Understanding Progression: How to Identify & Treat ESR1 Mutations in HR+ MBC
New therapeutic options are now available for HR+ MBC. Dr. Virginia Kaklamani will discuss endocrine therapy resistance, liquid biopsy/blood test, mutations, and treatment sequencing of targeted therapy. You will learn about oral selective estrogen receptor degraders (SERDS), clinical trials, and more.
Subjects and Terms Included in This Episode
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In scientific literature and trial results announcements, a p value of less than 0.05 generally is set as a benchmark to determine whether findings are "statistically significant," but the lay people often make the mistake of conflating that number with clinical significance, P values don't tell anything about clinical benefit. They only show how likely results are to be true and not a play of chance. A p value of <0.05 does not necessarily indicate that a treatment is effective. It means that one illegitimate effect (false-positive result) is expected in every 20 comparisons.
Researchers can conduct a trial in 2,000 patients and identify a difference of a few days in survival. It might be statistically significant, but it's not clinically important. When you try to see this same small difference in the general patient population, the effect is smaller and the toxicity is higher.
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The Kaplan-Meier curve is and. what it is used for. It shows the probability that a subject will survive up to time t. The curve is constructed by plotting the survival function against time.
The curve displays both those participants who have had the event, and the duration on study of those who have not yet had the event. The x-axis shows time, and the y-axis shows the proportion of patients who have or have not had the event. So at x=0 (the start of the trial) and y is 100%. The curve is downward sloping.
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HR = hazard in treatment arm
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Hazard in control arm
In clinical research, hazard ratios are often used in clinical trials to measure survival at any point in time in a group of patients who have been given a specific treatment compared to a control group given another treatment or a placebo. A hazard ratio of one means that there is no difference in survival between the two groups. A hazard ratio of greater than one or less than one means that survival was better in one of the groups.
What does a hazard ratio of 0.75 mean? Interpretation of a Hazard Ratio. HR (E vs C) = 0.75 for an overall survival end point. This means on average, under an exponential distribution, approximately • a 25% lower risk of death (25% as 1 − 0.75 = 0.25)
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Randomized controlled trials (RCT) are prospective studies that measure the effectiveness of a new intervention or treatment.
A study design that randomly assigns participants into an experimental group or a control group. As the study is conducted, the only expected difference between the control and experimental groups in a randomized controlled trial (RCT) is the outcome variable being studied.
Advantages
Good randomization will "wash out" any population bias
Easier to blind/mask than observational studies
Results can be analyzed with well known statistical tools
Populations of participating individuals are clearly identified
Disadvantages
Expensive in terms of time and money
Volunteer biases: the population that participates may not be representative of the whole
Loss to follow-up attributed to treatment
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In a randomized trial some study participants will be assigned to a “control arm” or “control group” in the study.
Those who are in the control arm will not receive the new treatment that is under study, to provide a comparison to see how the innovation compares against an old treatment. Members of the control group in MBC trial will receive the standard of care treatment and never placebo alone.
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An arm type in which a group of participants receives the intervention/treatment that is the focus of the clinical trial.
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Overall survival refers to the fact that a patient has not died from any cause. Thus, in a clinical trial the measure of overall survival would compare the number of patients who had died and the number who had not died.
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Progression free survival refers to survival without progression of the disease. In a clinical trial a measure of progression free survival would compare the number of patients whose disease had progressed (got worse) with the number whose disease had had not progressed.
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Clinical trial endpoints can be classified as primary or secondary. The primary endpoint is the most important outcome and is used to assess the primary objective of a trial.
Primary endpoints measure outcomes that will answer the primary or most important question being asked by a trial, such as whether a new treatment is better at preventing disease-related death than the standard therapy33.
Secondary endpoints answer other relevant questions about the same study; for example, whether there is also a reduction in disease measures other than death or outcomes rated by patients such as quality of life
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Antibody–drug conjugates (ADCs is anew class of anticancer agents, capable of exploiting the specificity of monoclonal antibodies toward cellular-antigens for a targeted release of potent cytotoxic drugs, with a potential increased activity and reduced toxicity compared with traditional chemotherapies.
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A type of protein that is made in the laboratory and can bind to certain targets in the body, such as antigens on the surface of cancer cells. There are many kinds of monoclonal antibodies, and each monoclonal antibody is made so that it binds to only one antigen. Monoclonal antibodies are being used in the treatment of breast cancer. They can be used alone or to carry drugs, toxins, or radioactive substances directly to cancer cells.
