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Could Some Her2 Negative Actually Be Her2+?

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    Posted: Dec 20 2012 at 12:07pm

Existing Drugs May Help More Breast Cancer Patients

Dec. 7, 2012 - More patients can benefit from highly effective breast cancer drugs that are already available, according to DNA sequencing studies by researchers at Washington University School of Medicine and the Siteman Cancer Center as well as other institutions.

The investigators found that some women with the HER2 negative subtype may benefit from anti-HER2 drugs even though standard tests don't indicate they are candidates for the drugs.

"These patients are going to be missed by our routine testing for HER2 positive breast cancer," says Ron Bose, MD, PhD, assistant professor of medicine. "Currently they're not going to receive a HER2-targeted drug because we don't have a way to identify them. And we predict they are going to have a more aggressive form of breast cancer."

Bose will present the data Dec. 7 at the San Antonio Breast Cancer Symposium.

Today, a type of breast cancer known as HER2 positive is treated with drugs that inhibit the function of the HER2 protein. To be classified as HER2 positive, a patient must have more than the normal two copies of the HER2 gene. Too much HER2 drives tumor growth, and some
HER2 positive patients may have as many as 20 copies of the gene. Doctors test for this gene "amplification" in every patient diagnosed with breast cancer. It must be present for a woman
to receive anti-HER2 drugs.

But instead of multiple copies of the gene churning out too much HER2, some patients deemed HER2 negative based on standard testing may have mistakes in just a few "letters" of the DNA in their two gene copies that result in excess activity of the protein. Bose and his colleagues estimate that these undetected HER2 mutations - rather than the HER2 amplification - may be driving tumor growth in 1.5 to 2 percent of all breast cancer patients. With about 230,000 new cases of breast cancer diagnosed in the United States each year, even this modest percentage translates into more than 4,000 patients per year.

The study, led by senior author Matthew Ellis, MD, PhD, of Washington University and published online Dec. 7 in the journal Cancer Discovery, analyzed data from eight DNA sequencing studies, which together included about 1,500 patients. Two of the sequencing studies were conducted by The Genome Institute at Washington University in collaboration with study co-author Elaine Mardis, PhD, co-director of the institute.

 bose.jpg
Ron Bose, MD, PhD

Of the 1,500 patients, 25 were found to have HER2 mutations without gene amplification. Not all mutations appeared to have the same effect, however. After analyzing 13 of the mutations, seven were found to drive cancer growth. In the laboratory analysis, most of these mutations responded well to the anti-HER2 drugs lapatinib and trastuzumab, both approved by the U.S. Food and Drug Administration. Although two of the mutations were resistant to lapatinib in lab tests, they responded well to neratinib, a newer anti-HER2 drug that is currently in phase II clinical trials.

Bose also cautions that some mutations were found to be "silent," meaning they did not drive the tumor's growth and therefore would likely not respond to anti-HER2 drugs.

The study's findings have led directly to the launching of a phase II clinical trial to test whether patients with HER2 mutations - but not the amplification - will benefit from anti-HER2 drugs. The trial will include patients with stage IV breast cancer classified as HER2 negative. Their HER2 genes will be sequenced to look for mutations. If mutations are present, they will be treated with neratinib in addition to the standard treatment they would otherwise receive.

At Washington University, the trial will be led by Cynthia Ma, MD, PhD, associate professor of medicine. The other centers participating in the study are the Dana-Farber Cancer Institute, Memorial Sloan-Kettering Cancer Center and the University of North Carolina, Chapel Hill.

Bose points to this study as an example of the potential value in sequencing the DNA of cancer patients, even when limited to a single gene of interest such as HER2.

"If we can identify mutations that we can act on, that information will help us better guide treatment," Bose says. "In this case, we don't even have to develop new drugs against HER2 mutations. It's just a matter of finding the patients."

http://www.siteman.wustl.edu/ContentPage.aspx?id=6710


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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Dec 21 2012 at 7:47am

HER2-Positive Stem Cells Found In HER2-Negative Breast Cancer

A multicenter study led by researchers at UC Davis describes new, paradoxical characteristics of the most common type ofbreast cancer. The findings shed light on how the disease can evade treatment and could improve diagnosis and treatment of breast cancer. 

The research, led by Jian Jian Li, director of translational research in the UC Davis Department of Radiation Oncology, examined breast tumors previously thought to lack the HER2 protein, which, when over-expressed, is associated with disease recurrence. Instead, researchers found in the tumors small groups of aggressive, treatment-resistant HER2-positive breast cancer stem cells (BCSCs). The findings were published in Clinical Cancer Research.

"These BSCSs are very resistant to traditional treatments, which can lead patients to relapse," said Li, the study lead author. "Despite chemotherapy, radiotherapy or even surgery, thecancer is still recurrent. These findings change our concept of breast cancer because now we know HER2-negative breast cancers can be treated effectively with anti-HER2 treatments." 

In the past decade scientists and clinicians have developed a better understanding of how breast cancers differ on the cellular level. Whether a tumor contains HER2, an estrogen receptor protein, a progesterone receptor protein or all three or none can have an enormous impact on the tumor's aggressiveness, the patient's overall prognosis and treatment choices. 

