T-DXd and Interpreting HER2 Expression in HR+ Metastatic Breast Cancer
Key Points
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Positive findings for anti-HER2 antibody-drug conjugates (ADCs) have shifted the understanding of HER2 expression in hormone receptor (HR)–positive metastatic breast cancer.
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Based on the DESTINY-Breast04 and DESTINY-Breast06 trials, trastuzumab deruxtecan (T-DXd) was approved for HER2–low and HER2–ultralow patient populations.
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The optimal sequencing for T-DXd and ADCs is an open question based on available data, although studies are ongoing.
Treatment Algorithm for HR+, HER2+ Metastatic Breast Cancer
Breast medical oncologist, Komal Jhaveri, MD, FACP, of Memorial Sloan Kettering Cancer Center, joined the Oncology Brothers podcast cohosts, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, Roswell Park Comprehensive Cancer Center, to discuss the treatment landscape for HR–positive, HER2–positive metastatic breast cancer. The doctors first covered how HER2 expression interpretation has evolved in response to trial data for T-DXd.
Trials Lead to More Refined HER2 Expression Categorization
HER2 expression in breast cancer cells is analyzed with immunohistochemistry (IHC) assays and scored from 0 to 3 based on presence and degree of membrane staining. IHC testing is further supported by in situ hybridization (ISH) testing for HER2 gene amplification. Historically, HER2 expression was only categorized as positive or negative. However, recent data have expanded the categorization of HER2 expression beyond this binary.
Findings from the DESTINY-Breast04 trial showed that T-DXd improved survival versus chemotherapy for patients with HER2–low metastatic breast cancer, which the study defined as either HER2 IHC 1+ or IHC 2+ with negative ISH for amplification. The subsequent DESTINY-Breast06 trial investigated T-DXd in patients with HER2–ultralow metastatic breast cancer, defined as HER2 IHC 0 with any observable membrane staining. In the study, T-DXd improved progression-free survival compared with chemotherapy for HER2–low and HER2–ultralow populations. Both trials showed T-DXd was effective for patients that historically would have been considered HER2–negative.
The doctors considered how to approach the more nuanced interpretation of HER2 expression when selecting treatments in practice. Given that HER2 expression can vary between disease sites and can change over time, repeating HER2 tests when appropriate could find expression emergence that would open up T-DXd or other targeted therapies as treatment options. Conversely, testing could show loss of HER2 expression, which may indicate treatment resistance. “As long as I have some HER2 expression, I offer T-DXd unless there is an obvious contraindication,” said Dr. Jhaveri.
T-DXd Sequencing in Metastatic Breast Cancer
Drs. Rahul and Rohit Gosain asked Dr. Jhaveri where she sequences T-DXd after an upfront CDK4/6 inhibitor plus endocrine therapy regimen in patients with HR–positive, HER2–positive metastatic breast cancer. Based on current data, the best approach still appears to be trying to maximize endocrine therapy-based options before moving on to single-agent chemotherapy or ADCs, said Dr. Jhaveri. The exact number of intervening treatment lines will vary depending on a patient’s prior therapies, and may be adjusted based on disease burden or other factors.
Dr. Jhaveri highlighted that around 9% of patients in DESTINY-Breast06 had less than 6 months of a first-line CDK4/6 inhibitor and were considered resistant to endocrine therapy. The study’s positive findings offer some confidence in jumping to T-DXd as the immediate next line of therapy for patients with endocrine therapy-refractory metastatic breast cancer.
The question of sequencing different ADCs is also gaining relevance as more agents become available. Small studies and retrospective analyses have suggested the first ADC used provides a better, more durable benefit than a second ADC does, regardless of which agent is used first. However, some patients did not respond to their first ADC but responded to a second, although the underlying mechanism remains unclear, said Dr. Jhaveri. Ongoing studies are evaluating various sequencing of T-DXd, datopotamab deruxtecan, and sacituzumab govitecan.
Toxicity Management of T-DXd
The discussion briefly discussed managing the side effects of T-DXd. Like other cytotoxic therapies, T-DXd is commonly associated with nausea, vomiting, fatigue, and alopecia. T-DXd has also shown a low rate of interstitial lung disease (ILD), which can be fatal.
For nausea and vomiting management, triple antiemetic regimens or quadruple regimens that include olanzapine are crucial. If fatigue persists, dose reductions may be effective if oncologists want patients to continue on T-DXd. Dr. Jhaveri emphasized that alopecia should be discussed with all patients, noting that rates in her practice are lower than those reported in trials. Scalp cooling therapies may help reduce alopecia, but their ability to fully prevent hair loss is unclear.
While not as common as the other toxicities, it’s essential to monitor for ILD with regular radiographic exams. Grade 1 ILD is asymptomatic, but T-DXd still needs to be paused until signs resolve. T-DXd can be rechallenged at the same dose if grade 1 cases resolve within 28 days, but the dose should be reduced if ILD takes longer to resolve. Grade 2 or higher cases likely call for discontinuation and higher-dose steroids, said Dr. Jhaveri.
In closing the discussion, the doctors highlighted the importance of partnering with pathology colleagues to perform HER2 testing and stratification, as well as the necessity to manage side effects when using T-DXd or other ADCs in HR–positive, HER2–positive metastatic breast cancer.