Topic: Progress in the treatment of triple-negative breast cancer

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Research Timeline: Post Approval

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What is this topic about?

This topic is about advances in the treatment of triple-negative breast cancer (TNBC).

Why is this topic important?

TNBC is a type of breast cancer that is aggressive and often difficult to treat. People who have an inherited mutation in BRCA1 are at especially high risk for TNBC compared with other types of breast cancer, although people with an inherited mutation in other genes are also at risk.

“Triple negative” means that the cancer lacks three tumor markers: estrogen (ER), progesterone (PR), and HER2. Treatments that target these markers (for example, Herceptin, which targets HER2) are not options for patients with TNBC. Treatment for TNBC has been limited mainly to chemotherapy, but new treatment options have improved patient outcomes. At the 2023 San Antonio Breast Cancer Symposium, Dr. Telli talked about how these new treatments have positively changed the outlook for patients with TNBC.

Progress in the treatment of TNBC

PARP Inhibitors

PARP inhibitors are a type of targeted therapy that works by blocking a protein that the body uses to repair damage to DNA. These drugs were initially developed to treat cancers in people with BRCA1 and BRCA2 mutations. Dr. Telli described research with the PARP inhibitors Lynparza (olaparib) and Talzenna (talazoparib) for patients with an inherited mutation in BRCA1 or BRCA2, including patients with TNBC. 

Two studies of patients with advanced TNBC: OlympiAD (Lynparza) and EMBRACA (Talzenna) found these PARP inhibitors reduced cancer progression compared to standard chemotherapy.

The OlympiA study looked at using Lynparza just after surgery for people with early-stage TNBC. In this study, Lynparza increased both the time until cancer came back and overall survival (how long patients lived). Read more here and here.

Immunotherapy

Immunotherapy is a type of targeted therapy that helps the body’s immune system detect and attack cancer cells. Immunotherapies are used to treat many different cancer types. TNBC has a tumor marker called PD-L1 that is often used to determine if a patient will respond to immunotherapy. An immunotherapy drug called Keytruda (pembrolizumab) can now be used as a treatment in earlier and later stages of TNBC.

For patients with advanced TNBC, the KEYNOTE-355 study looked at adding Keytruda to chemotherapy as the first treatment. Researchers found that among patients whose tumors had high levels of PD-L1, this drug combination significantly increased both the time until cancer came back and survival when compared to using chemotherapy alone.

Researchers also found that Keytruda benefited patients with early-stage TNBC who were at high risk for recurrence due to the size of their cancer or the number of positive lymph nodes. In the KEYNOTE-522 study, Keytruda was added to chemotherapy before surgery (neoadjuvant treatment) and continued after surgery (adjuvant treatment). The addition of Keytruda to chemotherapy significantly increased the time until cancer came back.  Read more about the approval of Keytruda for the treatment of early-stage breast cancer here.

Antibody Drug Conjugates

Antibody Drug Conjugates (ADCs) are drugs that combine two different types of molecules.  A chemotherapy drug is linked to an antibody that delivers the chemotherapy directly to the cancer cells. Two ADCs are approved by the FDA for patients with breast cancer: Trodelvy (sacituzumab govitecan or “SG”) and Enhertu (trastuzumab-deruxtecan or “T-DXd”).  Dr. Telli covered the study results of these drugs involving TNBC that showed significant improvements over chemotherapy.

In the ASCENT study, researchers treated patients who had metastatic TNBC with either Trodelvy or chemotherapy. The risk of the cancer coming back was reduced by more than 50 percent among patients in the Trodelvy group compared with the patients in the chemotherapy group. Read more about Trodelvy here and here.

Enhertu is an ADC that delivers chemotherapy to tumor cells that have the HER2 protein. Previously, a breast tumor was designated as either HER2-positive or HER2-negative based on a cutoff value for the amount of HER2 protein. The DESTINY-Breast04 study looked at patients who had HER2 levels below this cutoff (traditionally considered HER2-negative). This new “HER2-low” subtype of breast cancer can include some patients who were originally told that they had TNBC. In HER2-low patients with metastatic breast cancer, Enhertu increased the time until cancer came back by about 50 percent compared with standard chemotherapy. Read more about HER2-low breast cancers and Enhertu here.

Chemotherapy

For people with TNBC, different ways of giving chemotherapy have also led to better patient outcomes.

In one study, researchers added carboplatin (a type of chemotherapy) to a standard chemotherapy treatment before surgery (neoadjuvant). They also showed that carboplatin increased the time until the cancer came back, as well as overall survival compared with standard chemotherapy alone. Patients who had the greatest benefit were mainly premenopausal and age 50 or younger.

While improving outcomes is a primary goal for treatment, being able to achieve this with fewer side effects was another theme of recent research. The NeoSTOP study compared a four-drug treatment (carboplatin/paclitaxel followed by doxorubicin/cyclophosphamide) to a two-drug treatment (docetaxel plus carboplatin) prior to surgery. Both groups had similar survival rates, but patients taking the two-drug treatment (docetaxel plus carboplatin) had fewer side effects.

Another study (CREATE-X) looked at patients with TNBC who still had some cancer (residual disease) after neoadjuvant chemotherapy. The addition of capecitabine to treatment after surgery increased the time until their cancer returned and overall survival. This study led to a change in how physicians treat this patient group.

Future Research

While great progress has been made in the treatment of TNBC, more work needs to be done. Other areas of future study include:

• Finding treatments with the same or better benefits with fewer side effects.
• Figuring out the best order of giving different treatments.
• After treatment of early TNBC, using circulating tumor DNA (a way to see if cancer is still present) to better understand if more treatment is needed.
• Identifying markers that can predict how well the drug will work or its side effects.

Recent Drug Approvals in TNBC

You can find more information on these treatments here.

What does this mean for me?

Although more work in this field is needed, these recently approved drugs have made a positive difference for some patients by delaying the progression of their cancer and helping them live longer.

If you have been diagnosed with triple-negative breast cancer, you may want to ask your doctor about newer treatment options. You may also want to ask if your cancer is “HER2-low,” which can help in determining the best treatment for you.

Reference:

Telli M. Recent advances in triple-negative breast cancer. San Antonio Breast Cancer Symposium, December 2023.

Disclosure: FORCE receives funding from industry sponsors, including companies that manufacture cancer drugs, tests and devices. All XRAYS articles are written independently of any sponsor and are reviewed by members of our Scientific Advisory Board prior to publication to assure scientific integrity.

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posted 3/19/24