Blueprint for Breast Cancer Diagnosis

Years ago, treatment for breast cancer used to be “one-size-fits-all”: surgery, followed by chemotherapy and radiation. New research shows that doctors are now able to better diagnose breast cancer down to the subtype of the disease, using specialized molecular testing.  This new approach means life-saving individualized therapy for some patients.
Becky Kovatch was 44 and a mother of two when she felt a lump in her breast during a self-exam.  
Kovatch explained she felt fear and terror.
Becky had a biopsy. Doctors determined she had stage two aggressive breast cancer. 
Mark Gittleman, MD, Director of Breast Services at Coordinated Health Network in Philadelphia says in recent years, doctors have relied on standard pathology tests to plan treatment before surgery.  He says those tests aren’t foolproof. 
“Using those traditional tumor markers doesn’t always tell us how that tumor is living and how it’s multiplying,” Dr. Gittleman told Ivanhoe. 
Dr. Gittleman is testing a new diagnostic tool for breast cancer. The “BluePrint” test is designed to identify the specific type of cancer down to the molecule. Using biopsy tissue, the test analyzes 80 genes. 
In a study of 426 patients who had their cancer subtype identified by traditional lab tests, 22 percent had their tumors reclassified after “BluePrint” testing.
Dr. Gittleman said, “When the patients were reassigned based on molecular subtyping, there was a much better correlation of response to the chemotherapy if they were in the high risk group.”
Kovatch told Ivanhoe, “With the chemotherapy, it shrunk the tumor.” 
Becky is now cancer-free and can concentrate on her role as a basketball mom and family cheerleader.
Because the procedure is performed on tissue that has already been removed during an initial biopsy, the “BluePrint”, and a companion test, the “MammaPrint”, do not require an extra procedure. “MammaPrint” is covered by Medicare and other insurance. Coverage has been expanding for “BluePrint”.
Contributors to this news report include: Cyndy McGrath, Supervising Producer/Field Producer and Cortni Spearman, Assistant Producer.

BACKGROUND: An estimated one in every eight women will be diagnosed with breast cancer in her lifetime. Cancer occurs when cells grow out of control. In breast cancer, the cells form a malignant tumor that can spread, or metastasize, to distant parts of the body. Most people who are diagnosed with breast cancer are women, but men can get breast cancer, too. Recent research on breast cancer shows that genetics play a role. Inheriting certain genes could mean you have a higher risk of developing the disease. This genetic link has caused some women who know they inherited a certain gene, such as Angelina Jolie Pitt, to get mastectomies as preventative measures. A mass or lump in the breast is the most common sign of breast cancer. Swelling or pain in the breast can also be signs of breast cancer. Radiation, chemotherapy, surgery and hormone therapy are all part of possible treatments for breast cancer.
DIAGNOSIS: Many gynecologists recommend regular screenings for breast cancer because some early stages of breast cancer do not display signs or symptoms. Mammograms, or X-rays of the breast, involve compressing the breast between two plates to scan tissue. If the mammogram yields an abnormal result, the doctor will recommend a diagnostic mammogram, which consists of more images, of the suspicious area. Then if there is still cause for concern, a biopsy may be taken. The biopsy can be taken by inserting a needle to obtain a small sample of the area or removing a mass through surgery.

NEW TECHNOLOGY: Now, scientists are in the process of developing a new diagnostic test to determine the type of breast cancer found in patients. It’s called BluePrint functional molecular subtyping, and it classifies breast cancer into one of three subtypes: Luminal-type, HER2-type and Basal-type. By classifying tumors into these subtypes, doctors would be able to give a more effective treatment and give patients a more accurate long-term outcome. Unlike similar diagnostic tests, the BluePrint test goes beyond using characteristics on exterior surface of the cell to examine 80 different genes. 


Liz Dowling

If this story or any other Ivanhoe story has impacted your life or prompted you or someone you know to seek or change treatments, please let us know by contacting Marjorie Bekaert Thomas at

Mark Gittleman, M.D., Director of the Breast Services at Coordinated Health Network explains how a more targeted therapy is helping breast cancer patients.    
Interview conducted by Ivanhoe Broadcast News in February 2015.

