HER2: One Target, Many Drugs

Once a diagnosis with a very grim outlook, patients with HER2-positive breast cancer are now living longer than ever before: Aggressive science and precision medicine are allowing doctors to truly target their disease.

From “Targeting” With Cytotoxic Chemotherapy…

Normal adult cells don’t grow and divide much. Those processes are tightly regulated, and with good reason. A tumor arises when something goes wrong that allows a cell to divide without normal restrictions. For decades, doctors have been using poisons that kill all rapidly growing cells to try to “target” cancer cells while limiting the harm to a patient’s normal cells.

Given the widespread and sometimes devastating side effects of cytotoxic chemotherapy, it’s hard to imagine calling that a “targeted” treatment. Yet, in many patients, chemo can kill off a significant portion of a tumor, sometimes even the entire tumor, without also killing the patient. Chemotherapy takes advantage of the fact that cancer cells grow and divide rapidly, while most normal cells do not. The common side effects of cytotoxic chemotherapy are usually limited to the few groups of cells in the adult body with rapid turnover—white blood cells, hair follicles, and cells in the mouth and gut. While targeting rapidly dividing cells with cytotoxic chemotherapy has been effective in helping cancer patients live longer lives after a diagnosis, it is not without significant cost to patients in the form of immediate and long term side effects. Those side effects can also limit the dose a patient can tolerate, preventing the complete eradication of the tumor.

… To HER2 (An Answer To An Important Question)…

While noticing that cancer cells grow much more rapidly than normal cells was an important observation in the quest to treat cancer, the question that needs to be asked is, “Why does a cancer cell grow unchecked?”

NCI Definition HER2 PositiveIf scientists can identify what allows a cancer cell to grow so rapidly and then block it, side effects would be limited to the normal cells that are also using that pathway for growth instead of all dividing cells. An early success in this vein stemmed from the observation that around 15% of breast tumors overexpress the HER2 protein. HER2 (which stands for Human Epidermal growth factor Receptor 2) are normally distributed throughout a cell’s surface, and they are turned on only when two proteins are brought together because of the presence of their growth factor. Once two receptors are together, they are able to activate each other and turn on a series of events that lead to cell growth. In the case of HER2-positive breast cancer, there are so many of these receptors that they are able to activate each other even without the presence of their growth factor, allowing the cells to divide under conditions where they normally would not. Luckily, some really smart people figured out how to exploit this fact, and based on foundational research that began in the mid-1970s and with a little insistence of patients along the way, herceptin was approved to treat HER2 overexpressing breast cancer in 1998.

… And Beyond, To: “Me Too, HER2!”

Herceptin is a monoclonal antibody that specifically recognizes part of the HER2 protein, attaches to it, and prevents it from turning on its growth-promoting signals. In the years since its approval, many other drugs have been developed targeting this same protein: Perjeta is another monoclonal antibody that binds a different part of the HER2 protein, tykerb and neratinib are tyrosine kinase inhibitors that stop the “business end” of the HER2 protein from turning on the growth-promoting signals, and kadcycla is an antibody-drug conjugate that has a cytotoxic chemotherapy drug attached to the herceptin antibody, taking the drug specifically to cancer cells to kill them.

All of these “me too” drugs with essentially the same target might seem like overkill. Why spend the time and money making more drugs for the same kind of cancer when you could be investing in drugs for tumors using a different protein to grow? A valid question, certainly, and one drug companies must ask themselves. Yet, these drugs are not the result of a money-hungry pharmaceutical industry, nor is the practice of developing “me too” drugs one that should be abandoned, for a few simple reasons:

Targeting In Parallel: The identification of a good target follows years of published research. It’s not surprising that multiple scientists at multiple pharmaceutical companies will begin looking for the best ways knock down a target at the same time. They’re not tweaking someone else’s idea after it’s been approved, they’re all pursuing the same target in parallel. This is important because not all drugs work. In fact, most fail. If everyone waited for someone else to succeed, many worthy targets would be abandoned after an early failure. This kind of competition also increases the urgency of the drug companies—everyone wants to be first, and that gets good drugs to patients faster.

Side Effect Management:  Different drugs have different side effect profiles, and those even differ from patient to patient. Being able to use another drug with the same target may make a patient’s treatment much more tolerable or may allow them to complete their treatment without reducing their dose.

Cancer Cells Are Crafty: Treating cancer with a drug naturally leads to the survival of the fittest—while the vulnerable cells die off, the cells that can survive lead to new tumors that continue to grow in spite of the drug. Perhaps a small portion of a tumor had a HER2 protein that was mutated in such a way to still be active but lack the part recognized by herceptin. Having a second HER2 drug to target a different part of the protein could be critical in eradicating the patient’s disease. In fact, clinical trials (reviewed here) have shown that having multiple HER2 drugs in the arsenal, either to be taken in combination or in sequence, benefits patients.

Targeting the driver protein in HER2-positive breast tumors was an important early step in the march toward precision medicine. In fact, it has transformed a disease with a very grim prognosis into one that can be well managed for many years even in the metastatic setting. The continued exploration of this target could lead to an even bigger benefit for HER2-positive patients.

Jamie Holloway Precision Medicine Advocate

Jamie Holloway

Jamie Holloway is a both a scientist and a survivor, earning her PhD in tumor biology from Georgetown University a few years before her own breast cancer diagnosis. Now living with no evidence of disease after treatment for early stage triple negative breast cancer, she bridges the gap between scientists and researchers as a Precision Medicine Advocate for Cure Forward and as the Patient Advocate for the Metastatic Breast Cancer Project at the Broad Institute. She works with researchers as part of the Georgetown Breast Cancer Advocates and writes about her personal experience with cancer on her blog, Run Lipstick Chemo, and as a contributor to the Cure Magazine community.