HER2-directed antibody-drug conjugates (ADCs) are showing great promise in HER2+ metastatic breast cancer and are transforming the treatment paradigm. This chapterized activity examines the importance of HER2 status and incorporates a case presentation to demonstrate optimal therapy selection and the management of adverse events. Drs. Javier Cortes and Sara Hurvitz also examine efficacy and safety data of currently available and investigational agents. Tune in to explore exciting new therapies and the role they can play in improving outcomes for your patients with HER2+ metastatic breast cancer.
State of the Union: Advances in the Management HER2+ mBC
State of the Union: Advances in the Management HER2+ mBC
Metastatic breast cancer is the most advanced form of breast cancer, with a 5-year survival rate of only 28%.1 Advancements in drug therapies and the characterization of breast cancer subtypes have drastically changed the outlook for patients with metastatic breast cancer. Despite the continuous development of cutting-edge therapies, resistance to current treatment options represents a major hurdle for providers and patients, which in turn keeps metastatic breast cancer classified as an incurable disease. The discovery of new therapeutic options, the development of clear strategies for complicated case management, and continuing education of clinicians can all be used to optimize the clinical management of metastatic breast cancer.
Approximately 15% of breast cancer cases are classified as HER2-positive, a subtype of breast cancer that has significantly contributed to breast cancer mortality.2 However, the introduction of new targeted therapies has changed the outlook for patients with overexpressing HER2-positive breast cancer, who now have an equal, if not better, prognosis than those with HER2-negative breast cancer.
Another subtype of metastatic breast cancer is HER2 low-expressing breast cancer, which represents approximately 50% of breast cancer cases.2 Although this subtype accounts for a significant proportion of total cases, there are currently no therapies that are specifically indicated for the treatment of HER2 low-expressing tumors. This has made treatment decisions difficult for healthcare providers who are already struggling to optimize treatment options for patients with more advanced breast cancers.3 Availability of effective therapies to target this subtype could have a significant positive impact on outcomes for patients with breast cancer. Clear clinical data regarding the utility of therapeutic treatment options for this patient population could help guide clinical decision-making and further improve outcomes for patients with metastatic breast cancer.
The following is a patient case discussed by two leading experts: Dr. Javier Cortes, MD, PhD, Head of the Breast Cancer Program at the International Breast Cancer Center (IBCC) in Spain, and Dr. Sara A. Hurvitz, MD, FACP, Professor of Medicine at UCLA in Los Angeles, California.
Drs. Cortes and Hurvitz discussed one longitudinal case in the activity entitled “How ADCs Are Transforming HER2+ Metastatic Breast Cancer: Discover the Latest Clinical Trend.” The case involved a 44-year-old woman who was diagnosed with breast cancer. A mammogram and ultrasound were completed after the patient felt a lump in her left breast, and an 11 x 7 mm mass was detected with no abnormally enlarged lymph nodes. Mass biopsy revealed invasive ductal carcinoma that was ER 90%, PR 80%, and grade 2 with a Ki-67 of 5%. HER2 was 2+ by immunohistochemistry (IHC) and fluorescent in situ hybridization positive (FISH+). Her liver, lungs, and bones were without metastases. She underwent lumpectomy and sentinel lymph node biopsy which revealed a 9 mm, stage 1 breast cancer. The patient then received paclitaxel and trastuzumab for 12 weeks, followed by trastuzumab to complete a year. Tamoxifen was initiated after chemotherapy. Six months later, while on trastuzumab maintenance and tamoxifen, she was noted to have grade 1 AST and ALT increase, an increase in GGT, and an elevated tumor marker. A scan revealed she had small liver metastases. She was then offered trastuzumab emtansine (T-DM1).
Experts selected T-DM1 based on its evidence of benefit after trastuzumab/taxane.4, 5 This effectiveness was proven in the EMILIA trial, a phase 3, randomized, open-label clinical trial which compared the safety and efficacy of T-DM1 to that of lapatinib + capecitabine in women with HER2-positive breast cancer. In this trial, T-DM1 demonstrated superior overall survival, progression free survival, objective response rate and fewer adverse events.4
In part two of this case, the patient received T-DM1 and did well for approximately one year when her liver enzymes and tumor markers began to rise. She had a negative bone scan and her liver biopsy revealed ER 10%, PR 5%, and grade 2 breast cancer metastasis. The HER2 was 2+ by IHC and FISH+ with a Ki-67 of 15%. No brain metastases were detected.
When addressing the progression in this case, multiple therapy combinations were considered. Both trastuzumab deruxtecan and tucatinib-based therapies were identified as potential treatment options when the patient’s disease began to progress after T-DM1 treatment. While both options are equally appropriate, experts ultimately selected trastuzumab deruxtecan based on the DESTINY-Breast01 clinical trial results, which showed a 61% overall response rate and a prolonged progression-free survival period of 16.4 months. Experts also noted the utility of trastuzumab deruxtecan in heavily pretreated patients. Clinical trial data has shown promising results with the use of trastuzumab deruxtecan for patients with progression after treatment with T-DM1.