Is breast cancer treatment no longer “one size fits all”?  
Dr. Gittleman: Back in the days when I trained in surgery and did my residency, we really only had one option for a patient with breast cancer, and that was the surgical treatment of the radical mastectomy. That’s all we knew. That procedure was done for every patient with breast cancer regardless of their age, type of tumor they had, the stage of tumor and so on. 
Over the years, we’ve refined that treatment as far as the surgical aspects into lesser procedures which have been studied. Compared to the radical mastectomy, these treatments have shown to give just as good results with less surgery, less morbidity, and equal or better outcomes. We’ve learned over the years, through clinical trials, how to do less and tailor those lesser procedures for the patient’s stage of disease, their age and their various biological markers, so we can treat them more appropriately knowing which outcome will be better for them. 
We used to give radiation to the entire chest wall, the axillary area and the supraclavicular area, which is the area above the collarbone. But now, we’re treating patients with radiation after a lumpectomy with less than whole breast or entire breast radiation. We’re even using radiation given as a single dose as part of the operation for the lumpectomy, called intraoperative radiation therapy. 
The results are less surgery, less radiation, and less systemic therapy with medications, with chemotherapy, hormone therapy and biological agents. We’re tailoring those treatments, the systemic treatments, with those agents more specifically for the individual patients’ biological cancer cell type. We’re identifying the true thumbprint of their cancer by looking at genomics, the genes in their cancer cells, which have become altered and made it a cancer in the first place. 

