What Is Triple-Negative Breast Cancer?

Breast cancer is not a single disease, but a variety of subtypes that have different features, prognoses and treatments. Based on an analysis of the characteristics of the tumor, breast cancer can be classified into several molecular subtypes. This is important information for your doctor to collect at the time of diagnosis, as it will guide treatment decisions and next steps in your care. More precise diagnoses can lead to better treatment options for patients.

"At the time of diagnosis, we take a piece of tissue and stain it [to look] for three markers in the tissue," says Dr. Daniel Stover, a breast medical oncologist, translational scientist and member of the Translational Therapeutics Program at the Ohio State University Comprehensive Cancer Center. This test happens immediately after a breast biopsy removes some tissue from the tumor or lump that is suspected to be cancerous. The pathologist is looking for higher than normal numbers of estrogen receptors, progesterone receptors and HER2/neu proteins. All of these proteins are normal parts of breast cells, but in cancerous cells, they may be overexpressed, meaning that the cell makes too many of them. This overexpression can fuel the growth of the cancer.

"We test for these markers because we have targeted therapies that target the estrogen and progesterone receptors, and treatments that target the HER2 receptors," Stover says. "So we're looking to identify those patients that are either estrogen-receptor positive, progesterone-receptive positive, or HER2-positive."

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But about 15 percent of breast cancers do not overexpress these proteins and are thus classified as triple-negative. Triple-negative breast cancers don't use estrogen, progesterone or HER2 to grow, and this subtype of breast cancer tends to be more common in African-American women and in younger women. According to the American Cancer Society, incidence rates for triple-negative breast cancer are twice as high in black women -- 24 cases per 100,000 -- than in white women -- 12 cases per 100,00. Scientists aren't sure why.

People with a mutation on the BRCA1 gene, an inherited genetic mutation that significantly increases risk of breast and ovarian cancer in women and breast and prostate cancer in men, also have a higher chance of developing triple-negative breast cancer versus another subtype. The Triple Negative Breast Cancer Foundation reports that "approximately 75 percent of patients who have a BRCA1 mutation and in whom breast cancer develops will have the triple-negative type." Although this is a relatively small number of cases, given that fewer than 10 percent of breast cancers are attributable to an inherited BRCA gene mutation, it's still important to know your BRCA status if you have a strong family history of breast cancer or have been recently diagnosed with breast cancer.

In all cases where the tumor is classified as triple-negative, treatment options become a bit more limited than with other subtypes of breast cancer. "Essentially what triple-negative means is there's really no target that we have, and that's why triple-negative has to be treated with chemotherapy," says Dr. Nikita Shah, medical oncology team leader for the Breast Cancer Specialty Section and medical director of the Cancer Risk Evaluation Program at Orlando Health -- UF Health Cancer Center in Florida.

Currently there is no FDA-approved targeted therapy specific to triple-negative breast cancer. Estrogen and progesterone-receptor positive breast cancers can be treated with targeted hormonal therapies, such as tamoxifen. Patients with HER2-positive breast cancer also have some targeted treatment options, such as Herceptin, that can block cancer cells from receiving the chemical signals the cells use to grow. But researchers are still looking for such targeted treatments for triple-negative breast cancer.

In addition to a lack of targeted treatment, triple-negative breast cancers tend to be more aggressive than hormonally-driven breast cancers. "Biologically, these tumors tend to behave more aggressively, and we don't know exactly why. There's a lot of research going on right now in triple-negative," Shah says. "They're looking at various genetic markers or mutations -- something that may tell us why these cancers behave the way they do."

Stover says triple-negative breast cancers are also more likely to recur, or come back, "more quickly. If it's going to come back, triple-negative breast cancer tends to recur within the first five years after diagnosis while ER-positive cancers can recur 5, 10, even 15 years later," he says. While it's not impossible that a triple-negative cancer will come back after that five-year timeline, it's less likely.

Taken all together, this means triple-negative breast cancer is aggressive, but scientists still have a lot of questions about why. "There's still no good consensus on why they behave the way they do," Shah says, and therefore the blunt instrument of chemotherapy is the standard treatment for triple-negative breast cancers.

