The breast cancer treatments we have today are the result of innovative ideas, painstaking research, and serendipitous discoveries that stretch over centuries. The evolution of breast cancer treatments started in 3,000-2,500 B.C. with the first historical mention of the disease’s existence in the records of ancient Egyptians. So began the journey to understand the underpinnings of breast cancer in order to develop and improve breast cancer treatments.
Today, breast cancer is the most commonly diagnosed cancer and the leading cause of death in women globally. But our approach to breast cancer treatment is steadily being refined as researchers leverage cutting-edge technologies to develop better and better strategies. And currently, many breast cancer treatment options are available.
Here, we discuss breast cancer treatments ranging from surgery—the first treatment for the disease—to newer systemic therapies for breast cancer and targeted therapies for breast cancer.
The defined structure of the breast made surgery the first and most obvious breast cancer treatment option. As exploration of human anatomy increased during the Renaissance Age, surgical techniques were refined and ranged from excision of an identified lump (now called lumpectomy) to removal of the whole area, including the pectoral muscles that lie beneath the breast (now called radical mastectomy).
Until the 19th century, surgical techniques remained relatively stagnant. Success was limited by the lack of disinfection and sterilization procedures, which meant women were more likely to develop an infection, and the risk of death was high. The lack of anesthesia also hindered good outcomes because surgeons had a short window of time to complete the process as they considered a patient’s tolerance for pain.
Advances in breast cancer surgery promoted better outcomes from breast cancer as did other breakthroughs such as:
These and other discoveries enabled doctors to fine-tune breast cancer surgery. Ironically, it was surgeon Dr. Bernard Fisher’s studies in the 1980s that led to his advocacy for less surgery and limited radical mastectomy with a focus toward conserving the breast. This was a paradigm shift in breast cancer treatment.
Advancements in diagnostic techniques such as early detection by mammography and needle biopsies also helped to limit the need for radical mastectomies and to advance precision surgical procedures. And rapid advances in radiation and chemotherapy to target cancer cells as well as endocrine therapy to treat breast cancer provided strategies with and beyond breast surgery to improve outcomes.
Newer breast cancer treatment options fall into two categories: systemic treatments that travel throughout the body, and targeted treatments that are directed toward a specific molecule or protein present on or in cancer cells that helps them thrive. Targeted therapy for breast cancer may block the action of the specific protein or disrupt associated pathways that signal to the tumor cells to keep growing.
When breast cancer treatments are administered is another consideration. Neoadjuvant therapies are systemic therapies given before primary breast cancer treatments sometimes to shrink the tumor and minimize the amount of breast tissue to be removed. In the case of inoperable breast cancer, neoadjuvant therapy can help reduce the size of a tumor so that it can be managed surgically. Adjuvant therapies are given after the primary treatment to reduce the chance of recurrence—sometimes even if there’s no evidence of residual cancer. They may be targeted or delivered systemically.
Radiation treatment, also called radiotherapy or irradiation, uses high-energy particles to kill cancer cells or slow their growth. It is used after chemotherapy or surgery to stop the growth of any cancer cells that might remain after these procedures and to reduce the risk of breast cancer recurrence in the area or in nearby lymph nodes.
Radiation treatment can also be used alone in cases where the location prohibits surgical excision or in cases of inflammatory breast cancer, an aggressive cancer that spreads via the lymph ducts.
Originally used as a systemic therapy for breast cancer, radiation treatment can now be targeted to the breast or tumor area. This approach, called external beam radiation therapy (EBRT), is currently the most commonly used method of radiation for treating breast cancer.
All radiation treatment methods do have some disadvantages, including harming nearby healthy cells, requiring multiple days or weeks of treatment before the cancer cells die, and side effects. The effects on healthy cells can be mitigated by using low doses of radiation and spreading out treatment over time. Common side effects include fatigue, skin irritation, and breast or arm swelling. In rare cases, rib fractures, chest wall tenderness, inflamed lung tissue, heart damage, or secondary cancers may develop.