What is the benefit to the patient? 
Dr. Gittleman: The benefit for the patient is manifold because they don’t have to undergo radical procedures. For radiation, they don’t have to undergo as much extensive radiation, increased cost, increased damage to surrounding structures and so on. They have a better outcome and less morbidity. 
In the systemic treatment era, we know we’re giving treatment that will work as opposed to giving a treatment hoping it will work. Before “one size fits all”, we used to give all patients a certain standard chemotherapy knowing maybe 2 or 3 out of 100 would benefit.  We knew, very well, 97% wouldn’t benefit. Women benefit today knowing they’re getting the treatment that is going to help them. If a certain treatment regimen will not help them based on their molecular subtyping of their breast cancer, then there’s no sense giving it. Patients receive tailored treatment. 
Tell me about the trial you have going on.  
Dr. Gittleman: The trial that we’re involved just closed this past December of 2014 and was conducted in the United States at many centers. It involved patients who were going to have systemic therapy before their surgery and/or radiation. Patients who were getting neoadjuvant systemic therapy would have that therapy given for 3 or 4 months and then go on to have their surgery. 
Traditionally, we used to perform surgery first, and then give radiation and chemotherapy. Now, we’re finding there’s a lot of benefit in giving patients neoadjuvant therapy for a number of reasons. We have measurable disease to see that the treatment is working. If we give the chemotherapy after surgery, as has been traditionally done, we’re betting it’s going to work. But in those circumstances, we don’t have anything to measure. All we can do is follow these patients over many, many years and see the ones that do well and the ones that didn’t do well. 
By comparison, if we give the systemic treatment in the neoadjuvant setting, we have measurable disease to see if the patient responds. We are able to see that in three to four months. So, we have an immediate answer. We also find that some patients who get systemic therapy have what’s called a complete pathological response, meaning we know they have cancer, as we diagnose it with a needle biopsy before anything else is done, give the neoadjuvant systemic therapy and then proceed to surgery. At the time of surgery, there is no residual disease either in the breast or in the lymph nodes. That’s called a complete pathological response. We know then the treatment was effective. It becomes a nice prognostic indicator as to whether the patient will have distant recurrence years later. The surgery is also usually less extensive. It serves many, many purposes.  
How are you able to check recurrence? 
Dr. Gittleman: When we look for recurrences, we look for two things in breast cancer after treatment is over. We look if it recurs locally. We monitor the patients by physical examinations, breast imaging and so on. We also look at what’s called distant recurrence. Does the patient have or will the patient develop metastatic disease or stage IV disease? 
We monitor by patients’ symptoms. We don’t routinely order tests looking for metastatic disease in asymptomatic patients, but we rather order certain tests if there’s any clinical indication that there may be metastatic disease. The whole concept in giving neoadjuvant therapy is for the reasons I just stated, but we used to use traditional tumor markers called the estrogen receptor and the progesterone receptor. We would measure these tumor markers with immunohistochemical staining in the laboratory. Pathologists would put a stain on the slide and see, is this tumor estrogen receptor positive or negative, progesterone receptor positive or negative, HER-2/neu overexpressed positive or negative. This would be by traditional staining of the slides or by doing perhaps a slightly different type of testing with a hybridization called FISH hybridization. This is looking at the HER-2/neu protein, whether it’s there or not or if the messenger RNA is there or not. 
We found, however, that using those traditional tumor markers doesn’t always tell us how that tumor is living and how it’s multiplying and maintaining itself as a cancer and causing damage in the future. We found we can go ahead and look at what’s called molecular subtyping of the cancer, looking at the gene profile I mentioned earlier, and identifying the gene array to see what particular pattern of gene alterations are in this patient. Looking at those things correlates better with response to therapy. 
Can you tell me how you went about identifying the genomes? 
Dr. Gittleman: In order to test tumor cells for its gene profile, genomic profile, not only do we have the pathologist take a look for the traditional markers, but actually part of those cells or part of the slides that the tissue we’ve acquired in the needle biopsy, is sent to a special laboratory. That laboratory runs two tests called, the MammaPrint and BluePrint test. The MammaPrint and the BluePrint test are multiple gene arrays giving us an idea whether the patient fits into a luminal category, high risk luminal or low risk luminal, basal type or Her-2 type
In the study, the MammaPrint and the BluePrint test were run on every patient prior to starting their neoadjuvant treatment. The patients received traditional neoadjuvant treatment as determined by their medical oncologist. In other words, the BluePrint and the MammaPrint didn’t dictate to the treating medical oncologist what drugs to use, but the treating medical oncologist was aware of the result. We found out how patients responded to the chemotherapy they received, not dictated by the test, but dictated by the medical oncologist’s opinion and what he prescribed. We saw how patients responded and were then able to see whether they had a complete pathological response or not. 
In Becky’s case, were you able to target her specifically?   
Dr. Gittleman: Yes. Her traditional tumor markers showed that she was ER positive, PR negative and HER-2 positive. Traditionally, she would receive systemic chemotherapy along with Herceptin. The question is, could we have a good idea whether she truly was going to respond to that regimen? Because as I said, only about 50% of patients HER-2 positive will respond as far as having complete pathological response. When we ran her MammaPrint and BluePrint, the MammaPrint did confirm she was a high-risk luminal patient, meaning ER positive, but high risk because she also was HER-2 positive. So, we had a pretty good idea that she was quite likely to respond to the regimen of Herceptin and with the chemotherapy. 
She in fact did.  At the time of her surgery, she had what we called a complete pathological response, meaning no evidence of tumor in the breast where she had had the previous cancer. When we did our original biopsy, we put a little marker at the site, so the marker became the target of what to remove at surgery if there was going to be any more cancer. We removed the tissue containing the marker. That’s how we knew we were removing the correct tissue. We examined that under the microscope and there was no residual tumor, just some scar tissue as a result of the systemic treatment. Also, her sentinel lymph nodes that were removed showed no evidence of any cancer at all.
Becky had a complete pathological response. This gives us a pretty good prognostic indicator that she will do well in the future as far as a systemic recurrence is concerned.  
Is Becky’s cancer considered aggressive?  
Dr. Gittleman: It was aggressive in the sense that she was HER-2 positive. We know HER-2 positive cancers do have a higher risk of failure, meaning a local or systemic recurrence. But in a sense, the good news of having a HER-2 positive cancer is if it truly is HER-2 driven, it will have a good response to Herceptin. All in all, I would say to a patient, if you have a cancer, you don’t want it to be HER-2 positive — but if it is HER-2 positive, and your molecular subgrouping shows that you truly are assigned to a HER-2 positive group, you have a very good chance of responding to anti-HER-2 therapy such as Herceptin.  
Is there one message you would want to make sure we know from reading this?   
Dr. Gittleman: Yes, to be part of a clinical trial. It’s certainly going to benefit many other people in the future. In fact, the reason you’re benefitting today from targeted therapy is because of the women in the past who have been part of clinical trials. Also, ask your doctor what other tests can be done to better fine-tune the current state of knowledge. Ask how you should be treated today, outside of a clinical trial.  Ask your doctor: Should you have molecular subtyping of your tumor, should you find out what some of these gene tests are showing and what kind of a tumor you really have? Find out if it looks like you’re going to respond to this drug or won’t respond to that drug based on traditional parameters. Those are the questions to ask.  


This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.

If you would like more information, please contact:

Liz Dowling

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