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Chemotherapy can bring a lot of painful side effects, but until a more targeted treatment is developed, it's generally considered the best tool in the arsenal against triple-negative breast cancer. Stover says most women diagnosed with early-stage triple-negative get chemotherapy "either before surgery, which is increasingly common particularly if a tumor is over about 2 centimeters, or after surgery."

Shah says this move to what's called neoadjuvant chemotherapy, or chemotherapy before surgery, can help improve outcomes and reduce the chances of the cancer coming back later. "At our institution and most institutions that are academically oriented, we recommend doing chemotherapy first for multiple reasons. Number one, because you can visibly see the tumor shrinking so you know your treatment is working. And number two -- and this is probably more important -- because these aggressive tumors may have a higher risk of metastases, so doing chemotherapy up front kills the viable disease but also the microscopic disease in the blood."

Because chemotherapy is a systemic treatment, it can kill cancer cells anywhere in the body, not just in one specific place. So if cancer cells have started to metastasize, or travel to other parts of the body to set up new tumors, the chemotherapy may be able to stop that process. Shah says going through chemotherapy first is often recommended because it can help control that spread of cells and may mean less surgery for the patient later. This could mean the surgeon needs to take out just a portion of breast tissue during a lumpectomy instead of removing the whole breast during a mastectomy. Stover says completing chemotherapy before surgery can also give your doctor more information about how your particular tumor is likely to behave, and whether it's more likely to recur.

In patients with metastatic, or late stage, triple-negative breast cancer, chemotherapy is usually the recommended treatment and is meant to manage the disease, not cure it. Shah says there are several therapies being tested, but for now, "chemotherapy is the standard of care" for the management of metastatic triple-negative breast cancer.

The search for more targeted treatments for triple-negative breast cancer continues. Stover says there are several trials nearing completion that are looking at "a number of different treatments," including a "promising class of drugs called antibody-drug conjugates, in which a very potent chemotherapy is hooked to an antibody." In this method, the antibody (a blood protein that targets a specific disease agent) seeks receptors on the cancer cell, and then attaches to the cell. "It carries that payload and delivers that potent chemotherapy in higher doses and lesser doses elsewhere so we can get more chemotherapy to the target," and hopefully reduce side effects. He says a number of other studies are also investigating immunotherapies -- treatments that leverage the body's own ability to fight off infection to treat cancer. These approaches are often used in combination with other drugs and therapies.

In his lab, Stover says he's investigating "whether we can use liquid biopsies for sequencing tumor DNA to learn more about how a tumor is likely to act and what the genomic features are of that metastatic triple-negative breast cancer, maybe without needing a [tissue] biopsy." Liquid biopsies are detailed analyses of blood that look for DNA shed by the tumor. They're increasingly being used in lung cancer, because they tend to be less invasive than a surgical biopsy. As the technology improves, liquid biopsies may become a more reliable way of determining the genomic features of many different kinds of cancers without needing to surgically extract a sample of the tumor.

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If you've recently been diagnosed with triple-negative breast cancer, Shah recommends seeking genetic testing to find out your BRCA status. "Especially for women under the age of 60, if they have triple-negative breast cancer they need to have genetic testing and they need to do it with a genetic counselor."

Stover also wants patients who have triple-negative breast cancer to know that there are good ways of treating the disease, even if there aren't targeted therapies. "One of the key things that I convey to my patients is that even though patients with triple-negative breast cancer are at greater risk of their cancer coming back than other breast cancer subtypes, overall women with triple-negative still do well. We're fortunate in breast cancer that the majority of women diagnosed are ultimately cured. I think that for a lot of my patients, they hear 'triple-negative' and it brings a lot of fear or anxiety because of what's out there," but he wants to reassure you that "overall, patients do well."

Elaine K. Howley is a freelance Health reporter at U.S. News. An award-winning writer specializing in health, fitness, sports and history, her work has appeared in numerous print and online publications, including AARP.org, espnW, SWIMMER magazine and Atlas Obscura. She's also a world-record holding marathon swimmer with a passion for animals and beer. Contact her via her website: elainekhowley.com.