Throughout the last century, a great deal of progress has been made in understanding cancer and treating the disease. For decades, chemotherapy has been a mainstay in the arsenal against cancer. However, chemotherapy affects all cells equally, and collateral damage to healthy cells results in a number of unwanted side effects. This has motivated researchers to seek treatments that target cancer cells while sparing the healthy ones, resulting in fewer side effects while maintaining or even improving efficacy.

For example, there is Herceptin, a drug developed for use in certain types of breast cancer. In 1987, Dennis Slamon, MD, PhD, FAACR, and colleagues found that the Human Epidermal Growth Factor 2 (HER2) oncogene was altered in about 30% of breast cancer. These changes in a gene that helps control how cells grow, divide, and repair themselves were associated with a poorer prognosis. In a follow-up paper, the researchers confirmed that cells with too many HER2 receptors could lead to enhanced tumor growth in preclinical models.(1) Shortly afterward, scientists at Genentech designed a HER2-targeted antibody, initially to demonstrate that blocking HER2 boosts the efficacy of another breast cancer therapy under development. However, they soon discovered that the antibody was quite effective on its own. This antibody, called antibody 4D5, entered phase I clinical trials by 1992, and was eventually developed into a drug called trastuzumab, or Herceptin. Herceptin was approved by the U.S. Food and Drug Administration (FDA) in 1998 for use in HER2-positive metastatic breast cancer. Further study led to its approval for all stages of HER2-positive disease in 2006.

Targeted Therapies

Herceptin is an example of a targeted therapy. Unlike chemotherapy, which kills all rapidly dividing cells, targeted therapies interfere with specific processes that help tumor cells grow, divide, and spread.(2) Herceptin belongs to a class of drugs called monoclonal antibodies, which simply means it is a specific type of protein made in the laboratory.(3) Early in the development of targeted therapies, the hope was to treat cancer with minimal side effects. While that is true for certain targeted therapies, others carry a list of side effects, some serious. Still, these therapies have proven to be effective, and most side effects disappear after treatment ends.

Targeted therapies work in a number of ways. Some help the immune system find and destroy cancer cells. Others interrupt growth signals in cancer cells. And there are those that stop the signals that cause new blood vessels to form and feed the growth of tumors. Some monoclonal antibodies are chemically bound to chemotherapy drugs and deliver their toxic payload directly to the targeted cancer cells. Some cause apoptosis, or programmed cell death, in cancer cells that have developed resistance to this normal cellular process. And hormonal therapies starve hormone-receptor-positive cancer cells of the estrogen and/or progesterone they need to grow.(2) 

Tumor-Agnostic Therapies

Traditionally, cancer has been defined by the organ or area in the body where it began. Likewise, cancer treatments have been tested and approved by the FDA based on where the disease originated. For instance, drugs approved to treat breast cancer have not been used to treat liver cancer. Other drugs approved to treat lung cancer are mostly used for that purpose, although they may, in certain cases, be used to treat other types of cancer.

More recently, research has revealed a great deal about changes in specific genes, proteins, and other biomarkers that drive unchecked growth, allowing healthy cells to become cancer cells. Detecting these changes can sometimes affect the way the cancer is treated. Much has been learned about the specific gene and protein changes in cells that cause them to grow out of control and become cancer cells. Finding these changes in a person’s cancer cells can sometimes affect their treatment. For example, in people with lung cancer, the cancer cells are now tested for gene or protein changes to see if certain targeted therapy drugs might be helpful for them.

Some drugs are now approved based primarily on whether the cancer cells test positive for specific gene or protein changes, regardless of where the cancer started in the body. These types of targeted therapies are called tumor-agnostic drugs, or tumor-agnostic therapies.(5)

Examples of Tumor-Agnostic Therapies

The list of tumor-agnostic therapies is long and growing. These are just a few tumor-agnostic therapies that are used in the treatment of breast and/or gynecologic cancer.

