AACR 2020 Conference – Recent Advances in Breast Cancer Treatments
By T. Chakraborty, Ph.D.
Breast cancer is the second most common cancer in women, with approximately 300,000 women being diagnosed with the disease every year. On an average, every two minutes a new case of breast cancer gets reported, and it accounts for 15% off all new cases reported in the US every year, thus putting an extensive socioeconomic burden on the society.
With the advancements in technology and better screening procedures, breast cancer is one of the most treatable forms of cancer, with 91% survival expectancy at five years for invasive forms of breast cancer. The major types of treatments in breast cancer include surgery, radiation, chemotherapy, and targeted therapy. BRCA1 and BRCA2 are the predominant gene mutations found in breast cancer. These are tumor suppressor proteins that help in DNA repair. The American Association for Cancer Research meeting held on the 27th of April 2020 featured a session exclusively to discuss the emerging research endeavors in the field, both concerning target identification and clinical trials .
The EMBRACA Clinical Trial
Recent studies have identified the poly (ADP-ribose) polymerases (PARPs) as a potential target for breast cancer treatments. PARPs are involved in a variety of cellular processes like DNA repair and apoptosis. The mode of action of most chemotherapy and some targeted therapies is inducing DNA damage, which leads to cancer cell death. To bypass that mechanism, cancer cells can utilize PARP to perform DNA repair, which makes these cells resistant to therapies. Hence, recent studies have been concentrating on the efficacy of PARP inhibitors as a potential therapy in clinical trials.
Dr. Jennifer Litton, from MD Anderson Cancer Center, gave an update on a Phase 3 clinical trial of one such PARP inhibitor, Talazoparib, at the AACR meeting. The EMBRACA trial is a Phase 3, open label randomized trial evaluating Talazoparib in 431 participants and to date the largest clinical trial for PARP inhibitors in breast cancer.
Talazoparib significantly improved progression-free survival when compared to chemotherapeutic agents. Interestingly, the overall survival rate was not significantly different between the two arms, but Dr. Litton noted that the patients receiving Talazoparib also received subsequent treatment with other PARP inhibitors or were subjected to Platinum therapy, which may both be confounding factors for the overall survival rate. Talazoparib further improved the global health quality of life by significantly delaying the clinical deterioration in breast cancer patients, an effect not observed with chemotherapy alone. The drug was well tolerated in patients with a few side effects, including nausea and anemia. Dr. Litton concluded that Talazoparib is a treatment option favorable to treat BRCA1/2 breast cancer.
Loss of BRCA1/2 Heterozygosity as a Biomarker for HER2 Negative Breast Cancer Therapy
PARP1 inhibition has been successfully used in the clinical trial of BRCA1/2 mutated breast cancer patients, but the dependency of tumor genomics towards sensitization of these drugs was not known and is an active area of research.
Dr. Lida Mina, from Banner Health, further provided an insight into the role of loss of BRCA1/2 heterozygosity and its effect on Talazoparib and chemotherapy benefit, which was studied in the EMBRACA trial as discussed above.
In the EMBRACA study, BRCA1/2 mutation was almost universal among the patients, with 44% of them having BRCA1 mutation, 51% having BRCA2 mutation and 1% having a mutation in both. Out of the 236 tumor samples sequenced, 83% recorded a loss of heterozygosity, where the mutated form of BRCA1/2 was retained. Interestingly, there was no correlation found between the progression-free survival rate in patients and BRCA1/2 loss of heterozygosity. Further, there was no correlation noted in drug efficacy either. Thus Dr. Mina concluded that genomic loss of BRCA1/2 heterozygosity might be a biomarker for identification of Human Epidermal growth factor receptor 2 (HER2) negative patients who can be treated with Talazoparib .
IMPRIME: A Probable Treatment for Triple Negative Breast Cancer
Immune checkpoint proteins are often hijacked by cancer cells to try and evade attack by the immune system. Immune checkpoint inhibition has shown much promise in treating several cancers. Immune checkpoint inhibitor (ICI) monotherapy has been deemed to show finite progress in metastatic triple negative breast cancer (mTNBC) patients.
To improve the success rate, researcher Steven J O’day, along with a team of other collaborators worked on using Imprime PGG (henceforth known as Imprime), to enhance the clinical benefit and quality of life in mTNBC patients. Inprime helps in activating the innate immune system to help reprogram/rejuvenate the immunosuppressive tumor environment and stimulate antigen specific T cells. In preclinical models, it has shown to dramatically augment the success rate of the ICI therapy based on which an open-label, Simon 2 stage study (12 patients, Stage 1, 32 patients, Stage 2) was designed (named IMPRIME 1) with a primary deadline of December 2019. Patients in this study received Imprime (4 mg/kg IV days 1, 8, 15 of each 3-week cycle) + pembro (humanized antibody used in cancer immunotherapy) 200 mg on D1 of each cycle. To monitor the effects of the drugs, CT scans were taken at baseline and six weeks until the end of the study. Primary and secondary endpoints were determined as ORR (RECIST v1.1), safety, PFS, and OS, respectively. For evaluating the immune activation in the patients, biopsies and blood samples were collected. Patients enrolled in this study had sufficient anti-beta glucan antibodies (≥20mcg/ml) as activation of innate immune cells require these antibodies.
Patients receiving the drug had an overall response rate of around 16%, which, when compared to other monotherapies like Keytruda, is significantly better. Further, the survival rate was 16.4 months, which was also considerably higher than Keytruda. Further treatment with Imprime activated the host immune cells like T cells and macrophages, which were able to penetrate the tumors. The treatment was well tolerated in patients, and no safety concerns were observed. The authors concluded that larger clinical trials are warranted to further test the efficacy of this drug.
ESR1 Mutation as a Probable Mechanism for Developing Endocrine Therapy Resistance in Primary Breast Cancer Tumors
The Estrogen receptor alpha (ESR1) mutation that leads to constitutive activation of the receptor has been reported in a majority of breast cancer patients. More than 60 mutations in this gene have mostly been linked to the development of resistance toward endocrine therapy, but the role of the mutations associated with ESR1 in primary tumors is not well documented.
In this study presented by Dr. Saal’s group from Lund University, the authors analyzed the mutation rate of ESR1 in approximately 3200 real-world and population-based early-stage primary breast cancers to determine the level of ESR1 mutation. Only 30 patients had primary ESR1 mutations, and most of the mutations were present in the C terminal ligand binding domain. These patients had a four times higher risk of relapse at any given time. The mutation in the primary tumor further predicted the failure of endocrine therapy in these patients. Furthermore, ESR1 mutation was a significant factor in the multivariable analysis, which prompted the authors to conclude that ESR1 mutation screening may help in the choice of therapy selection .
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