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A substance that kills cells, including cancer cells. These agents may stop cancer cells from dividing and growing and may cause tumors to shrink in size.
Chemotherapy drugs are made to kill all the cells that are growing fast—even normal cells. However, not all drugs that treat cancer are cytotoxic. New treatments like targeted therapies and immunotherapies are not cytotoxic. Instead, they work by getting in the way of a cancer cell's growth.
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Antibody drug conjugates (ADCs) employ the exquisite specificity of tumour-specific monoclonal antibodies (mAb) for the targeted delivery of highly potent cytotoxic drugs to the tumour site. The chemistry of the linker, which connects the drug to the mAb, determines how and when the drug is released from the mAb. This, as well as the chemistry of the drug, can dictate whether the drug can diffuse into surrounding cells, resulting in ‘bystander killing’. Initially, any bystander killing mechanism of action of an ADC was understood to involve an essential sequence of steps beginning with surface antigen targeting, internalisation, intracellular linker cleavage, drug release, and diffusion of drug away from the targeted cell. However, recent studies indicate that, depending on the linker and drug combination, this mechanism may not be essential and ADCs can be cleaved extracellularly or via other mechanisms.
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Genomic testing is used to predict how cancer cells will grow and which treatments might work best against it. It's sometimes called "DNA sequencing." The test looks at all your genes rather than a specific one.
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A liquid biopsy is a blood test that detects cancer cells or DNA that are circulating in the blood, called “circulating tumor DNA” or “ctDNA.” Like healthy cells, cancer cells die and are replaced. When these dead cells break down, they are released from the tumor into the bloodstream. A liquid biopsy detects the small pieces of DNA in the bloodstream from these cancer cells.
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Circulating tumor DNA (ctDNA) is tumor-derived fragmented DNA in the bloodstream that has come from primary or metastatic cancer sites.
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ESR1 (estrogen receptor 1 or estrogen receptor alpha gene, also known as ER) is a gene that encodes the estrogen receptor protein. A mutation in the ESR1 gene is often found in metastatic hormone-receptor positive breast cancer.
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Phosphoinositide 3-kinases (PI3Ks) comprise a family of lipid kinases, or enzymes, that affect cell death, reproduction, and differentiation. In breast cancer, mutations of the PIK3CA gene have been linked to the initiation and progression of breast cancer cells.
Novel Therapies Mentioned in the Episode
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Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate composed of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. In a phase 1 dose-finding study, a majority of the patients with advanced HER2-positive breast cancer had a response to trastuzumab deruxtecan (median response duration, 20.7 months). The efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab emtansine requires confirmation.
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Sacituzumab govitecan-hziy is an antibody–drug conjugate that combines a humanized monoclonal antibody, which targets the human trophoblast cell-surface antigen 2 (Trop-2), with SN-38, which is conjugated to the antibody by a cleavable linker. Sacituzumab govitecan-hziy enables delivery of high concentrations of SN-38 to tumors.
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Elacestrant is used to treat certain types of hormone receptor-positive breast cancer (breast cancer that depends on hormones such as estrogen to grow) in adults. It is currently FDA approved for those who have had disease progression following treatment with at least one other hormone therapies and have an ESR1 mutation. ESR1 mutations are mutations acquired from using aromatase inhibitors and is thought to be associated with endocrine resistance
Elacestrant is in a class of medications called estrogen receptor antagonists. It works by stopping growth of cancer cells, dependent on estrogen, by blocking the ability of estrogen to bind.
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Capecitabine is a type of chemotherapy drug called an antimetabolite. In the body, capecitabine gets broken down into substances that interfere with the production of DNA, RNA, and proteins. This stops or slows the growth of cancer cells and other rapidly growing cells and causes them to die.
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Palbociclib is a medication developed by Pfizer for the treatment of HR-positive and HER2-negative breast cancer. It is a selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6. Palbociclib was the first CDK4/6 inhibitor to be approved as a cancer therapy.
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Ribociclib is a targeted treatment for hormone receptor (HR)-positive, (HER2)-negative metastatic breast cancer . It’s typically used in combination with an aromatase inhibitor as the first endocrine-based therapy, or with Fulvestrant as the first endocrine-based therapy or following disease progression on endocrine therapy in postmenopausal women or in men.
