How Combination Therapies Are Changing the Landscape of Breast Cancer Care
By BCRF | March 30, 2020
By BCRF | March 30, 2020
Over the last 50 years, we have seen breast cancer treatment evolve from a single approach to more personalized treatments that focus on the characteristics of the tumor and the patient. In the last two to three decades, tremendous progress has been made in the development of targeted therapies—drugs that are directed to a specific characteristic of a tumor, like a protein or a cellular process that is driving the tumor’s growth. But many of these promising agents have failed as mono (single agent) therapy, largely because of a tumor’s ability to activate alternate growth-promoting pathways to overcome the therapy’s effects.
Scientists now recognize that combining effective treatments is a strategy to beat tumors at this game of “whack-a-mole.” The American Society of Clinical Oncology recently highlighted the success of this approach across breast cancer subtypes (via results from three clinical trials) in its report, Clinical Cancer Advances 2020.
For patients with triple-negative breast cancer (TNBC), which lack three common markers (estrogen receptor, progesterone receptor or overexpression of the HER2 receptor), targeted treatments are only just emerging.
One class of immunotherapy drugs called checkpoint inhibitors were recently approved for patients with advanced TNBC. Results from the IMpassion130 trial demonstrated that atezolizumab (Tecentriq®) dramatically extended survival for some patients when combined with chemotherapy, compared to chemotherapy alone. Those patients whose immune cells had high levels of a protein called PD-L1 were most likely to benefit (with an overall survival of 25 months on atezolizumab compared to 18 months on chemotherapy alone.) The FDA has since approved atezolizumab and it is now being used for this group of patients.
Breast cancers that depend on estrogen—called estrogen receptor (ER)-positive—make up more than 70 percent of all breast cancers. Because the tumor cells depend on estrogen, anti-estrogen therapies are very effective in treating this form of the disease. But these therapies tend to be less effective in metastatic breast cancer—cancers that have spread beyond the breast.
When combined with anti-estrogen therapy, a class of drugs called CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) have proven successful for postmenopausal women with ER-positive/HER2-negative metastatic breast cancer. The MONALEESA-7 trial was the first to show that younger women, who tend to be diagnosed with more aggressive breast cancers, also benefit from this combination approach. The trial reported overall survival at 42 months in 70 percent of patients receiving the CDK4/6 inhibitor ribociclib compared to 46 percent in women who received anti-estrogen therapy alone.
In December 2019, BCRF announced a $5 million partnership with Eli Lilly and Company as part of its Drug Research Collaborative. The partnership will fund investigator-initiated studies of the Lilly CDK4/6 inhibitor, abemaciclib (Verzenio®). Read more about this exciting program on our blog.
About 15 to 20 percent of breast cancers overexpress the protein HER2, a growth factor that is normally only active during tissue development. Trastuzumab (Herceptin®) and other HER2-directed therapies have transformed HER2-postive breast cancer from one with a poor prognosis to a treatable disease. Despite their ability to block HER2-stimulated growth, however, some HER2-positive breast cancers become resistant to these therapies. Combining them with chemotherapy or with dual HER2 targeting reduces the risk of these breast cancers coming back.
A more recent combination for HER2-driven breast cancers is in the form of an antibody-drug conjugate—meaning a drug attached to an antibody. Trastuzumab emtansine (TDM-1, Kadcyla®) combines a drug (emtansine) with trastuzumab, an antibody that recognizes HER2. The drug is released into the cancer cell when trastuzumab makes contact with the HER2 receptor.
Following the results of the KATHERINE trial, TDM-1 was approved for adjuvant (postoperative) therapy in high-risk, early-stage HER2-postive breast cancer. Patients in the KATHERINE trial received neoadjuvant (preoperative) chemotherapy plus trastuzumab. Those who had residual tumor at the time of surgery received either TDM-1 or trastuzumab as single agents following surgery. The study reported that patients receiving TDM-1 had a 50 percent less chance of recurrence than those who received trastuzumab.
Collectively, these three studies highlight the progress we’ve made in treating breast cancer—and particularly aggressive breast cancers. Systemic therapies have had a tremendous impact on reducing deaths from breast cancer, which have declined by 40 percent since the late 1980s. But there is always more work to be done. BCRF remains laser-focused on funding research to continue to improve patient outcomes.
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