Dr. Shanu Modi: How to Get a Standing Ovation at ASCO?
Episode Notes
The short answer to our title question is that you present a clinical trial that’s a game-changer for treating metastatic breast cancer. That’s what happened in June when Shanu Modi, MD, medical oncologist and attending physician at Memorial Sloan Kettering Cancer Center, shared the results of the DESTINY-Breast04 trial at the American Society of Clinical Oncology meeting.
DESTINY Breast04 showed that trastuzumab deruxtecan aka Enhertu aka TDXd, a drug that combines an antibody with a chemotherapy, can extend survival in HER2-low MBC patients. It is the first HER2 targeted therapy to demonstrate statistically significant and clinically meaningful improvements in progression-free survival and overall survival compared to standard chemotherapy for patients with HER2-low metastatic breast cancer. Further, its benefits were seen across breast cancer subgroups including both hormone receptor positive and negative patients.
In this episode, we continue the exploration of HER2-low and Enhertu we began in Episode 2 of our season 5 series. Our MBC Life’s Victoria Goldberg and Lynda Wetherby both saw the history-making presentation at ASCO and were thrilled to have the chance to follow up with Dr. Modi, who was lead researcher on the DESTINY trial. The following are some of the questions and issues covered in their lively conversation.
What makes Enhertu (Trastuzumab deruxtecan) different from other chemotherapy? What does it mean that it is an “antibody drug conjugate”
Who can benefit from the drug? What does that look like for TNBC as well as ER+ patients?
What “adverse events” or side effects were seen in the trial? How can they be minimized and managed?
What comes next—what do the results of the DESTINY Breast 04 trial mean for current and future research?
If you have not done so already, listen to our October 12 Episode, MBC101: the HER2-low Show, for a deep dive on how pathologists are dealing with the new challenge of HER2-low—and what you can do to make sure you know your HER2 status.
Glossary
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The ImmunoHistoChemistry assay (IHC)
IHC is the most commonly used test to see if a tumor has too much of the HER2 receptor protein on the surface of the cancer cells. With too many HER2 receptors, the cells receive too many signals telling it to grow and divide.
Done to see if breast cancer cells have too many HER2 protein receptors.Gives a score of 0 to 3+ that measures the amount of HER2 receptor protein on the surface of cells in a breast cancer tissue sample
The In-Situ Hybridization test (ISH). Looks at the gene amplification of the sampleThe results of this test are also classified as positive, negative, or equivocal
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The IHC test gives a score of 0 to 3+ that measures the amount of HER2 receptor protein on the surface of cells in a breast cancer tissue sample. If the score is 0 to 1+, it’s called HER2 negative. If the score is 2+, it's called borderline. A score of 3+ is called HER2 positive.
We know that a large number of breast cancers considered HER2-negative have some HER2 proteins on the surface of its cells. There just aren’t enough HER2 proteins for the cancer to be considered HER2-positive. Doctors now consider these cancers HER2-low.
HER2-low breast cancer has a 1+ score on an IHC test or a 2+ score on an IHC test plus a negative FISH test.
IHC test results are most reliable for fresh or frozen tissue samples. IHC tends to be an unreliable test for tissue that's preserved in wax or other chemicals.
This information is provided by Breastcancer.org.
Donate to support free resources and programming for people affected by breast cancer: https://give.breastcancer.org/give/294499/#!/donation/checkout?c_src=clipboard&c_src2=text-linkbecome evident that their dysregulation, as a consequence of gene amplification, protein overexpression, or activating mutations, leads to the development of cancers.
Of the ERBB family members, HER2 and EGFR are frequently overexpressed in breast cancer. Two main classes of anticancer agents affect HER2 and EGFR. They are monoclonal antibodies like Herceptin which target the ligand binding domain, and small molecule tyrosine kinase inhibitors like Lapatinib and Tukatinib that target intracellular TK domain. Contrary to other ERBB family members, HER2 does not directly bind to any known ligands. Instead, activation of HER2-mediated signaling pathways occurs by cross-linking with adjacent ligand-activated EGFR or ERBB3. By blocking the EGFR and HER2, the growth of cancer cells can be curbed significantly.