While radiation therapy is generally non-invasive, doctors also employ internal radiation or brachytherapy. This procedure is done following surgery with a radiation-delivery device placed where breast tissue was removed. It provides several advantages over external beam radiation therapy. Higher doses can be used with more precision so that healthy tissue is less affected and treatment time can be shortened, which decreases side effects. BCRF investigators are exploring ways to improve radiotherapy and combat radio-resistance through several avenues, including management of side effects, increasing our understanding of breast cancer tumor biology to develop ways to make radiation more effective, and more.
Chemotherapy is the systemic delivery (intravenously or orally) of one or more anti-cancer drugs into the body. All chemotherapy drugs work by interfering with some stage of a cancer cell’s life cycle. As such, they may prevent cell division or inhibit the cell’s ability to repair damaged DNA, both of which promote cell death. Since the hallmark of cancer is rapidly growing and dividing cells, cancer cells may be particularly vulnerable to chemotherapies. But with systemic delivery, these drugs may also affect some normal cells, which contributes to their toxicity and side effects. Typically, chemotherapy drugs are used as part of a breast cancer treatment plan that includes one or more other approaches such as surgery, radiation, endocrine therapy, and targeted therapy.
Currently, there are several classes of chemotherapy drugs FDA-approved as breast cancer treatments:
The discovery that some breast cancers rely on hormones to fuel their growth led investigators to focus on the best ways to neutralize this effect in cancer cells. Hormone receptor (HR)–positive breast cancer cells have receptors for the hormones estrogen and progesterone and are stimulated to grow by the binding of estrogen and progesterone to their respective receptors. In addition, they are responsive to hormonal or endocrine therapy, which involves manipulation of the endocrine system to disrupt the binding and stop cancer cells from growing. Hormone/endocrine treatments for breast cancer were the first targeted therapies for breast cancer, and there are currently several types being used in the clinic.
The oldest systemic hormone treatment for breast cancer and the first systemic adjuvant treatment to be tested in a clinical trial was ovarian suppression. The ovaries are the primary producers of estrogen in premenopausal women, and those with ER-positive breast cancer can benefit from ovarian suppression. Ovarian suppression drugs, a type of endocrine therapy, were developed to prevent estrogen production by the ovaries. Current drugs such as goserelin (Zoladex®) and leuprolide (Lupron®) work by disrupting signals from the brain that tell the ovaries to produce estrogen. Although they work by different mechanisms, the net effect is to switch off estrogen production.
BCRF has long supported the Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT) clinical studies in ovarian suppression. These studies are ongoing and will result in 10–20-year follow-up analysis.
Other hormonal breast cancer treatments for breast cancer can decrease the effect of estrogen on cancer cells’ growth by interfering with the binding of estrogen to its receptor. So far, BCRF researchers and others have devised two classes of drugs to accomplish this: selective estrogen response modulators (SERMs) and selective estrogen receptor degraders (SERDs).
SERMs bind to estrogen receptors and cause a structural change that prevents estrogen from connecting to its breast cancer cell receptors, thus keeping the cells from receiving growth signals. Tamoxifen (Nolvadex®, Soltamox®), raloxifene (Evista®), and toremifene (Fareston®) are SERMs used to stop ER-positive breast cancer from growing and spreading.
Although SERDs also bind to estrogen receptors, they work in a slightly different way. As the name implies, the interaction serves to target the receptor for destruction or degradation. Thus, SERDs prevent estrogen from having a means to signal to breast cancer cells to keep growing. Fulvestrant (Faslodex®) was the first SERD to be available for breast cancer treatment. Most recently (2023), elascestrant (Orserdu®) was FDA approved for treating postmenopausal women with ER-positive breast cancer.
BCRF investigators have also been instrumental in developing and testing other hormonal breast cancer treatments called aromatase inhibitors (AIs) that inhibit hormone synthesis. These drugs are important for treating HR-positive breast cancer in postmenopausal women whose ovaries no longer produce estrogen. Without ovarian production, the body uses other ways to produce estrogen by converting androgens (other sex hormones) into estrogens. The enzyme aromatase mediates this conversion, and aromatase inhibitor drugs were developed to stop the enzyme. The AIs anastrozole (Arimidex®), letrozole (Femara®), and exemestane (Aromasin®) can lower the estrogen levels in the body and slow or stop the growth of tumor cells that require estrogen to grow. Aromatase inhibitor drugs may also be used alone or after tamoxifen treatment (see below) to lower the risk of breast cancer recurrence.
