The Brightening Outlook for Patients with HER2+ Breast Cancer

Not all breast cancers are created equal. Historically those patients with hormone-driven breast cancer had better outcomes compared to those with HER2+ breast cancer.

Human epidermal growth factor receptor 2 (HER2)/Neu is a kinase protein involved in normal cell growth. Sometimes there are errors in the genes that control the HER2 protein. This causes us to make too much of it helping breast cancer cells to grow quickly. This overexpression of HER2 occurs in 15-20% of breast cancers, sometimes in combination with hormone-positive disease, but sometimes independent of hormone positivity.   Expression of the protein on the cancer cell forms the basis of how we diagnose HER2+ breast cancer if the tumor strongly expresses the protein (3+) or moderately expresses (2 +) but shows signs that a cell is amplifying HER2 genes (FISH amplified). There is growing interest in HER2 low tumors that express HER2 weakly (1+, 2+ but FISH negative).

When compared to breast cancers fueled solely by hormones such as estrogen and progesterone, HER2+ cancers will grow about 25% more aggressively, if left untreated. They grow faster, are more likely to metastasize and recur.  Recurrences tend to happen earlier when compared to hormone-driven cancers, typically within 2-5 years. Brain metastases are more common, as well.

In the past, people with HER+ breast cancers had poor prognoses, but by targeting these protein receptors researchers have been able to develop treatments to equalize the gap.

How have treatments evolved?

The evolution of HER2+ breast cancer treatments has focused on maximizing outcomes while minimizing toxicity. Although the HER2 gene was identified in 1984, a targeted therapy to address the issue of protein overexpression was not available until the development of the monoclonal antibody treatment, Herceptin (Trastuzumab) in 1998. Prior to this drug, chemotherapy was the standard of care for systemic treatment of HER2+ breast cancer. When Herceptin was given alongside chemotherapy, not only was it well tolerated by patients, but recurrence rates decreased by 50% and mortality was cut by 30%. Outcomes improved further with the development of Pertuzumab, which works synergistically with chemotherapy and Herceptin.

Sometimes the receptor can be activated below the surface of the cancer cells, and the oral drugs known as tyrosine kinase inhibitors (TKI) work to block this activation downstream of receptor.  Lapatinib, developed in 2007, was the first of its kind, with Neratinib and Tucatinib developed  later. These drugs can penetrate and target brain metastases, which can be seen even in those patients with early disease, resulting in longer survival. The addition of this class of drugs to the standard regimen of chemotherapy and targeted therapy provides a double whammy to cancer growth.

Antibodies alone are only 20-25% effective as compared to the combination with chemotherapy, but researchers wanted to know how much chemo was really needed.  The newest tools for blocking HER2 are antibody-drug conjugates (ADC), monoclonal antibodies combined with a low-dose chemotherapy drug. The antibody acts like a warhead honing in on the HER2 on cancer cells, delivering the chemo directly to them. Research reveals that with this approach patients are living longer with less side effects. TDM-1, ado-trastuzumab emtansine (Kadcyla), was the first ADC approved for HER2+ breast cancer . TDxD, trastuzumab deruxtecan (Enhertu), another more potent ADC has further moved the needle and improved outcomes for patients with metastatic HER2+. Most recently, HER2-low tumors with lower expression of the protein, have also been shown to respond to TDxD which has broadened use beyond just what we know as HER2+ cancer.

Where do we go from here?

The advancements that have been made in developing targeting therapies for HER2+ have helped to improve progression-free and overall survival for patients, with outcomes approaching levels seen in patients with hormone positive breast cancers. But, there is still work to be done. Currently, there are clinical trials studying if we can minimize or in some cases even avoid chemotherapy completely in women with early stage HER2+ breast cancer. This strategy of using response to these agents neoadjuvantly as a guide, minimizes toxicity without compromising outcomes . Brain metastases remain an area of unmet need as most traditional chemotherapies and even HER2 antibodies do not  get into the brain. Newer oral agents and ADC’s have changed that as they show responses even in the brain. Studies are now looking at whether using these drugs early on can actually reduce the chance of  developing brain metastases in the first place.  

Participation in clinical trials is the only way we can continue to make advancements in breast cancer treatment. If you are interested in learning more about clinical trials that you may qualify for, you should speak with your doctor and visit  https://clinicaltrials.gov/.