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We define the new HER2-low type using IHC scores of 1+ or 2+ without gene amplification, and this group includes both hormone receptor positive and hormone receptor negative breast cancers. And based on this definition, the majority of HER2-negative breast cancers are actually HER2-low. The remaining much smaller group with IHC 0nscore is now defined as HER2-negative
Even though we call HER2-low a new subtype of breast cancer it really does not appear to have a unique biology and there are no differences in molecular subtypes or gene expression profile between HER2-low and the HER2 0. Take their hormone receptor status for example, the hormone receptor positive breast cancers are mostly luminal and the hormone receptor negative breast cancers (we call these cancers TNBC) are all basal like.And this is regardless of HER2-low or HER2-zero expression.
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HER2 status in breast cancer is assessed to select patients eligible for targeted therapy with anti-HER2 therapies. According to the American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP), the HER2 test positivity is defined by protein overexpression (score 3+) at immunohistochemistry (IHC) and/or gene amplification at in situ hybridization (ISH).
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Human epidermal growth factor receptor 2 (HER2) is a gene that creates HER2 proteins. HER2 proteins are found on the surface of breast cells and promote breast cell growth. In a healthy breast cell, HER2 is responsible for repairing the cell and growing more cells. If the HER2 gene is mutated, it causes an abnormal increase in the amount of HER2 proteins on the surface of the cells. This causes cells to grow and divide out of control. About 15% of breast cancers are HER2-positive, meaning the HER2 gene doesn’t function correctly.
HER2-positive breast cancer is not inherited. Instead, it’s considered a somatic genetic mutation. This type of mutation occurs after conception. Having a close relative with HER2-positive breast cancer does not increase your risk for breast cancer or HER2-positive breast cancer.
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Recently, a potential for HER2 targeting in HER2 “ultra-low” (i.e. score 0 with incomplete and faint staining in ≤10% of tumor cells) and MutL-deficient estrogen receptor (estrogen receptor)-positive/HER2-negative breast cancers has been highlighted.
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HER2 pathogenic activating mutations occur irrespectively of HER2 IHC status as they do not necessarily lead to protein overexpression, representing an alternative mechanism for activating the HER2 pathway in breast cancer. For example V777L ERBB2 mutation has demonstrated to be an activating mutation as it strongly increased the phosphorylation of signaling proteins, indicating enhanced activity of the tyrosine kinase and showed sensitivity to TKIs: lapatinib and neratinib
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The National Comprehensive Cancer Network® (NCCN®) is a not-for-profit alliance of 32 leading cancer centers devoted to patient care, research, and education. NCCN is dedicated to improving and facilitating quality, effective, equitable, and accessible cancer care so all patients can live better lives.
The NCCN Guidelines are a comprehensive set of guidelines detailing the sequential management decisions and interventions that currently apply to 97 percent of cancers affecting patients in the United States.
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Microtubules are part of the cytoskeleton, a structural network within the cell's cytoplasm. The roles of the microtubule cytoskeleton include mechanical support, organization of the cytoplasm, transport, motility and chromosome segregation. Microtubules extend throughout the cell providing it with proper shape and keeping the organelles in place
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Vinca alkaloids are a subset of drugs obtained from the Madagascar periwinkle plant. They are naturally extracted from the pink periwinkle plant. This type of drug blocks cell growth by stopping mitosis (cell division). Vinca alkaloids interfere with microtubules (cellular structures that help move chromosomes during mitosis). They are used to treat cancer.
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The word cytotoxic means damaging or destroying living cells
Cytotoxic drugs (sometimes known as antineoplastics) describe a group of medicines that contain chemicals which are toxic to cells, preventing their replication or growth, and so are used to treat cancer.