During a cell’s growth cycle, DNA damage occurs on average 60,000 times a day and efficient DNA repair is necessary for normal cell growth. Poly (ADP-ribose) polymerase (PARP) is a family of proteins known to mediate the repair of damaged DNA and serves a vital function in the cell growth cycle. A hallmark of cancer is genomic instability that often arises because rapidly dividing cancer cells cannot repair DNA efficiently.
BRCA1 and BRCA2 (discovered by BCRF investigators and their colleagues) are proteins also important for the repair of DNA. When the gene for one of these proteins is mutated, the change can lead to errors in DNA repair that can eventually cause breast cancer. Researchers postulated that these cells are more reliant on PARP to repair DNA, so perhaps PARP would be an attractive target for therapy. PARP inhibitors could potentially exacerbate the DNA repair defect in BRCA1/2 mutated cells and promote cancer cell death.
PARP inhibitors oloparib (Lynparza®) and talazoparib (Talzenna®) were developed and clinically tested in patients with BRCA1/2 mutated breast cancer. They target and trap PARP proteins on DNA to block the proteins’ normal function. This disrupts cell replication and preferentially causes cell death in cancer cells, which grow faster and accumulate damaged DNA faster than non-cancerous cells. Chemotherapy and radiotherapy also work by inducing high levels of DNA damage but may also affect healthy tissues. Targeted PARP inhibitors combined with either chemotherapy or radiation may help to increase the efficacy of these treatments and minimize the damage to normal cells.
Cyclin-dependent kinases 4 and 6 (CDK4/6) are proteins found in healthy and cancerous cells and control how quickly cells grow and divide. Discovered by a BCRF investigator, cyclin-dependent kinases can become overactive and cause cells to grow and divide uncontrollably, including breast cancer cells. CDK4/6 inhibitors interrupt these proteins to slow or even stop the cancer cells from growing.
Several CDK4/6 inhibitors have been FDA-approved for treating HR-positive/HER2-negative metastatic breast cancer based on the studies of BCRF investigators and others.
Monoclonal antibodies are often thought of as a relatively new targeted therapy for breast cancer. But the existence of antibodies was postulated in the 1890s, and scientific observations over the last century have unmasked their potential to precisely target cancer cells. Researchers have since isolated them, identified their functions, and replicated them in the laboratory to fight cancer.
Antibodies are produced by the body as a natural defense against foreign substances, binding to them and marking them for destruction. They can also stimulate the body’s immune system to promote long-lasting responses to these substances. Monoclonal antibodies (mAbs) are produced by B cells, one component of the immune system, with a specific subset or clone of B cells selectively producing one mAb that recognizes one specific portion of a protein or antigen. Researchers have developed laboratory models to recapitulate mAb production and leveraged this technique to create mAbs that can target cancer cell antigens.
At the intersection of mAb technology and the identification of specific proteins on breast cancer cells such as HER2, Trop2, and PD-1, targeted mAbs for treating breast cancer emerged.
The HER2 protein is a receptor found on the surface of normal cells and transduces growth signals from the surface into cells. In some breast cancers, HER2 protein can be overexpressed up to 100 times more than in normal cells. The elevated levels result in the delivery of sustained signals into the cell to keep growing and can therefore lead to tumor formation. Several mAbs have been developed against HER2:
PD-1 receptor is an immune checkpoint protein, so called because it prevents the immune system from attacking the body’s own tissues. Present on immune cells called T-cells, it binds to the PD-L1 or PD-L2 proteins on normal cells, deactivating any potential immune response against these cells. But cancer cells also make these proteins and are therefore recognized and protected by T-cells, which allows tumor cells to evade the body’s immune system. Pembrolizumab (Keytruda®) is a mAb that binds to, and blocks PD-1 receptor protein found on immune cells. By binding to PD-1 receptors, pembrolizumab prevents tumor cells from hiding from the immune system and allows the immune system to recognize, target, and destroy these cancer cells.
