Report Back from SABCS 2023: Spotlight on the Latest in MBC
Today we are bringing you a special episode that we created in partnership with SHARE Cancer Support. It’s an audio version of a live webinar that was done this past February called Report Back from San Antonio Breast Cancer Symposium 2023. SABCS is the world’s leading breast cancer research meeting where scientists, patient advocates, and others dedicated to working in the field of cancer gather.
In this podcast, Dr. Timothy Pluard highlighted promising research, targeted therapy, the evolving treatment after CDK 4/6 inhibitors, liquid biopsy and more.
Subjects and Terms Included in This Episode
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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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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.
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A mutation of the AKT1 gene. The gene provides instructions for making a protein called AKT1 kinase. This protein is found in various cell types throughout the body, where it plays a critical role in many signaling pathways. For example, AKT1 kinase helps regulate cell growth and division (proliferation), the process by which cells mature to carry out specific functions (differentiation), and cell survival. AKT1 kinase also helps control apoptosis, which is the self-destruction of cells when they become damaged or are no longer needed. When mutated, it has the potential to cause normal cells to become cancerous.
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A transmembrane glycoprotein encoded by the Tacstd2 gene. It is an intracellular calcium signal transducer that is differentially expressed in many cancers. It signals cells for self-renewal, proliferation, invasion, and survival. It has stem cell-like qualities
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Phosphoinositide 3-kinases, also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer.
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A type of targeted drug treatment that block the action of enzymes called tyrosine kinases. Tyrosine kinases are a part of many cell functions, including cell signaling, growth, and division. These enzymes may be too active or found at high levels in some types of cancer cells, and blocking them may help keep cancer cells from growing.
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Phosphatase and tensin homologue, or PTEN, is a gene that provides instructions for making an enzyme that is found in almost all tissues in the body. The enzyme acts as a tumor suppressor, which means that it helps regulate cell division by keeping cells from growing and dividing (proliferating) too rapidly or in an uncontrolled way. Loss of PTEN can then lead to uncontrolled cell proliferation.
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Programmed death ligand-1, or PD-L1, is a crucial protein for tumor immune escape and its presence indicates a potential target for immune checkpoint inhibitors. PD-L1 emerged as an early biomarker to be tested in immunotherapy clinical trials.
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Cyclin-dependent kinase 4 & 6, or CDK 4/6, are proteins that regulate cellular transition by promoting cellular proliferation, meaning they control how quickly cells grow and divide.
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Endocrine resistance is seen in ER+ breast cancer and is the resistance to estrogen receptor suppression. When this happens the endocrine treatment used to treat the cancer is no longer effective and cancer cells have the ability to survive and grow. Approximately 30-50% of ER+ breast cancer patients will develop endocrine resistance.
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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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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
Novel Therapies Mentioned in the Episode
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Aromatase inhibitors lower estrogen levels by stopping an enzyme in fat tissue (called aromatase) from changing other hormones into estrogen.
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Fulvestrant is an antiestrogen that binds to proteins called estrogen receptors, which are found in some breast cancer cells. These proteins may cause cancer cells to grow. Fulvestrant blocks these proteins and may keep cancer cells from growing. t is used alone or with ribociclib (kisqali) in postmenopausal women who have not been treated with hormone therapy or whose disease got worse after treatment with hormone therapy. It is also used with palbociclib (ibrance) or abemaciclib (verzenio) n women whose disease got worse after treatment with hormone therapy.
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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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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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Durvalumab is an FDA-approved immunotherapy for cancer, developed by Medimmune/AstraZeneca. It is a human immunoglobulin G1 kappa monoclonal antibody that blocks the interaction of programmed cell death ligand 1 with the PD-1. Durvalumab is an immune checkpoint inhibitor drug.
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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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Alpelisib is indicated in combination with fulvestrant for the treatment of postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer with a PIK3CA mutation after disease progression following endocrine therapy.
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Truqap in combination with Faslodex (fulvestrant) has been approved in the US for the treatment of adult patients with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer with one or more biomarker alterations (PIK3CA, AKT1 or PTEN).
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Neratinib ( is a tyrosine kinase inhibitor used with capecitabine (xeloda) to treat adults with HER2-positive metastatic breast cancer and who have received 2 or more anti-HER2 therapy medicines for metastatic breast cancer. It is also used as an extended adjuvant therapy (within 2 years of completing surgery & chemotherapy) to treat early-stage HER2-positive breast cancer
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Tucatinib is used with other drugs to treat adults with certain types of HER2-positive breast cancer. It works by blocking a protein called HER2, which may help keep cancer cells from growing and may kill them. It is a type of tyrosine kinase inhibitor.
