How Different Treatments Work Together to Treat HR+/HER2- mBC

On their own, these medications can slow tumor growth. But because cancer cells are often mutating and adapting, combining these options with a second mechanism is the most effective way to treat your cancer. 

Adding on CDK4/6 inhibitors

Enter CDK4/6 inhibitors. These drugs, which include abemaciclib (Verzenio), palbociclib (Ibrance), and ribociclib (Kisqali), block proteins CDK4 and CDK6. These proteins push cancer cells through phases of the cell cycle, so when CDK4/6 inhibitors step in and block them, the cells can’t divide. In addition, the CDK4/6 inhibitors harness your immune system to attack the cancer cells. 

The combination of endocrine therapy with a CDK4/6 inhibitor hits both the fuel line (hormone signaling) and the growth engine (cell division machinery) for your cancer cells. That dual blockade delays resistance and prolongs tumor control. 

“When we compare this combination to aromatase inhibitors alone, for example, the progression of survival doubles,” Assad says.  

Sequencing and Combining Targeted Therapies

Some cancers learn to outsmart hormone therapy. When that happens, doctors may test the tumor’s genes through next-generation sequencing (NGS) to find other mutations they can target. 

“We always check next genomics sequencing on the tumor, either up-front or prior to your second-line therapy, to see what mutations exist and which targeted therapies your patient could respond to,” Assad says.

A few examples include if:

• The cancer has a PIK3CA mutation, it may respond to PI3K inhibitors like alpelisib (Piqray) or inavolisib (Itovebi) when combined with hormone therapy
• If the cancer does not have a detected PIK3CA mutation, gedatolisib (Revtorpyk) may be used with fulvestrant, with or without palbociclib, after the cancer progresses during or after at least one endocrine therapy for metastatic disease
• You have an ATK1 gene mutation or a PTEN alteration, capivasertib (Truqap) may be an option
• You have a NTRK gene fusion, your doctor may choose entrectinib (Rozlytrek) or larotrectinib (Vitrakvi)
• There’s an ESR1 mutation, your doctor may recommend oral SERDS such as camizestrant (Etcamah), elacestrant (Orserdu), or imlunestrant (Inluriyo)

Assad says the key is tailoring each new treatment line based on how the cancer evolves. 

“We try to combine the second-line hormone therapy,” she says. “We change the endocrine backbone, and we try to also add a second targeted agent based on mutations that the cancer may have either acquired or had from diagnosis.”

The Role of Chemotherapy

For breast cancers that are triple negative or HER2-positive, doctors usually use chemotherapy as a first-line treatment, Assad says. But for HR+/HER2-negative breast cancer, that’s not always necessary. 

“We don’t have to treat with chemotherapy up-front, and that's huge,” Assad says. “When you’re diagnosed with metastatic hormone receptor-positive breast cancer, the first-, second- and third- line therapies are all endocrine therapies. We actually don’t use chemotherapy until you are considered endocrine refractory, which means you’re no longer sensitive to endocrine therapies and don't respond anymore.”

When that time comes, chemotherapy works by attacking all rapidly dividing cells directly, including normal cells like hair cells and the cells that line your gut. This can cause side effects like hair loss and fatigue. That’s why oncologists delay it as long as possible. Although it’s effective, it can negatively affect your quality of life. 

The Future of Immunotherapy 

Immunotherapy activates your immune system to fight your cancer. Immunotherapy options have revolutionized treatment for other cancers such as triple-negative breast cancer. But so far studies on HR+/HER2-negative metastatic disease show it has only limited benefit. Research is exploring combinations of hormone therapy and immune checkpoint inhibitors to see whether they can help the immune system “see” HR+ tumors better.

Assad says clinical trials are key to progress. 

“The most important thing I always tell my patients to ask is, ‘What clinical trials are an option for me?’”

Side Effects of Combination Therapies

Combining therapies can give you a more effective treatment, but it can also increase your risk of side effects. 

“Whenever you’re adding or combining a second or a third drug, you’re going to see more in the way of toxicity,” Assad says. 

Because of this, she says she favors using a two-drug combination approach first. 

“I prefer a combination of two rather than a combination of three drugs,” she says. “And then I just use the drug that we didn’t use with the first combination the second time if there’s progression.”

Fortunately, many of these side effects are treatable and potentially preventable.

How Doctors Decide What to Combine

Your oncologist will consider several factors before choosing a combination:

• Tumor biology, meaning which mutations or receptors are present
• Previous treatments you had and how you responded
• Your overall health and tolerance for side effects
• Personal preferences and quality-of-life goals

Assad says that in metastatic breast cancer, choosing a treatment is mostly about overall wellness, not getting rid of the cancer completely. 

“We aren’t expecting to cure the disease in the stage IV setting, so it’s very important that the therapy we choose prioritizes quality of life,” she says.

She also emphasizes the importance of asking questions to better understand your options when it comes to combination treatment, even if that means going to additional experts. 

“Because this is more of a chronic illness and your treatment is going to be lifelong, I think second opinions should be a norm, not the exception,” Assad says.