The overarching conclusion from this case discussion was that there are multiple treatment options available for HER2+ metastatic breast cancer. It is important that each therapeutic be evaluated for its effectiveness based on the patient’s disease characteristics, including disease progression and treatment history. Current and emerging clinical data can provide valuable information about the utilization and effectiveness of these therapies in different patient scenarios.
DESTINY-Breast01: Trastuzumab Deruxtecan Trial
In DESTINY-Breast01, trastuzumab deruxtecan showed promising results for patients with HER2+ metastatic breast cancer in an open-label, multicenter, phase 2 trial. In this clinical trial, trastuzumab deruxtecan was evaluated in adults with HER2+ metastatic breast cancer who had received previous treatment with T-DM1. A positive response to therapy was seen in 60.9% of trial participants. Median duration of progression-free survival was 16.4 months (Figure 1). Participants in the treatment arm had a median of 6 lines of therapy, indicating that trastuzumab deruxtecan was effective even in the heavily pretreated patient population.6
HER2CLIMB: Tucatinib Trial for Brain Metastases
Up to 50% of patients with advanced HER2-positive breast cancer will develop brain metastases during their disease course; however, effective treatment options for patients with brain metastases are limited.7 Tucatinib is one therapy that is being investigated for its effectiveness in this patient population.
HER2CLIMB was a randomized, double-blind, placebo-controlled, phase 2 trial that compared tucatinib plus trastuzumab and capecitabine to placebo plus trastuzumab and capecitabine. A total of 612 patients with unresectable, locally advanced, or metastatic HER2+ breast cancer were enrolled. Notably, patients with treated stable brain metastases, untreated metastases not? in need of immediate treatment, previously treated progressing metastases not in need of immediate therapy, and no evidence of brain metastases were all eligible for participation. This provided valuable information about the effectiveness of this therapy for patients with or without brain metastases.8,9
Trial results showed the median overall survival in the tucatinib arm was 24.7 months versus 19.2 months in the placebo arm. Median progression-free survival in the tucatinib group was 7.6 months as compared to 4.9 months in the placebo group.8 Progression-free survival evaluated by a blinded independent central review revealed that risk of progression or death was reduced by 40% in patients with brain metastases (Figure 2).9
Adverse Event Management
Clinicians must be mindful of the unique adverse event profiles of the new breast cancer therapies. Both efficacy and therapeutic index should be considered when utilizing these medications.
Trastuzumab deruxtecan is associated with nausea, diarrhea, and significant hair thinning. Clinicians must carefully tailor therapies to mitigate these side effects and provide proper education to help set patient expectations. Two approaches to help patients manage the side effects of trastuzumab deruxtecan are the use of antiemetics and the provision of education about hair thinning. Potentially life-threatening side effects associated with trastuzumab deruxtecan are interstitial lung disease (ILD) or pneumonitis. Trastuzumab deruxtecan should not be used in patients who have a history of ILD, pneumonitis, or significant pulmonary fibrosis at baseline. Patients should be advised to notify their healthcare providers if they develop shortness of breath, dyspnea, fever, or other relevant symptoms. Additionally, when scans are done to assess tumor response to treatment, if ground-glass opacities are observed in the lungs in an asymptomatic patient (grade 1 ILD), medication should be stopped, steroid use should be considered, and patients should be monitored closely. Therapy should be stopped permanently if grade 2 pneumonitis occurs.
The main side effect associated with tucatinib-based therapy is diarrhea. Patients may need to take anti-diarrheal medications and should be monitored for dehydration. Liver enzymes should also be monitored. Given that targeting HER2 can be associated with cardiomyopathy, periodic cardiac imaging and monitoring are also recommended.
The case-based activity, “How ADCs Are Transforming HER2+ Metastatic Breast Cancer: Discover the Latest Clinical Trend,” chronicled a longitudinal case of a woman diagnosed with metastatic breast cancer. Based on their clinical experience, two experts discussed pivotal clinical trial data and treatment considerations through progression of the patient’s disease.
Upon diagnosis, the patient was treated with paclitaxel and trastuzumab for 12 weeks, followed by trastuzumab to complete a year. Tamoxifen was also initiated after chemotherapy. However, 6 months later while on trastuzumab maintenance and tamoxifen, her disease began to progress. At this point in the case, experts recommended the use of T-DM1 based on results from the EMILIA trial, which revealed that T-DM1 had a better overall survival, PFS, objective response rate and fewer adverse events when compared to lapatinib + capecitabine.
The patient went on to receive T-DM1 and did well for one year before her cancer began to progress again. Upon progression, experts recommended treatment with trastuzumab deruxtecan. This recommendation was based on DESTINY-Breast01 clinical trial results, which showed a positive overall response rate and prolonged progression-free survival. Notably, as noted by Dr. Hurvitz during the patient case presentation section of the activity, "The patient did receive trastuzumab deruxtecan, and she had normalization of her liver enzymes, improvement of her tumor markers down to normal, PET/CT and liver MRI confirmed a complete response, which I’ve seen with this drug, as well, very phenomenal.”
Experts also considered further treatment options in the case that the patient were to develop brain metastases. Tucatinib was selected as an appropriate therapeutic option based on HER2CLIMB trial outcomes, which revealed positive results in relation to improved median PFS and overall survival.
