Evolving Treatments and Advances in HER2-Positive Breast Cancer

Dr. Sara M. Tolaney discussed HER2-positive breast cancer, highlighting key trials, evolving treatment strategies and the potential for improved outcomes.

In a presentation at the recent 42^nd Annual Miami Breast Cancer Conference and the Educated Patient Breast Cancer Summit, Dr. Sara M. Tolaney gave a discussion on the topic of HER2-positive breast cancer for patients.

In the discussion, she highlighted what exactly HER2-positive disease entailed and the evolution of treatment for this disease space, highlighting key trials in the armamentarium that patients should be aware of. Moreover, she touched on the potential for cure in patients with metastatic disease due to the influx of new treatment methods being introduced in the space.

Tolaney works as a breast medical oncologist at Dana-Farber Cancer Institute, where she is the chief of the Division of Breast Oncology, and serves as an associate professor of medicine at Harvard Medical School, located in Boston.

Breaking Down HER2+ Breast Cancer and the Evolution of Treatment

HER2-positive — or human epidermal growth factor receptor 2 — breast cancer is one of the disease’s few subtypes and is largely driven by having copies of HER2 on its cell surface which, in turn, acts as an oncogenic driver of the cancer, telling the disease to grow. Because of this powerful driver of the disease, HER2-positive breast cancer was previously associated with poor outcomes.

“It used to be many years ago that this subtype of breast cancer was actually associated with worse outcomes than all the other subtypes, really because of this powerful driver of cancer cell growth,” Tolaney explained.

However, ongoing research within the treatment armamentarium has led to the discovery of game-changing therapies which target HER2, providing patients with improved outcomes.

Herceptin (trastuzumab) has since served as one of these game-changing therapies and is an antibody which is directed towards HER2. The agent works by blocking HER2 signaling to "shut off" the cancer growth signal, thereby halting cancer growth and leading to a tremendous impact on outcomes. Herceptin has since revolutionized treatment outcomes and recurrence rates associated with the disease, which are now comparable with that of HER2-normal breast cancer, and in some cases, even better, according to Tolaney.

“Since the introduction of Herceptin, we have seen that outcomes actually become the same as someone who has a HER2-negative cancer, because we're able to really convert that cancer to one that is so much better behaved,” she explained

Coming off of the tails of Herceptin, many drugs have been manufactured and developed to target HER2.

Because of this uptick in treatment’s, Tolaney said, “Not that anyone wants to choose to have a breast cancer — but if you had to pick one, sometimes people think, ‘Well, maybe it's good to think about a HER2-positive one’. [This is] because there are just so many drugs that will shut off that signal to the cancer cell and have dramatically changed outcomes.”

Another shift in the treatment of HER2-positive breast cancer which has impacted outcomes is the utilization of neoadjuvant therapy. What does this mean? Although a patient's first instinct upon a breast cancer diagnosis, according to Tolaney, may be to remove it (understandably so), this may not always be the best course of action. Because of the effectiveness of HER2-targeted therapies, neoadjuvant care allows for the administration of treatment before surgery, which kills off the cancer. This provides the benefits of pre-surgical therapy, allowing for tumors to shrink and physicians to assess response, tailoring the treatment to each individual patient.

Using Combination Therapies to Treat HER2+ Disease

Herceptin and chemotherapy are now no longer the only therapies given to treat this disease. Now, patients are being treated with combination therapies — such as Herceptin and Perjeta (pertuzumab) to effectively shut down the HER2 signal into the cancer cell as well as block the signals that tell the cancer cells to grow. Because of this multi-pronged approach, these approaches are very effective, according to various clinical trial results which evaluated this combination.

“There are lots of trials that were done where [investigators] combined Herceptin and Perjeta with chemotherapy. When they did this, and then took people to surgery, somewhere between 40% to 60% of people who went to surgery had no cancer seen in their breast at the time of surgery. It was that effective at killing the cancer cells, and that's why we really like to do this up front,” she emphasized.