Antibody drug conjugates (ADCs) are a relatively new class of targeted therapy for breast cancer that are engineered to deliver drugs to cancer cells with substantially less toxicity to surrounding normal cells. ADCs are composed of three parts: an antibody, a drug or payload, and a dissolvable linker that connects the antibody to the drug. They are powerful tools that leverage the specificity of an antibody and strategic release of a potent drug directly to the tumor cell site.
Although ADC technology has been around for decades, ADCs have only recently been FDA approved for treating breast cancer including metastatic, HER2-positive breast cancer and recently, triple-negative breast cancer. They include:
At this point, there are 17 ADCs in clinical trials. Nine HER2-directed ADCs are being tested in combination with novel payloads, and eight ADCs are being studied in combination with novel antibody targets.
Tyrosine kinases are part of a family of enzymes that transfer a phosphate group to specific proteins in a cell. Phosphorylation of proteins is a mechanism used by cells to communicate signals that mediate certain cell processes such as growth and division. The HER2 protein contains a tyrosine kinase domain that is involved in cell growth and provided an attractive target for development of drugs called tyrosine kinase inhibitors (TKIs). These small molecule inhibitors bind to the tyrosine kinase domain of HER2 and halt activation of the cell signaling pathway.
Three tyrosine kinase inhibitors have been FDA-approved as HER2-positive breast cancer treatments: tucatinib (Tukysa®), lapatinib (Tykerb® or Tyverb®), and neratinib (Nerlynx®). BCRF investigator–led studies showed that tucatinib is the first TKI to demonstrate clinical efficacy in breast cancer with brain metastases, presumably because these small molecules can cross the blood-brain barrier.
There are several signaling pathways also used by cells to relay messages important for cell functions. The phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is one. In approximately 30–40 percent of HR-positive/HER2-negative breast cancer cases, genetic abnormalities in the pathway’s components can lead to its activation, sustained cell growth, and tumor formation.
One such genetic aberration was discovered in PI3K, the PIK3CA gene. Endocrine therapy is the standard treatment for patients with HR-positive/HER2-negative advanced breast cancer. However, resistance to endocrine-based therapy can occur. The connection between mutations in the PIK3CA gene and overactivation of PI3K led researchers to suspect that PI3K inhibitors could cancel the effects of the mutations and possibly provide a way to overcome endocrine therapy resistance. The PI3K inhibitor alpelisib (PIQRAY®) was developed and clinically tested in trials led by BCRF-investigators. These trials were instrumental in its FDA approval in combination with fulvestrant to treat PIK3CA-mutated, HR-positive/HER2-negative breast cancers that had prior endocrine therapy.
Another key component of the PI3K/AKT/mTOR pathway is the serine/threonine kinase AKT, which exerts a pivotal role in cell growth, proliferation, survival, and metabolism. Targeting AKT is an attractive treatment option for many breast cancers, particularly those resistant to conventional breast cancer treatments. In 2023, a first-in-class AKT inhibitor called capivasertib (TRUQAP™) was FDA approved for treating HR-positive/HER2-negative locally advanced or metastatic breast cancer following recurrence or progression on or after an endocrine-based regimen.
Scientists are constantly making advances in breast cancer treatments. Several new drugs and strategies are under investigation, including additional endocrine therapies, mAbs, and ADCs, uncovering new targets for treatment and leveraging new technologies such as bi-specific antibodies—all built on previous discoveries made over decades and indeed centuries. Researchers are also exploring new combinations of existing treatments and working to optimize dosing strategies with patients in mind—balancing the efficacy of treatments with side effects.
BCRF investigators have led the way in developing and testing of recent breast cancer treatment strategies. As the pace of discovery and advancements in research and technology are accelerating, they will no doubt be instrumental in fine-tuning breast cancer treatments with more and more precise options. BCRF is committed to supporting efforts to move us closer to the promise of precision medicine—therapies tailored to an individual’s tumor characteristics, and expanding breast cancer treatment options.
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Swain, S. M., Shastry, M., & Hamilton, E. (2022). Targeting HER2-positive breast cancer: advances and future directions. Nature Reviews Drug Discovery, 22(2), 101–126. https://doi.org/10.1038/s41573-022-00579-0
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