Advocates drive progress in metastatic breast cancer research and care | 2024 Mets Conference

A future in tumor-agnostic drugs

People diagnosed with MBC will soon see more options in tumor-agnostic drugs. These drugs target certain cell characteristics that may be present in any kind of cancer—not just breast cancer. Recent approval of trastuzumab deruxtecan (Enhertu) for any HER2-positive cancer type is just the beginning. “This is going to be a major advance for other indications. This is setting the precedent that we can use tumor-agnostic ways to bring more drugs to you more quickly,” says Dr. Lustberg.

Treating by subtype

Dr. Lustberg also shared updates on three major subtypes that drive breast cancer treatment.

Hormone receptor-positive (HR-positive) breast cancer

“This one target has completely revolutionized how we treat breast cancer,” says Dr. Lustberg on estrogen receptors and the importance of endocrine therapy in treating HR-positive breast cancer. Endocrine therapies such as tamoxifen and aromatase inhibitors interfere with estrogen’s ability to help breast cancer cells grow and multiply. The RIGHT Choice study recently confirmed the benefit of starting with combination endocrine therapy and targeted therapy instead of chemotherapy. Other drugs are effective when taken along with endocrine therapy. Now a standard first treatment, CDK4/6 inhibitors slow cancer growth so endocrine therapy has more time to work. When choosing a second-line treatment, Dr. Lustberg suggests “hitting pause and exploring what clinical trials are available.” Third and fourth lines might include chemotherapy or depend on whether the cancer tests positive for very low levels of HER2 (HER2 low).

Treatments for HR-positive MBC also include drugs that target the PI3K pathway, which is active in 30% to 40% of HR-positive breast cancers. Approved last year, capivasertib (Truqap) is the second drug of this kind (alpelisib [Piqray] was the first), with more to come. Another new drug, elacestrant (Orserdu), focuses on the ESR1 pathway.

For people diagnosed with HR-positive MBC who also have an inherited BRCA1 or BRCA2 mutation, PARP inhibitors may be a treatment option.

Researchers are also looking at new kinds of drugs for HR-positive MBC, including:

• PROTACS, which tag tumor cells so the body’s own internal processes can destroy them
• CERANS, which completely block the estrogen receptor
• Immunotherapies, which work with the body’s own immune system

HER2-positive breast cancer

HER2-positive breast cancers respond well to chemotherapy combined with trastuzumab (Herceptin) and pertuzumab (Perjeta). Second-line therapy depends on the presence of brain metastases. The HER2CLIMB study showed that tucatinib (Tukysa) can be effective against breast cancers with brain metastases. Future lines of therapy may involve different drug combinations and sequences. Trials to watch include:

• A phase I trial of ZN-A-1041 and other trials focused on treating brain metastases
• A phase Ib/II trial of the PARP inhibitor niraparib with trastuzumab
• The SAPPHO study, which gives patients access to more drugs early on, in rapid sequence, to see what works
• The STOP HER2 trial, comparing ongoing therapy to a treatment break

Triple-negative breast cancer (TNBC)

Treatment for TNBC focuses on immune pathways, potential HER2 low status, PARP inhibitors for cancers driven by an inherited genetic mutation, and smarter drugs.

Antibody drug conjugates (ADCs) deliver powerful chemotherapy drugs directly to tumor cells. The FDA has approved the ADCs sacituzumab govitecan (Trodelvy) and trastuzumab deruxtecan. If the cancer tested negative for HER2 expression in the past, Dr. Lustberg recommends retesting to confirm whether the cancer could be HER2 low, as test results can vary by lab. No matter when testing is done, if the result is HER2 low, you may be eligible for treatment with trastuzumab deruxtecan.

Immunotherapy is especially promising with the approval of pembrolizumab (Keytruda) and exciting ongoing work in cell therapies, including CAR T-cell therapy. CAR T-cell therapy strengthens the immune system to fight cancer by removing T cells, reprogramming them, and returning them to the body. This process takes several weeks. Dr. Lustberg recommends exploring immunotherapy clinical trials early on so that you can plan for when to try them.

Ongoing clinical trials are testing:

• Biphasic ADCs targeting the tumor cell and the T cell at the same time
• A CAR T-cell therapy that targets a receptor called ROR1
• Cancer vaccines and other immunotherapies

Looking ahead

Dr. Lustberg is excited about the potential of blood tests to diagnose and monitor cancer and new thinking around how to treat oligometastatic disease (usually defined as five or fewer areas of metastases). Right-size dosing is a priority area, thanks to the work of patient advocates. “It’s not about giving you too much drug or too little drug. I want to give you the right amount of drug,” she says.

Areas of unmet need include more effective treatments for de novo stage IV breast cancer and cancers with brain metastases. Responding to a question on high drug costs, Dr. Lustberg recommended continued advocacy around drug pricing and relief programs.

Progress, while significant, isn’t happening fast enough for many of us, acknowledges Dr. Lustberg. As our understanding of cancer deepens, the discoveries of new proteins and pathways add complexity. The path to cure is at once more challenging and more promising.

What can you do now?

• When you look for a doctor, ask about their approach to care—whether they follow the standard of care tightly or are willing to be more flexible to better meet your needs.
• Ask about genetic counseling and testing for inherited breast cancer genetic mutations.
• Ask about clinical trials early on and whenever you are making treatment decisions.
• Know your HER2 status and ask to be tested again. One-third of TNBC tumors are HER2 low and 63% of HR-positive tumors are HER2 low. If the cancer tests HER2 low at any time , you may be eligible for a drug that targets HER2-low breast cancer.
• If you have been diagnosed with brain metastases, ask about targeted treatments. If your doctor recommends whole brain radiation, ask for a second opinion.

Watch the session

Watch the full session with Maryam Lustberg, MD, MPH from the 2024 Conference on Metastatic Breast Cancer. See more sessions here.