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
Novel Therapies Mentioned in the Episode
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This is a novel payload Enhertu
Topoisomerase I inhibitors are a new class of anticancer agents with a mechanism of action aimed at interrupting DNA replication in cancer cells, the result of which is cell death. Most if not all Topoisomerase I inhibitors are derivatives of the plant extract camptothecin.
Topoisomrase I inhibitors include lamellarin D, irinotecan (CPT-11), topotecan, and camptothecin chemical drugs. The topoisomerase I inhibitor agent camptothecin is known as the most effective anticancer agent around the world (with respect to agents which are used in clinical side).
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Novel Therapy of the Antibody Drug Conjugatee (ADC) class
Trastuzumab deruxtecan is a monoclonal antibody, called trastuzumab, linked to a chemotherapy drug, called deruxtecan. Trastuzumab attaches to HER2 positive cancer cells in a targeted way and delivers deruxtecan to kill them.
FDA approved HER2-positive and HER2-low MBC
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Neratinib is a protein kinase inhibitor used to treat breast cancer that over expresses the HER2 receptor
Based on updated findings from the phase 2 SUMMIT trial, a neratinib triplet with capecitabine and trast uzumaband neratinib and doublet with trrastuzumab alone can induce responses in patients with HER2-positive breast cancer.
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Durvalumab is a checkpoint inhibitor and currently approved to treat non-small cell lung cancer (NSCLC) that has not spread and cannot be removed by surgery in patients who have received other cancer medicines (eg, platinum) and radiation treatment for their NSCLC.
Durvalumab improves long-term outcome in TNBC: results from the phase II randomized GeparNUEVO study investigating neodjuvant durvalumab in addition to an anthracycline/taxane based neoadjuvant chemotherapy in early triple-negative breast cancer (TNBC).
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Trastuzumab duocarmazine is an investigational next-generation, HER2-directed antibody-drug conjugate (ADC) that received fast track designation from the FDA in January 2018 based on phase 1 data (NCT02277717) in heavily pretreated patients with HER2-positive metastatic breast cancer
It is a homogeneous and highly stable antibody drug conjugate (ADC) targeting the HER2 receptor. ARX788 is a Precision Biologic ADC that consists of two cytotoxic payloads site-specifically conjugated to a Herceptin® (trastuzumab) based antibody.
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Disitamab vedotin (RC48) is a novel ADC comprised of a humanized HER2-specific monoclonal antibody mAb (hertuzumab) linked to the cytotoxic MMAE via cleavable linker. Vedotin, referring to MMAE and the mc-val-cit-PABC linker, has already been validated for an approved ADC, brentuximab vedotin (Adcetris®) Compared to trastuzumab, hertuzumab possesses a higher HER2-specific affinity. With a cleavable linker, RC48 was shown to exhibit significant bystander effects where the payloads diffused to adjacent cells, which was not the case with T-DM1. In addition, RC48 showed superior antitumor activity than T-DM1 not only in HER2-overexpressing xenograft tumor models but also in trastuzumab- and lapatinib-resistant xenograft tumor models
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Trastuzumab emtansine (T-DM1) is composed of: 1) trastuzumab, a humanized HER2-targeting mAb that have been approved for the treatment of HER2-positive breast cancer; 2) a non-cleavable linker, 3) a potent microtubule-depolymerizing maytansinoid derivative, DM1 . The mechanism of action of T-DM1 are believed to be involved with the functions of both trastuzumab and DM1, which include trastuzumab-mediated inhibition of HER2 signaling, induction of antibody-dependent cell-mediated cytotoxicity (ADCC)
