Atezolizumab Gives Hope to Triple-Negative Breast Cancer Patients

 

According to the Centers for Disease Control and Prevention, more than 1.5 million people are diagnosed with cancer each year and nearly 600,000 die of the disease.¹ This makes cancer the second most leading cause of death in the U.S. By the year 2020, the number of new diagnoses is expected to increase to almost 2 million per year.¹ Breast cancer is the most common cancer in women, excluding skin cancer. Nearly 250,000 new cases are diagnosed each year. Of these new cases, about 10- 20 % are triple-negative breast cancers. ² Triple-negative breast cancers (TNBCs), as the name suggests, lack receptors for estrogen, progesterone, and HER2.

Figure 1: Rates are per 100,000 people and age-adjusted to the 2000 US standard population.¹

          

          Since hormones and HER2 are not involved in supporting cancer growth, individuals with triple-negative breast cancers fail to respond to hormonal therapies or HER2 targeted therapies. In addition, triple-negative breast cancers tend to more aggressive and more likely to recur than other forms of cancer. Once the disease becomes metastatic, the median survival is around 12 to 15 months.²  The first line of treatment for TNBCs is chemotherapy, but many patients develop resistance to chemotherapy within a few months of treatment.³ Fortunately, researchers in Munich, Germany have found a new therapeutic target, PD-L1 receptor, against TNBC.

 

            PD-L1 or programmed cell death protein 1 receptor is a receptor on the surface of T-cells which inhibits T-cell-mediated immune response when it binds to its respective ligand, programmed death ligand 1 (PD-L1).⁴ Current evidence suggests that cancer cells evade antigen-specific T-cell immunologic response by activation of PD-1/PD-L1 signaling. By blocking or inhibiting PD-1/PD-L1 signals, cancer becomes subjected to T-cell mediation immune response.^4,5 Atezolizumab, is a monoclonal antibody against the PD-L1 receptor, was used by the researchers in Munich in their clinical trials with patients with metastatic triple-negative breast cancer.  

Figure 2: Mechanism of action of PD-1 and PD-L1 inhibitors. ⁵

 In a phase II trial, 902 patients with TNBC, without prior treatment, were randomized into 2 groups: standard chemotherapy (nab-paclitaxel) plus atezolizumab or standard chemotherapy plus placebo. The two main objectives were to measure if the drug combination could slow cancer growth (progression-free survival) and prolong life (overall survival) in all patients and in a subset of patients expressing PD-L1.⁶

 

Dr. Schmid and colleagues found that combination therapy (chemo plus atezolizumab) reduced the risk of disease worsening or death by 20% in all patients and 38% in the subgroup expressing PD-L1.⁶ The median progression-free survival was 7.2 months with the combination compared to 5.5 months with chemotherapy alone.⁶ In the PD-L1 positive group, the median progression-free survival was 7.5 months with the combination versus 5.0 months with just chemotherapy.⁶ In patients with PD-L1 positive tumors, the median overall survival was 25.0 months with the combination compared to 15.5 months with standard chemotherapy alone. In all patients, survival was 21.3 months with the combination versus 17.6 months with just chemotherapy.⁶

These results suggest the Atezolizumab is the first targeted treatment to improve survival up to 10 months in TNBC patients expressing PD-L1. Dr. Schmid believes the outcomes can be further improved by selecting for a better chemotherapy backbone for the combination therapy. Many clinical trials are still ongoing, investigating the effectiveness of PD-L1 antibodies in head, neck, and lung cancers. Other studies are looking at CTLA-4 as potential checkpoint target in myeloma and other forms of cancers. Bi-specific antibodies and cancer vaccines are currently in development as well.⁵ Our fight against cancer appears more hopeful than ever before thanks in large part to recent advances in cancer biology and immunotherapy. 

References: 

1. National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP). (2017, November 13). Retrieved November 2, 2018, from https://www.cdc.gov/chronicdisease/resources/publications/aag/dcpc.htm
2. What Is Triple-Negative Breast Cancer? (n.d.). Retrieved November 2, 2018, from https://www.breastcancer.org/symptoms/diagnosis/trip_neg/behavior
3. Study may explain why some triple-negative breast cancers are resistant to chemotherapy. Retrieved November 4, 2018, from https://www.mdanderson.org/newsroom/2018/04/study-may-explain-why-some-triple-negative-breast-cancers-are-resistant-to-chemotherapy.html
4. Immune checkpoint inhibitors to treat cancer. (n.d.). Retrieved November 2, 2018, from https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy/immune-checkpoint-inhibitors.html
5. Gong, J., Chehrazi-Raffle, A., Reddi, S., & Salgia, R. (2018). Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: A comprehensive review of registration trials and future considerations. Journal for ImmunoTherapy of Cancer,6(1). doi:10.1186/s40425-018-0316-z
6. Schmid, P. (2018). ESMO 2018 presidential symposium—IMpassion130: Atezolizumab nab-paclitaxel in triple-negative breast cancer. ESMO Open,3(6). doi:10.1136/esmoopen-2018-000453
   
   

   By Satyanarayana Alluri, Master of Medical Sciences Student, University of Kentucky