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Pembrolizumab is a type of targeted therapy drug called an immune checkpoint inhibitor (a type of immunotherapy). It is a monoclonal antibody that binds to the protein PD-1 on the surface of immune cells called T cells. It works by keeping cancer cells from suppressing the immune system. This allows the immune system to attack and kill the cancer cells.
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A specifically engineered TROP2-directed DXd antibody drug conjugate (ADC) being jointly developed by AstraZeneca and Daiichi Sankyo
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Zanidatamab is an investigational HER2-targeted bispecific antibody-drug conjugate.
Clinical Trials Mentioned in this Episode
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Phase III trial results of capivasertib, an oral AKT inhibitor, plus fulvestrant was found to be beneficial to all regardless of AKT alteration status. On November 16, 2023, the Food and Drug Administration approved capivasertib (Truqab, AstraZeneca Pharmaceuticals) with fulvestrant for adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN-alterations, as detected by an FDA-approved test, following progression on at least one endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy.
https://pubmed.ncbi.nlm.nih.gov/37256976/
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BEGONIA (NCT03742102) is an ongoing 2-part, open-label platform study in 1L a/mTNBC, evaluating D, an anti–PD-L1 antibody, plus novel therapies, including Dato-DXd, an antibody-drug conjugate made of a anti-TROP2 antibody covalently linked via a cleavable linker to a topoisomerase I inhibitor payload. Early data from BEGONIA Arm 7, Dato-DXd + D, showed promising responses.
https://www.annalsofoncology.org/article/S0923-7534(23)01392-3/fulltext
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The TROPION-Breast01 trial studied the antibody-drug conjugate datopotamab deruxtecan (Dato-DXd) in previously treated HR+, HER2- breast cancer patients and showed improved progression-free survival to 7 months compared to 4.5 months with standard chemotherapy, with less high grade toxicity observed with Dato-DXd.
https://www.annalsofoncology.org/article/S0923-7534(23)04159-5/fulltext
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In this randomized trial, there was a significant progression free survival benefit for patients with HR+/HER2– MBC who switched estrogen therapy and received ribociclib (kisqali) compared with placebo after previous CDK4/6i and different estrogen therapy.
https://ascopubs.org/doi/abs/10.1200/jco.22.02392
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This study will evaluate the efficacy, safety, and how the body interacts with inavolisib in combination with palbociclib (ibrance) and fulvestrant compared with placebo plus palbociclib and fulvestrant (faslodex) in participants with PIK3CA-mutant, hormone receptor (HR)-positive, HER2-negative metastatic breast cancer. At it’s primary endpoint, the combination of inavolisib with palbociclib and fulvestrant in the first line demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) vs palbociclib and fulvestrant alone.
https://www.targetedonc.com/view/inavolisib-combo-meets-primary-end-point-in-pik3ca-mutated-breast-cancer
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Phase 3 trial of Tucatinib (tukysa) and Trastuzumab Emtansine also known as T-DM1 (kadcyla) for previously teated HER2-positive metastatic breast cancer. Conclusions to the study showed that adding tucatinib to T-DM1 significantly improved progression free survival on patients with previously treated HER2+ LA/MBC.
https://www.onclive.com/view/her2climb-02-primary-analysis-of-a-randomized-double-blind-phase-3-trial-of-tucatinib-and-trastuzumab-emtansine-for-previously-treated-her2-positive-metastatic-breast-cancer
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Trial that studied adding alpelisib (piqray) along with fulvestrant (faslodex) to women with MBC in the second-line setting after progression on the first-line aromatase inhibitor therapy. A clinically meaningful almost 6 month improvement was shown in progression-free survival.
Meet the Guest of this Episode
Timothy Pluard, MD
Dr. Pluard is a breast oncologist who focuses exclusively on metastatic breast cancer. He is the founder and director of the Saint Luke’s Koontz Center for Advanced Breast Cancer. The Koontz Center was among the first centers to focus exclusively on the comprehensive care of patients with MBC. An extensive research program focused on new therapeutics for MBC has contributed to multiple new approved treatments that have significantly improved outcomes in metastatic breast cancer. The Koontz Center also imbeds psychology, nutrition, physical therapy/exercise and social work support into the routine care of MBC patients.