• Pembrolizumab (Keytruda): The first tumor-agnostic drug received FDA approval in 2017 when pembrolizumab (Keytruda) was allowed for use to treat solid tumors with deficient mismatch repair (dMMR) and microsatellite instability-high (MSI-H) biomarkers.⁶ Pembrolizumab is a type of immunotherapy known as an immune checkpoint inhibitor. It is a monoclonal antibody that binds to PD-1 (programmed cell death protein 1), a protein on certain immune cells called T-cells. PD-1 normally helps keep T-cells from attacking other cells in the body, which can prevent autoimmune disease, but can also keep the immune system from attacking cancer cells. By blocking PD-1, pembrolizumab allows T-cells to recognize and kill cancer cells.(4) It is used alone or with other drugs to treat certain forms of advanced breast cancer, cervical cancer, endometrial cancer, esophageal cancer, melanoma, and non-Hodgkins lymphoma, among many other cancers.(7)

• Fam-trastuzumab deruxtecan (Enhertu) belongs to a class of drugs known as antibody-drug conjugates. In this case, the antibody trastuzumab (Herceptin) is chemically linked to deruxtecan, a topoisomerase I inhibitor, which means that it interferes with DNA replication, resulting in cell death.(8) When infused into the body, the Herceptin attaches to HER2 receptors on cell surfaces, then releases the deruxtecan directly into those cells. HER2-positive cancer cells contain far more HER2 receptors than healthy cells, so they are the main targets of this antibody-drug conjugate. Originally approved on December 20, 2019 for use in patients with metastatic breast cancer following two or more prior anti-HER2 regimens, Enhertu has gradually been approved for different types of HER2-positive tumors until, on April 6, 2024, it received approval in the U.S. as the first tumor-agnostic HER2-directed therapy for previously treated patients with all types of metastatic HER2-positive solid tumors.(9)

• Olaparib (Lynparza) belongs to a class of drugs called PARP (poly ADP ribose polymerase) inhibitors. BRCA (BReast CAncer) 1 or 2 mutations can cause cancers other than breast cancer, and a number of these cancers seem to rely on PARP to repair damaged DNA in their cells, allowing them to continue to grow and multiply. Inhibiting PARP can slow or stop tumor growth. Lynparza is used alone or with other drugs to treat certain types of BRCA1 or 2 positive prostate cancer, pancreatic cancer, breast cancer, ovarian, fallopian tube, or primary peritoneal cancer.(10)

Many more tumor-agnostic therapies are currently in use or under development.

Detecting Biomarkers

Each person’s cancer has a unique pattern of biomarkers, some of which can affect treatment decisions. Testing for these biomarkers may involve:

• Pathology reporting, which offers information on tumor subtypes, hormone receptor status, HER2 status, and more.
• Genetic testing checks for inherited mutations such as BRCA 1 or 2, among a panel of potential mutations depending on your personal risk of cancer as determined by a Certified Genetic Counselor.
• Tumor testing, a type of genomic profiling that looks for acquired mutations within the tumor.

Whether a particular biomarker is found or not, it is a matter of discussion with your oncologist about how the information impacts you as an individual and what your next steps will be.

Looking Forward

Tumor-agnostic therapies may be the next step in precision medicine; however, you and your medical providers need to sort through the complex medical information that applies uniquely to you to determine whether it’s the right course for you. Still, the treatment of cancer according to its molecular features, rather than its site of origin, represents a new understanding of the disease; one that may take us far in our evolving knowledge of how cancer works, why it happens, and – ultimately – how to end it.

1. https://www.aacr.org/blog/2023/10/17/25-years-of-trastuzumab-a-legacy-of-innovation/
2. https://www.cancer.gov/about-cancer/treatment/types/targeted-therapies
3. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/monoclonal-antibody
4. www.cancer.org/cancer/managing-cancer/treatment-types/tumor-agnostic-drugs.html
5. www.cancer.gov/publications/dictionaries/cancer-terms/def/tumor-agnostic-therapy
6. https://www.sabcsmeetingnews.org/tumor-agnostic-therapies-advance-possibilities-for-precision-medicine/
7. https://www.cancer.gov/about-cancer/treatment/drugs/pembrolizumab
8. https://pubmed.ncbi.nlm.nih.gov/10388070/
9. https://www.drugs.com/history/enhertu.html
10. https://www.oncolink.org/cancer-treatment/oncolink-rx/olaparib-lynparza-r