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Abemaciclib is a kinase inhibitor that is used in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of adult patients with HR-positive, HER2-negative metastatic breast cancer or in combination with fulvestrant for disease progression following endocrine therapy. It can also be used as monotherapy for disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. Lastly, it is used in the treatment of HR-positive, HER2-negative, node-positive early stage breast cancer at high risk of recurrence in combination with endocrine therapy in the adjuvant setting.
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Diclofenac is a gel applied to the skin used to prevent and/or treat hand-foot syndrome in people taking capecitabine.
Clinical Trials Mentioned in this Episode
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Study focused on determining if repeat biopsy would have an impact on Her2-low status in patients diagnosed with TNBC.
Conclusions: Findings show that Her2 status is dynamic in patients with TNBC and supports the idea that Her2- low status can change over time. In patients diagnosed with TNBC without Her2-low who have repeat biopsy on progression have an increased chance of obtaining a Her2-low result.
https://ascopubs.org/doi/abs/10.1200/JCO.2023.41.16_suppl.1005
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This was a randomized trial of fixed dose capecitabine compared to standard dose capecitabine in metastatic breast cancer.
Conclusion: Fixed dose capecitabine (1500mg twice daily) on a 7/7 schedule has less toxicity and similar survival when compared to standard dosing on a 14/7 schedule in MBC.
https://ascopubs.org/doi/abs/10.1200/JCO.2023.41.16_suppl.1007
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This study looked at the use of topical diclofenac in prevention of capecitabine associated hand foot syndrome in patients with breast cancer.
Conclusion: The study showed found that topical diclofenac gel significantly reduced hand foot syndrome in breast cancer patients taking capecitabine. It also found that patients using topical diclofenac required less dose reductions of capecitabine.
https://ascopubs.org/doi/abs/10.1200/GO.2023.9.Supplement_1.18
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Patritumab deruxtecan phase 1/2 trial (NCT02980341) showed the agent induced a response in patients with HER3-expressing metastatic breast cancer.
Clinical Trial is ongoing
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Phase 3 SONIA trial (BOOG 2017-03) analyzed selecting the optimal sequence of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors for patients with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer(ABC)
This SONIA study randomized patients to start first-line treatment with an anti-hormonal therapy; an aromatase inhibitor with palbociclib vs aromatase inhibitor by itself. In the second-line setting, on progression, patients were switched to fulvestrant by itself, if you got CDK4/6 in the first line, or fulvestrant and palbociclib in the second line.
Conclusion: There wasn’t a difference in progression free survival and there wasn’t a difference in overall survival, which would suggest you could use CDK4/6 inhibitors either in the frontline or second-line setting. There end results were similar. When the CDK4/6 was used in the second line the cost analysis showed a savings of about $200,000 because at the end of the day, you actually use less
https://ascopubs.org/doi/abs/10.1200/JCO.2023.41.17_suppl.LBA1000?role=tab
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ER+,Her2- MBC patients who had rising rates of ESR1 mutations in the blood in first line therapy of patients taking aromatase inhibitor and palbociclib were randomized to stay on the same combination or switch to fulvestrant combined with palbociclib.
Conclusions: Study supported the clinical benefit observed in Fulvestrant and palbociclib arm over the aromatase inhibitor with palbociclib arm and the type of ESR1 mutation did not impact the benefit of the treatment switch.
https://ascopubs.org/doi/abs/10.1200/JCO.2023.41.16_suppl.1002
Meet the Guest of this Episode
Virginia Kaklamani, MD
Dr Kaklamani is Professor of Medicine in the Division of Hematology/Oncology at the University of Texas Health Sciences Center in San Antonio and is the Leader of the Breast Cancer Program at the Mays Cancer Center. Dr Kaklamani completed her medical training with honors at the University of Athens and her residency in Internal Medicine at Newton-Wellesley Hospital in Boston, MA. She completed her fellowship in hematology/oncology at Northwestern University. She also received a Master of Science in Clinical Investigation from Northwestern University. She was Head of the Translational Breast Cancer Program at Northwestern University and co-director of the cancer genetics program at the same institution. Dr Kaklamani has also served as the Associate Director for Clinical Research at UT Health San Antonio. Her research interests include designing clinical trials with targeted agents. Dr Kaklamani has also identified several genetic mutations that link obesity and breast cancer.
