As medicine continues to advance, a lot has changed regarding the scope of breast cancer treatment over the years. However, what has not changed is that breast cancer remains the most common type of cancer in women in the US, except for skin cancers, according to the American Cancer Society.
Of all female breast cancers by cancer subtypes, HER2+ (human epidermal growth factor receptor 2) represents about 10 percent, according to the National Cancer Institute. While this subtype is known as more aggressive, new treatments have shown promise in rapidly evolving therapies available.
“To be HER-2 positive means there is too much of a protein receptor on the cancer cell because there are too many copies of the gene for HER2 in that cancer cell,” explained Sara Hurvitz, MD, Medical Director of the UCLA Jonsson Comprehensive Cancer Center Clinical Research Unit, Co-Director of the Santa Monica-UCLA Outpatient Oncology Practice, and Director of UCLA’s Breast Cancer Clinical Trials Program. “A genetic mistake has happened along the course of that cell becoming cancerous that causes too many HER2 genes and leads to too much of the HER2 protein expressed on the cell.”
Hurvitz further explained that, back in the 1980s, Dennis Slamon, MD, the UCLA doctor who helped develop the breast cancer drug trastuzumab, was able to show when patients had too much HER2 on their cancer cells. The cells then behaved much more aggressively and were associated with a worse outcome and life expectancy, even after surgery and radiation.
Yet, in the time between then and now, scientists have been able to figure out that specifically designed treatments can actually be used to kill the HER2-positive cancer cells. For example, today antibodies can be engineered and infused into a patient to target the abnormal expression of these receptors on cancer cells.
“[Trastuzumab] was first approved in 1998, and since [then], we’ve seen the approval of seven additional therapies that are able to specifically go after HER2 on the cancer cell. These therapies are either given as pills or as intravenous infusions,” Hurvitz noted. “In the age where we have these highly targeted therapies, a patient diagnosed with HER2-positive breast cancer has a much better prognosis.”
The prognosis for HER2-positive breast cancer patients today may be as good as or better than that of a patient with HER2-normal or HER2-negative breast cancer, according to Hurvitz. Of the effective therapies that have followed trastuzumab, which was a monoclonal antibody that was generally well-tolerated but not especially effective as a single agent and thus needs to be given with chemotherapy, another is pertuzumab. This antibody therapy also targets the HER2 receptor and can be given with trastuzumab and chemotherapy.
Next came the development of pill formulas that target the inside of the HER2 receptor. The first of these was a drug approved in 2007 called lapatinib, a HER2 inhibitor that works by interfering with HER2-positive breast cancers by blocking certain proteins that can cause uncontrolled cell growth. As the therapy was not able to specifically target one receptor inside the cell, lapatinib was associated with some side effects, namely diarrhea.
“Other pill therapies have been developed similarly, such as neratinib, which is very potent but, like lapatinib, inhibits other HER receptors such as HER1, leading to relatively high rates of diarrhea,” Hurvitz said. “Most recently tucatinib has been developed, which is a pill that for the first time specifically can go after HER2; and because it’s not hitting HER1 with much potency, it doesn’t have much diarrhea. It actually can get into the brain of patients to help treat patients who have HER2-positive breast cancer metastases to the brain.”
These therapies alone enabled a “jump” in clinicians’ ability to effectively treat patients with brain metastases because, according to Hurvitz, about 30-50 percent of patients with advanced or metastatic HER2-positive breast cancer may develop brain metastases.
She added that there also has been a newfound development of a class of therapies that can be thought of as “smart bomb therapies” or “Trojan horse-type” therapies, called antibody-drug conjugates (ADC). These are therapies where an antibody such as trastuzumab is used with chemotherapy loaded onto it so that the chemotherapy is not active in the blood circulation. Rather, the chemo is only released when the trastuzumab binds to and is internalized into the HER2 overexpressing cancer cell. She noted that, at that point, the chemo is released and the “bomb goes off.”
“This ADC has really revolutionized the way we treat cancer, including breast cancer, because it targets the chemo to the cancer cells. This allows the chemo to not be distributed in high quantities to normal cells, leading to lower toxicity with this type of therapy,” Hurvitz explained. “This allows the delivery of high concentrations of chemo primarily to the cancer cells, with lower amounts of chemo to normal cells.”
She added that this class of medications is comprised of three components. It first requires a receptor to target the cancer cell using an antibody, as well as a chemotherapy payload, and then finally requires the use of a linker to bind this chemotherapy payload to the antibody. Altering any one of those three components will generate a new type of therapy with differing effects against cancer.
Hurvitz believes this to be a huge area of discovery, with numerous drugs in development that are using this technology. The hope is that they continue to show positive results.
Within this class are two drugs that have since been approved for HER2-positive breast cancer, including trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd). T-DM1 was the first to be approved and was the standard therapy for second-line treatment of metastatic disease for almost a decade until T-DXd was shown recently to be associated with a significantly better response rate and progression-free survival compared to T -DM1 in a randomized controlled trial.
“[In the future], I think we’re going to be seeing the development of newer ADCs, as well as HER2 selective small molecule inhibitors like tucatinib. I also think we’re going to be seeing some interesting studies looking at combining HER2-targeted therapies with immune-based therapies or other targeted treatments such as CDK4/6 inhibitors,” Hurvitz predicted. “In addition, we have a number of ongoing studies looking at these newer treatments in the curative setting. The next few years are going to be very exciting as these data emerge.”
To get to this future, Hurvitz believes it’s important that community oncologists who are treating every different type of cancer in their medical practice challenge themselves to keep up with the pace of discovery. While it may seem like there are new data or recommendations every few months, these collective amendments to practice standards are all helping to speed up the rate of the HER2-positive treatment revolution.
“For a general clinician treating breast cancer, lung, prostate, neck, pancreas, and so on, it’s challenging to keep up on the latest treatments and discoveries for each of those tumor types,” Hurvitz said. “One way that I think is helpful for clinicians to keep apprised of the latest data for their patients is to participate in certified medical educational activities, either online or by attending conferences. These types of activities give clinicians an opportunity to hear how people who are treating that disease only, are experts in that field, and are integrating these new data into their practice.”
Hurvitz concluded that, in the near future, she thinks the field is going to see continued improvements in outcomes for this subtype of breast cancer, especially for patients who have brain metastases. She also expects that the field will see data supporting the use of several of the mentioned novel therapies in the earlier-line setting, possibly becoming a standard of care in the curative setting in the next 5 years.
Lindsey Nolen is a contributing writer.
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