How to Treat Triple-Negative Breast Cancer: Keytruda Shows Promising Boost in Survival

Triple-negative breast cancer is one of the most aggressive forms of the disease and accounts for about 10-20% of all breast cancers. It's called triple-negative because it does not have any of the main drivers of breast cancer: the estrogen receptor, the progesterone receptor, and the HER2 receptor. What this means is that hormonal therapy can't be used because the cancer cells lack these receptors, and it also means that therapies targeted at HER2 will not be an effective treatment option.

Top oncologists in the breast cancer field explain how triple-negative breast cancer is classified.

Triple negative breast is more common in people younger than age 50, and is more likely to be diagnosed in Black women and Hispanic women. The majority of breast cancers diagnosed in people with an inherited BRCA mutation are triple-negative breast.

RELATED: Metastatic Triple-Negative Breast Cancer Treatments To Consider

What is Immunotherapy?

Keytruda is an immunotherapy drug. The immune system uses its white blood cells to attack cells in the body that are abnormal or foreign. Cancerous cells have the ability to prevent the immune system from doing its job. The cancer produces certain proteins to protect the tumor from white blood cells. As a result, the body does not recognize the tumor as abnormal.

Immunotherapy drugs stop this from happening and ensure the white blood cells recognize the cancer cell properly and attack it. The cancer cells themselves are not necessarily difficult to fight. However, they continue to divide rapidly. So, immunotherapy drugs help a patient's immune system control their cancer on its own before it can spread.

What are checkpoint inhibitors and how do they work?

Pembrolizumab (Keytruda), the drug used in the study, is a form of immunotherapy called a checkpoint inhibitor.  Simply put, checkpoint inhibitors are a class of immunotherapy drugs that specifically target proteins found either on immune or cancer cells to prevent their binding together. The advantage of checkpoint inhibitors in treating cancer is that it doesn't kill cancer cells directly, but it stimulates the immune system to find the cancer cells and attack them while hopefully not affecting other surrounding healthy cells.

Checkpoint inhibitors work on the background knowledge that the immune system can protect our bodies by getting rid of any foreign cell that isn't produced in the body. It sets out to do this by identifying specific proteins (also known as checkpoint proteins) that are only found on normal cells; when it finds them, it binds to this cell to mark it as safe and leave it be.

However, sometimes cancer cells can trick the immune system by displaying these same proteins and bind to the immune cells, switch them off and start to divide and reproduce, which manifests in the onset of cancer.

Nevertheless, checkpoint inhibitors can help with this by specifically targeting these proteins found on normal or cancer cells to prevent this binding and keep the immune cells alert to any foreign cells to be able to find and stop cancer cells.

What's the data?

For patients with stage 2 or 3 triple negative breast, adding the immune-boosting medication pembrolizumab to combination chemotherapy before surgery, increases chances of living free of breast cancer, explains oncologist Dr. Sylvia Adams, director of the Breast Cancer Center at NYU Langone's Perlmutter Cancer Center. "It changes the standard of care and should be discussed with all patients who are diagnosed with stage 2 or 3 triple negative breast," she adds. "Yes, it's a game-changer, though there is much more to be learned."

Dr. Sylvia Adams explains when immunotherapy can be used to treat breast cancer.

In the phase III trial that preceded the FDA's approval, a regimen of pembrolizumab with neoadjuvant (before surgery) chemotherapy and then pembrolizumab alone extended event-free survival in patients with early-stage triple negative breast cancer. The trial included 1,174 people, with 784 receiving 200 mg of pembrolizumab every three weeks in addition to neoadjuvant chemotherapy. The other 390 study participants received chemotherapy plus placebo.

At the median follow-up of 39 months, pembrolizumab showed a significant event-free survival benefit compared with chemotherapy alone.  Event-free survival is a measure of time after treatment that a group of people in a clinical trial has not had cancer come back or get worse.

All patients underwent surgery and received radiation therapy as indicated. Adjuvant treatment (after surgery) included up to nine cycles of pembrolizumab or placebo, depending on which randomized group the patient belonged. The number of cycles varied depending on factors such as disease recurrence or unacceptable toxicity.

"We are proud to offer a new treatment option for patients faced with this challenging cancer," Dr. Vicki Goodman, vice president of clinical research at Merck Research Laboratories, said in a press release. "This neoadjuvant and adjuvant combination with Keytruda is the first immunotherapy regimen to be approved in high-risk early-stage triple negative breast, marking a meaningful milestone for the breast cancer community."

The need to stop or slow the progression of triple negative breast is critical, as disease recurrence can be as high as 30 – 40% after standard neoadjuvant chemotherapy and surgery, even when the cancer is diagnosed early. "Metastatic triple negative breast is difficult to treat and has a poor prognosis, therefore prevention of metastatic disease is crucial," Dr. Adams says.

Physicians and researchers will be watching how well pembrolizumab performs over the long-term and whether other immunotherapy drugs may be able to provide similar or improved benefits as part of a comprehensive treatment approach to triple negative breast.

Practice changing updates

Because of this incredible news, the American Society of Clinical Oncology (ASCO), changed their treatment recommendations for this specific subset of patients (stages II or III). The panel recommends use of Keytruda (200 mg once every 3 weeks or 400 mg once every 6 weeks) in combination with neoadjuvant chemotherapy, followed by adjuvant pembrolizumab after surgery. Adjuvant pembrolizumab may be given either concurrent with or after completion of radiation therapy.

RELATED: ‘It’s A Game Changer’: FDA Approves Keytruda, Chemo Combo To Treat Aggressive Triple-Negative Breast Cancer

Possible Side Effects

The most common side effects from Keytruda include:

• Feeling tired (fatigue)
• Rash
• Cough and shortness of breath
• Decreased appetite
• Itching
• Low levels of thyroid hormone.
• Nausea and vomiting
• Diarrhea or constipation
• Abdominal pain

What about HER2 'low' breast cancer?

Traditionally, the presence of HER2 has been divided into two groups, either positive or negative, leaving about 50% of patients somewhere in the middle. These groupings are based upon the way the tumors appear under a microscope when graded by the pathologist or with additional testing a pathologist may perform.

Patients with HER2 positive tumors have tumors that show HER2 over-expression while patients with HER2 negative tumors show minimal or no expression.

Recently, however, researchers have looked to further expand this definition to include patients that have a minimal amount of HER2 expression but do not meet the classic definition for HER2-positive tumors. This group has been called HER2 "low" and is very important as it represents approximately 50% of all patients with breast cancer.

If you have or a loved one has been diagnosed with triple negative breast cancer, it's important to ask physicians about HER2 status, and if your tumor could be reclassified as HER2 “low,” instead of negative.

Questions to Ask Your Doctor

• Do I really have triple-negative breast cancer? Or could my tumor be reclassified as HER2-low?
• Am I eligible to receive Keytruda?
• Am I more, or less, likely to respond to this treatment?
• How will I feel during treatment?
• What are the most common side effects of it?
• What will my treatment cost? Will my treatment be covered by my medical insurance?

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