However, if a patient still has cancer cells at the time of surgery or residual cancer are identified after surgery, there are additional treatment options available to them. For instance, the phase 3 KATHERINE trial showed that these residual cells can be killed effectively with the use of Kadcyla (trastuzumab emtansine; T-DM1), which is just Herceptin linked to chemotherapy. According to the trial, this agent was able to deliver Kadcyla into the HER2-positive cancer cell in a positive manner and when the use of Kadcyla was compared with the use of just chemotherapy after breast surgery, this cut the risk of recurrence by half.

Enhertu (fam-trastuzumab deruxtecan-nxki; T-DXd) is another HER2-directed therapy that has shifted the landscape of treatment. The agent is an advanced antibody-drug conjugate, which means it is a therapeutic agent which combines a monoclonal antibody with a cytotoxic (cancer-killing) drug, according to Nature Medicine. Essentially, Enhertu uses the same mechanism of delivering the potent chemotherapy into the HER2 cell. According to recent studies, there is now potential that Enhertu will replace Kadcyla.

Managing Metastatic HER2-Positive Breast Cancer

The treatment of metastatic HER2-positive breast cancer once followed a stringent treatment algorithm, but now, due to new drug approvals, this is changing. However, at present, the very first (first-line) treatment patients with metastatic disease are given is made up by a taxane (Taxol or Taxotere) with Herceptin and Perjeta for six to eight cycles to attempt to shrink down the tumor. Moreover, patients are not kept on chemotherapy the entire time and often switch over to maintenance with the antibody treatment.

Following the first-line treatment, Enhertu is given if the cancer drug, which is highly effective. Next, in the third-line of treatment, patients will often receive capecitabine, a type of chemotherapy, given with Tukysa (tucatinib), an oral drug, and Herceptin. The fourth-line of treatment is then made up by treatment with Kadcyla. Overall, there many treatment options that can help patients with metastatic HER2-positive breast cancer live over many years.

The phase 3 CLEOPATRA trial established the first treatment to be a taxane-based chemotherapy with Herceptin and Perjeta which led to "impressive" long-term outcomes over many years, and now, eight to nine years out, many patients are still alive, and some of them without progression on this first treatment. In turn, this raises the question if some of these patients with metastatic HER2-positive disease may potentially be cured. Based on this question, the STOP-HER2 registry study is aiming to evaluate if patients with metastatic disease may even be able to stop treatment with their antibody drugs.

“It's interesting to see the very different mindsets of some patients who are very eager to stop, and others who are [say, ‘Never in a million years would I stop these drugs.’ It's such an interesting thing to see. But in fact, the study passed its safety interim analysis where we have not seen any patients who've stopped so far have a recurrence or progression. That's really fascinating,” Tolaney explained. She added that, “We do need to understand this better.”

Moreover, additional research that has been presented at previous meetings have investigated treatment with CDK4/6 inhibitors, a class of targeting drugs, in combination with HER2 therapies for improved outcomes. It was reported that patients who received this therapy had their cancer controlled, on average, 15 months longer than those who didn’t get the additional inhibitor, according to the AFT-38 PATINA study. This was evaluated in patients who had HER2-positive, as well as HR-positive disease.

The Future of HER2+ Breast Cancer Treatment

Overall, the treatment algorithm for HER2-positive metastatic breast cancer is going to continue to evolve, according to Tolaney.

“Patients, when they're first diagnosed, get Taxol with Herceptin and Perjeta, then after that, go on to Enhertu, then often go on to Tukysa, capecitabine and Kadcyla, and then go from one treatment to the other with, usually chemotherapy and Herceptin,” she explained. “[However], this algorithm, I think, is going to continue to evolve.”

Investigators reportedly anticipate forthcoming data on Enhertu in the first-line setting, potentially within the next few months. If these findings prove significant, they could reshape current treatment paradigms for newly diagnosed patients. As research continues to yield new insights, sequencing strategies will inevitably evolve, incorporating emerging therapies into clinical practice.

Tolaney concluded her presentation by saying, “There's so many choices and so many new therapies that are being studied in this setting, including multiple new antibody-drug conjugates targeting HER2 with different chemotherapy being delivered. I do expect that we are going to continue to see outcomes continue to improve for our patients, which is really very nice.”

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