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Patritumab deruxtecan (HER3-Dxd; U3-1402) is composed of an anti-HER3 mAb (patritumab), a cleavable GGFG linker, and the topoisomerase I inhibitor DXd U3-1402 displayed a high HER3-specific binding affinity among other human HER family receptors, including EGFR, HER2 and HER4, and was also shown to possess potent antitumor activity in patient-derived xenograft models with an acceptable safety profile. A mechanism of action study showed that the activity of U3-1402 was driven by an efficient internalization and intracellular trafficking of ADCs to lysosome to release the toxic compounds
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Dato-DXd is an antibody-drug conjugate (ADC) consisting of a humanized anti-TROP2 IgG1 monoclonal antibody attached to a topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. In the ongoing phase 1 TROPION-PanTumor01 study (NCT03401385; DS1062-A-J101), Dato-DXd 6 mg/kg monotherapy
Clinical Trials Mentioned in this Episode
Phase 1b/2 BEGONIA study of durvalumab combinations in locally advanced/metastatic triple-negative breast cancer (TNBC) ( NCT03742102)
Phase 3 DESTINY-Breast03 study (NCT03529110)
Phase 3 DESTINY-Breast04 Trastuzumab Deruxtecan (DS-8201a) Versus Investigator's Choice for HER2-low MBC (NCT03734029)
Phase 3 DESTINY-Breast06 Trastuzumab Deruxtecan (T-DXd) vs Investigator's Choice Chemotherapy in HER2-low, Hormone Receptor Positive, Metastatic Breast Cancer (NCT04494425)
Platform Phase 1b/2 DESTINY-Breast07 Study of T-DXd Combinations in HER2-positive Metastatic Breast Cancer (includes active brain mets arm) (NCT04538742)
Platform Phase 1b/2 DESTINY-Breast08 Study of T-DXd Combinations in HER2-low Metastatic Breast Cancer (includes immunotherapies) (NCT04556773)
Phase 3 DESTINY-Breast12 Study of T-DXd in Participants With or Without Brain Metastasis Who Have Previously Treated Advanced or Metastatic HER2 Positive Breast Cancer (NCT04739761)
Phase 2 DAISY Study of T-DXd for Advanced Breast Cancer Patients, With Biomarkers Analysis (NCT04132960
Phase 3 TULIP Study o trastuzumab duocarmazine vs. Physician's Choice in Participants With HER2-positive Locally Advanced or Metastatic Breast Cancer (NCT03262935)
Want more?
Check out Last Week’s MBC101 Episode
Meet the Guest of this Episode
Shanu Modi, MD
Associate Professor of Medicine, Department of Medicine Weill Cornell Medical College,New York
Associate Member of the Breast Medicine Service at MSKCC
Section Head, HER2 Positive Breast Cancer, Breast Medicine Service Memorial Sloan Kettering Cancer Center New York, NY
Dr. Modi is a medical oncologist specializing in the care of patients with all stages of breast cancer. She has been a full-time faculty member of the Breast Medicine Service at MSKCC since 2005.
Dr. Modi received her medical degree from the University of Alberta in Edmonton, Canada where she also completed a residency in internal medicine. She followed this with subspecialty training in medical oncology at the Cross Cancer Institute and subsequently completed a 4-year fellowship in breast cancer research at MSKCC.
She has had a clinical research career in the development of HER2- targeted therapies and is currently the Section Head for HER2 Positive Breast Cancer for the Breast Medicine Service at MSKCC. Dr. Modi is also a member of the Expert Committee to establish Guidelines for Patients with Advanced HER2+ Breast Cancer, where she serves on the Breast Cancer Consensus Panel. She is also a member of the Scientific Committee for the European Society of Medical Oncology (ESMO) as part of the metastatic breast cancer track responsible for abstract selection. She is an ad hoc reviewer for Journal of Clinical Oncology, Clinical Breast Cancer, Breast Cancer Research and Treatment, and Journal of Surgical Oncology. She has authored or co-authored more than 50 peer-reviewed articles as well as books, book chapters, and reviews. Dr. Modi holds memberships in ASCO, ESMO, the American Association for Cancer Research, ALLIANCE for Clinical Trials in Oncology, and the Translational Breast Cancer Consortium. She has been an invited speaker for national and international congresses, meetings, and symposiums.
The DESTINY-Breast04 trial at ASCO 2022 introduced many people to the term “HER2-low.” But how do you know if you’re HER2-low? In this episode, with the help a breast pathologist and a clinical oncologist we dive into this subtype and what it means to us.