HER2-positive breast cancers are routinely treated with drugs that target the HER2 protein, such as Herceptin or Tykerb, with good results. However, until recently, there has been little reason to administer these targeted treatments to patients with HER2-negative cancer. 

The team, which included researchers from the University of Michigan Comprehensive Cancer Center, the Holden Comprehensive Cancer Center at the University of Iowa, Emory University School of Medicine and MD Anderson Cancer Center, isolated the HER2-positive BCSCs from irradiated, HER2-negative breast tumors. They also analyzed the stem cells for CD44 and CD24, cell surface proteins that indicate cancer aggressiveness and act as BCSC markers. 

The team found that the HER2-positive, CD44 positive, CD24 negative/low BCSCs were more aggressive and highly resistant to radiotherapy. These characteristics were significantly reduced by Herceptin or short interfering RNA. HER2 and CD44 positive BCSCs were found in 57.1 percent of primary tumors and 84.6 percent of recurrent tumors. 

In addition to identifying this previously hidden group of HER2-positive stem cells, further examination provided new insights into how these BCSCs maintain their resistance to treatment. A complex network of proteins, including HER2 and STAT3, modulate metastasis, programmed cell death and other functions. As a result, these cells survive the gamut of traditional anti-cancer therapies. 

"We feel this research will have a major scientific, as well as clinical, impact," says Li. "We now have a better understanding of how BCSCs resist radiation and other treatments." 

While recent research has shown that patients with HER2-negative breast cancer can indeed benefit from HER2 treatments, prior to this work no one understood the mechanisms. This research provides detailed confirmation that HER2 treatment can potentially improve outcomes in HER2-negative breast cancers. 

In addition to opening up new treatment options for HER2-negative patients, the research also provides a diagnostic pathway. Markers, such as CD44, could help clinicians identify aggressive, HER2-positive BCSCs in cancers that are ostensibly HER2-negative, individualizing treatment to match each patient's needs. These findings may also advance treatment for other cancers. 

"This may open the possibility of treating HER2-positive stem cells in bone, lung or brain cancers, which are all difficult to treat in the later stages," says Li. 
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Boo Quote  Post ReplyReply Direct Link To This Post Posted: Dec 31 2012 at 4:50pm
Donna, thank you so much for posting as always.  I have a low expression of HER2 in my mix.  I am a 1.5/1 ratio and they give treatment if you are above or at 2 (2/1). I have felt and still wonder if I should receive some HER2 meds in my mix somewhere along the line.  I am negative for BRCA 1 and 2 and androgen so the only lead I have so far is that I am slightly HER2 positive as well as 95 - 97% TP53 mutated.  I was tested for gene mutations but not HER2.  Did the king lab study test for HER2 mutations?

I would like to wish you and all those on line a Very Happy New Year.  May we all find our path to peace and content.  May the researchers blaze a path to new hope.  See you in the New Year.  Anne
dx 12/2010 age 50 TNBC 12 X 9 cm tumor 1 node, 3 X FEC 9 X Doxitaxol with concurrent rads - 2X3 cm residual tumor 20/1/12 mets in lungs METMAB trial May 7 to Oct. 21, CHK1 /Gem trial 26/12/12 fails
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Jun 22 2014 at 8:46pm
Breast cancer is categorized into different subtypes, so when doctors diagnose breast cancer, they try to classify it into one particular subtype. Researchers from the Dartmouth-Hitchcock Norris Cotton Cancer Center examined how accurately testing was able to classify cancers in one specific subtype, those that are human epidermal growth factor receptor 2 (HER2) positive.

The authors state that the accurate assessment of HER2 status is essential to determine optimal treatment options. If breast cancer is found to be HER2 positive, then there are particular treatments for preventing recurrence and improving outcome for this type of cancer that are extremely effective.

The researchers re-tested tumor samples from a group of 530 women to see if their initial HER2 negative classification had been correct.

When retesting the samples, the researchers utilized two different tests: immunohistochemistry (IHC) and florescence in situ hybridization (FISH). Both tests are approved by the US Food and Drug Administration (FDA) and used widely.

They found that 22 out of 530 patients had had their tumor type incorrectly classified - 4% of the total number.

Dr. Peter Kaufman discusses the implications of their study:

"We, and other groups, have previously shown that a certain percentage of cases found to be HER2 positive in local laboratories are in fact HER2 negative when tested in more experienced central labs. There has, however, been almost no research evaluating the accuracy of a negative HER2 result. This is the first large study to look at this. What is comforting is that we found that re-testing in experienced larger labs confirmed the original local lab results in the majority of cases."

Dr. Kaufman acknowledges that the incorrect classification of 4% of patients is problematic, as therapies that specifically target HER2 are critically important for people with HER2 positive breast cancer. The 4% did not receive potentially efficacious therapy because their HER2 positivity was not determined to begin with.

To read more:

http://www.medicalnewstoday.com/articles/278506.php?tw

DX IDC TNBC 6/09 age 49, Stage 1,Grade 3, 1.5cm,0/5Nodes,KI-67 48%,BRCA-,6/09bi-mx, recon, T/C X4(9/09)
11/10 Recur IM node, Gem,Carb,Iniparib 12/10,MRI NED 2/11,IMRT Radsx40,CT NED11/13,MRI NED3/15

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