The characterization of metastatic breast cancer subtypes and the introduction of newer targeted therapies have significantly improved prognoses for patients with metastatic breast cancer. However, optimization of therapeutic treatment options for patients with more advanced breast cancers can be difficult for clinicians due to the rapidly changing treatment landscape and lack of expert consensus on therapy recommendations. It is imperative that clinicians are aware of the latest clinical trial data so they can select optimal treatments for their patients given their unique disease profiles. They must also be familiar with the unique side effect profiles associated with these treatments in order to proactively mitigate side effects, prevent treatment interruptions, and provide appropriate patient monitoring and education.
- American Cancer Society. Survival rates for breast cancer. Revised January 27, 2021. https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-survival-rates.html
- Rinnerthaler G, Gampenrieder SP, Greil R. HER2 directed antibody-drug-conjugates beyond T-DM1 in breast cancer. Int J Mol Sci. 2019;20(5):1115.
- Wanchoo P, Larrison C, Rosenberg C, et al. Identifying educational needs of the multidisciplinary cancer team in the treatment of metastatic breast cancer. J Natl Compr Canc Netw. 2017;15(2):205-212.4.
- Cardoso F, Senkus E, Costa A, et al. 4th ESO–ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4). Ann Oncol. 2018;29(8):1634-1657. doi:10.1093/annonc/mdy192
- Larionov AA. Current therapies for human epidermal growth factor receptor 2-positive metastatic breast cancer patients. Front Oncol. 2018;8:89.
- Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382(7):610-621. doi:10.1056/nejmoa1914510
- Pernas S, Tolaney SM. HER2-positive breast cancer: new therapeutic frontiers and overcoming resistance. Ther Adv Med Oncol. 2019;11:1758835919833519.
- Seagen announces long-term results from TUKYSA® (tucatinib) pivotal trial in patients with HER2-positive breast cancer during the Virtual Scientific Program of the 2021 ASCO Annual Meeting. Business Wire. June 3, 2021. https://www.businesswire.com/news/home/20210603005326/en/Seagen-Announces-Long-Term-Results-from-TUKYSA%C2%AE-tucatinib-Pivotal-Trial-in-Patients-with-HER2-Positive-Breast-Cancer-During-the-Virtual-Scientific-Program-of-the-2021-ASCO-Annual-Meeting
- Mycek S. Tucatinib continues to show promise in HER2-positive breast cancer. Targeted Oncology. June 6, 2021. https://www.targetedonc.com/view/tucatinib-continues-to-show-promise-in-her2-positive-breast-cancer
In accordance with the ACCME Standards for Commercial Support, Global Learning Collaborative (GLC) requires that individuals in a position to control the content of an educational activity disclose all relevant financial relationships with any commercial interest. GLC resolves all conflicts of interest to ensure independence, objectivity, balance, and scientific rigor in all its educational programs.
Javier Cortes, MD, PhD
Head, Breast Cancer Program
IOB Institute of Oncology
Madrid & Barcelona
Consulting Fees: AstraZeneca, Athenex, Bioasis, BioInvent, Biothera Pharmaceutical, Boehringer Ingelheim, Celgene, Cellestia, Clovis Oncology, Daiichi Sankyo, Eisai, Ellipses, Erytech, GEMoaB, GSK, HiberCell, Kyowa Kirin, Leuko, Lilly, Merck Sharp & Dohme, Merus, Novartis, Pfizer, Polyphor, Roche, Samsung Bioepis, Seattle Genetics, Servier
Contracted Research: Research funding to the Institution: ARIAD Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer Healthcare, Eisai, F. Hoffmann-La Roche, Guardant Health, Merck Sharp & Dohme, Pfizer, PIQUR Therapeutics, Puma C, Queen Mary University of London, Roche
Ownership Interest: MEDSIR
Sara A. Hurvitz, MD, FACP
Associate Professor of Medicine
Los Angeles, CA
Contracted Research: Ambrx, Amgen, Arvinas, AstraZeneca, Bayer, Daiichi Sankyo, Dignitana, Genentech/Roche, Gilead, GSK, Immunomedics, Lilly, MacroGenics, Novartis, OBI Pharma, Pfizer, Phoenix Molecular Designs, Ltd., Pieris, Puma, Radius, Samumed, Sanofi, Seattle Genetics, Zymeworks
Ownership Interest: NKMax (self), ROMTech, Ideal Implant (spouse)
- Jorge Bacigalupo has nothing to disclose.
- Ann Early has nothing to disclose.
- Amanda Hilferty has nothing to disclose.
- Libby Lurwick has nothing to disclose.
- Brian P. McDonough, MD, FAAFP, has nothing to disclose.
After participating in this educational activity, participants should be better able to:
- Demonstrate optimal therapy selection based on individual patient characteristics in the HER2-positive metastatic breast cancer setting
- Formulate strategies to manage potential adverse events associated with current treatment options for HER2-positive metastatic breast cancer
This activity is designed to meet the educational needs of medical oncologists, pathologists, and other healthcare professionals treating breast cancer.
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