	Duke University
ClinicalTrials.gov Identifier:	NCT01526473

Purpose

HER2 is a protein that is over expressed in 20-30% of breast cancers. It is also found associated with lung, gastric, ovarian, and pancreatic cancers. Although there are existing therapies that can target HER2, most patients will eventually experience progression of their disease even though their cancer continues to express HER2. Therefore, new approaches are needed for treating tumors that express HER2.

This clinical trial will use an investigational cancer vaccine called HER2 VRP or AVX901. The vaccine is based on a virus called Venezuelan equine encephalitis but it has been changed so it cannot cause active infection. Instead, the virus has been changed so it tells the immune system to attack cancer cells which make HER2.

The objectives of the study are to evaluate the safety of immunization with HER2 VRP in patients with advanced or metastatic malignancies that express HER2, and to test whether immunization will causes a strong immune system attack against the cancer.

Condition	Intervention	Phase
HER2+ Cancer	Biological: AVX901	Phase I

Study Type:	Interventional
Study Design:	Endpoint Classification: Safety Study Intervention Model: Single Group Assignment Masking: Open Label
Official Title:	A Phase I Study To Evaluate The Antitumor Activity And Safety Of DUKE-002-VRP(HUHER2-ECD+TM), An Alphaviral Vector Encoding The HER2 Extracellular Domain And Transmembrane Region, In Patient With Locally Advanced Or Metastatic Human Epidermal Growth Factor Receptor 2-Positive (HER2+) Cancers Including Breast Cancer

Target-specific, histology-independent, randomized discontinuation study of lapatinib in patients with HER2-amplified solid tumors.

Target-specific, histology-independent, randomized discontinuation study of lapatinib in patients with HER2-amplified solid tumors.:

Background:

To explore the activity of lapatinib with a novel trial design focused on the drug target rather than on histology.

Methods:

Patients with HER2 amplified gastro-esophageal, bladder, ovarian, or uterine tumors were enrolled into a double-blinded randomized discontinuation study of lapatinib 1,500 mg PO daily. The planned sample size was 250 patients with HER2 amplified tumors, with the goal of randomizing 100 patients with stable disease (SD) at week 12 to either lapatinib or placebo. Patients responding after 12 weeks continued on lapatinib; those who progressed were discontinued from study. The primary objectives were response rate after 12 weeks and the percentage of patients who remained progression free 12 weeks after randomization to placebo versus lapatinib.
Secondary objectives were duration of response and determination of the incidence of HER2 amplification in multiple tumor types.

Results:

A total of 141 patients were screened and 32 patients with HER2 amplified tumors were enrolled.
At week 12, 1 (3%) patient had a complete response, 9 (28%) had stable disease, 20 (63%) had progressive disease, and 2 (6%) were unknown. Only 7 patients with SD underwent randomization. The low response rate coupled with slow screening and enrollment led to early study closure.

Conclusions:
Basing trial eligibility on the presence of a genetic target, versus histologic classification, is challenging. While HER2 amplifications appear to be prevalent in select non-breast tumors, lapatinib monotherapy is associated with modest activity. The target-specific histology-independent randomized discontinuation design still merits consideration for targets clearly implicated in "oncogene addiction".

What Is the Current Standard of Care for Anti-HER2 NEOADJUVANT Therapy in Breast Cancer?

Researchers find discordance between standard human epidermal growth factor receptor 2 (HER2) testing and HER2 status reported on Oncotype DX

"“Our study on HER2 discordance highlights the fact that one test cannot provide all the answers [regarding optimal treatment for women with breast cancer]. The oncology community needs to continue using the validated HER2 assays in clinical treatment decisions and reexamine their overreliance on the Oncotype DX test,” Dr. Bhargava says.

Dr. Hayes agrees, noting that the Oncotype DX HER2 assay was not developed, validated, or approved as a predictive test to determine which patients should receive anti-HER2 therapies."

HER3 - Turning off cancer's growth signals (pancreatic/ovarian)

Drugs that interfere with HER3’s better-known cousins, EGFR and HER2, have already proven effective in treating many types of cancer, and early-stage clinical trials are underway with antibodies directed against HER3. HER3 is of great interest to cancer biologists because it is commonly involved in two of the deadliest forms of the disease, ovarian and pancreatic cancer, says MIT Professor Linda Griffith, who led the research team with Harvard Stem Cell Institute and Brigham and Women’s cardiologist Richard Lee.
The study, published online May 26 in the Journal of Biological Chemistry....

Editorial: Whither HER2-Related Therapeutics? (breast cancer) -- Journal of Clinical Oncology

Note: references to solid tumours

"Evidence suggests that most solid tumors, regardless of their type, cannot grow beyond approximately 1 mm3 until they establish a blood supply by inducing new blood vessels from existing host capillaries, called tumor-induced angiogenesis......It follows then that tumor cells with low HER3 mRNA are more likely to respond to pertuzumab, given that these are the cells where the pathway is activated. We would conjecture that this signature does not apply exclusively in ovarian cancer, but may also be found in other solid tumors, such as non–HER2-positive breast, colorectal, and so on."

Full access: HER2 overexpression and amplification is present in a subset of ovarian mucinous carcinomas and can be targeted with trastuzumab therapy

Abstract/free full access HER2 overexpression and amplification is present in a subset of ovarian mucinous carcinomas and can be targeted with trastuzumab therapy

Abstract | HER2 overexpression and amplification is present in a subset of ovarian mucinous carcinomas and can be targeted with trastuzumab therapy