Targeted Therapies, Immunotherapy, and Chemotherapy: What’s New in Breast Cancer?

Memorial Sloan Kettering medical oncologist Komal Jhaveri

Medical oncologist Komal Jhaveri says many combination therapies reported at SABCS are showing encouraging results.

Memorial Sloan Kettering medical oncologist Komal Jhaveri played a role in a number of studies presented at the 2020 San Antonio Breast Cancer Symposium (SABCS) held December 8-11. Here, Dr. Jhaveri gives her perspective on some of the most significant trends in breast cancer treatment and research.

Perhaps the most encouraging trend is the emergence of a wide array of combination therapies to treat endocrine-resistant breast cancer. Most breast cancers are estrogen receptor (ER) positive, meaning they carry a receptor that enables them to be fueled by estrogen. We have drugs that cut off that fuel supply by either stopping estrogen from attaching to those cells or preventing hormone production altogether, and thus stopping or slowing breast cancer growth.

However, when the cancer spreads (metastasizes), it usually becomes resistant to these drugs. Over the last decade, we have successfully added other drugs to foil this resistance by combining hormone therapy with a targeted therapy.  One good example of these complementary drugs are CDK4/6 inhibitors. These drugs block enzymes that are important for cell division. CDK4/6 inhibitors have really changed the treatment landscape for metastatic ER-positive breast cancers and are now showing early hints of success even in the early-stage setting, when disease can be cured. But they also can stop working or fail to work in the first place. Hence we have now focused our efforts to gain a better understanding of how resistance to CDK4/6 inhibitors develops.

Breast Cancer
Breast cancer is divided into two categories: invasive breast cancer and noninvasive breast cancer. Learn more about how breast cancer is diagnosed and treated.

At MSK, we can test all breast tumors using MSK-IMPACTTM, which can detect more than 500 alterations and other critical changes in the genes. Some of these alterations are very rare and others are more common. Regardless, this has helped us understand resistance to endocrine therapies and, in turn, enabled us to match these alterations with the best targeted therapies. One example of this is a mutation in the ERBB2 gene, which is seen in 7-8% of metastatic ER-positive breast cancers. This alteration has been targeted by a drug called neratinib (Nerlynx®), and we presented encouraging activity for the triple combination of neratinib with fulvestrant (an ER inhibitor) and trastuzumab (an antibody against HER2) at this meeting.

We made several presentations at SABCS describing other triplet therapies for ER-positive patients, including drugs called PI3K inhibitors and FGFR inhibitors for patients whose tumor harbor a PIK3CA mutation or amplification of the FGFR gene respectively. For example, we reported results from an ongoing phase I clinical trial testing a combination of fulvestrant (an ER inhibitor), palbociclib (a CDK4/6 inhibitor), and GDC-0077 (a PI3K inhibitor). Notably, results have been encouraging, and a phase III trial testing this combination is now enrolling first-line metastatic patients with ER+ PIK3CA-mutated tumors.

As we learn more about different genomic alterations, we can more precisely match a plethora of effective therapies to improve the outcomes for endocrine-resistant breast cancer patients. Every year at SABCS and other meetings, you see results from more and more of these combination therapies.

Are there immunotherapy advances that have shown promise in breast cancer?

Trials at MSK and elsewhere are testing immunotherapy drugs called checkpoint inhibitors in combination with chemotherapy. Two checkpoint inhibitors — atezolizumab and pembrolizumab — have received accelerated approval by the US Food and Drug Administration to be paired with chemotherapy in certain metastatic triple negative breast cancer patients. These are patients with PD-L1-positive tumors. PD-L1 is a protein that helps keep immune cells from attacking normal, nonthreatening cells in the body, but it also prevents the immune cells from attacking cancer cells. Approximately 40% of triple-negative tumors are PD-L1 positive.  Blocking the PD-L1 protein makes anti-cancer treatments more effective. Triple-negative breast cancers have been previously hard to treat because they don’t respond to drugs that target estrogen, progesterone, or HER2 receptors.

Checkpoint inhibitors work by releasing a natural brake on your immune system so that immune cells called T cells recognize and attack tumors.

The phase III trial that led to this accelerated approval evaluated the combination of pembrolizumab with several chemotherapy partners. Results presented at the meeting confirmed that a benefit was seen regardless of the chemotherapy partner. This means we have different choices for patients with PD-L1 positive tumors.

What is the role of chemotherapy today?

Chemotherapy has been routinely used in breast cancer treatment. Some of the more interesting research relates to identifying people who can be treated without chemotherapy, depending on the specifics of their tumor. This is referred to as de-escalation of therapy. MSK participated in a large clinical trial called TAILORx examining whether genes frequently associated with risk of recurrence for women with early-stage breast cancer can be used to assign the best treatment to patients – for example, endocrine therapy alone or endocrine therapy plus chemotherapy. In 2018, results from that trial demonstrated that postmenopausal women with and low-to-intermediate-risk breast cancer may not need chemotherapy.

That trial looked at women whose disease had not spread to lymph nodes in the armpit and whose genetic makeup — in the tumor — suggested they may be at lower risk of the cancer returning. We are now looking to see if more women can safely skip chemotherapy even if the cancer has spread to a small number of nodes (up to three lymph nodes). Data presented at the meeting suggested that this can be done in postmenopausal women if the genomic risk is low to intermediate. This will now have practice-changing implications for our patients today.

As we learn more about different genomic alterations, we can more precisely match a plethora of effective therapies to improve the outcomes for endocrine-resistant breast cancer patients.
Komal Jhaveri medical oncologist

In addition, a big advance in the past year was the approval by the US Food and Drug Administration of trastuzumab deruxtecan, a drug called an antibody drug conjugate to treat an aggressive subtype of breast cancer called HER2. Antibody conjugates have two parts — the antibody that targets cancer cells and the chemotherapy attached it to — which work together to kill cancer cells. This particular drug is called trastuzumab deruxtecan.

At the meeting, MSK presented updated data from the clinical trial that led to the accelerated approval of trastuzumab deruxtecan in December 2019. The drug was approved for people with metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based treatment regimens. About 20% of breast cancers are HER2 positive, and these cancers tend to be aggressive.

Because most HER2 cancers eventually stop responding to drugs and begin growing again, the approval of trastuzumab deruxtecan was a major advance. It is exciting to see that as more data has come in after the approval, the results are even more encouraging.

With research moving so quickly in this field, what are the advantages of receiving breast cancer treatment at MSK?

We have all the latest tools at our disposal to provide the best, personalized care. We can conduct genetic sequencing to determine which mutations are present in the tumor — in addition to which mutations have been inherited — to assign the best treatments. In many cases, results from the sequencing suggests a patient is eligible to enroll in one of the large number of clinical trials we offer. MSK continues to be deeply involved in breast cancer research, helping to advance the field. Each new study gives us valuable information to make breast cancer treatments even better.