Despite the volume of research and a number of therapeutic options, breast cancer is still a devastating disease for many people afflicted by it. Breast cancer can affect both men and women and is one of the most common forms of cancer in the US, accounting for upwards of a third of newly diagnosed cases. A frequent complication of breast cancer is metastasis, when cells from the primary tumor establish new tumors in other sites around the body. The lungs, brain, bone, and skin are common metastatic sites in patients with breast cancer and are the primary cause of breast-cancer associated mortality.
When it comes to treatment, there are non-specific treatment options, such as radiation and surgery, as well as targeted therapies, which are chosen based on the molecular characteristics of an individual’s tumor. One such factor is the overexpression of a protein called HER2, found in roughly 20% of breast cancer patients. Even with available HER2-targeted drugs that have been successful in improving prognosis, between 30-50% of patients with metastatic HER2-positive disease will still develop brain metastases (BM), which are difficult to treat and associated with poor prognosis. As current treatment options have only managed to provide moderate improvement, there is still a need for new and more effective treatment options for these patients.
One new therapeutic with promising results is trastuzumab deruxtecan (T-DXd) or Enhertu, which was the focus of the recent paper, published in Annals of Oncology, led by Dr. Sara Hurvitz, the Senior Vice President and Director of the Clinical Research Division. T-DXd is an antibody-drug conjugate that delivers a cytotoxic compound to HER2-expressing cells so that it selectively kills tumor cells while sparing healthy normal cells. It is currently approved for use in patients with metastatic breast cancer, including, but not limited to BM, whose disease grew worse on or after at least 1 prior therapy. Dr. Hurvitz was a part of the original phase II trials for T-DXd, and she explained that there was “such remarkable efficacy with T-DXd in the phase II DESTINY-Breast01 trial, that this single arm study led to the accelerated FDA approval of this drug in 2019.”
In their recent study, Dr. Hurvitz and her research team were interested in determining if T-DXd had improved efficacy for patients with BM compared to other treatments. To approach this, they performed a retrospective pooled analysis on breast cancer patients enrolled in any of three previous trials for T-DXd, selecting patients with or without known BM, who were given either T-DXd or an alternative HER2-targeting therapy. While the research team included non-BM patients, the majority of their analyses focused on those with known BM. They defined two groups of patients: (1) those who were previously treated for their BM as treated/stable, and (2) those who were not previously treated as untreated/active. For both patient groups, the research team observed an increased intracranial objective response rate (ORR) and duration of response, compared to other treatments. Dr. Hurvitz pointed out that it was particularly exciting to see that there was an improved response in untreated/active BM patients, as she noted that it was “interesting such a bulky molecule is working on nearly half of brain metastases in patients who never had radiation or surgery to the brain (thus the blood brain barrier is less disrupted).” The research team also assessed central nervous system progression-free survival (CNS-PFS), which was also extended in the T-DXd-treated patients with either treated/stable or untreated/active, compared to other treatments. Lastly, the team looked at the safety profile of T-DXd-treated patients, which they observed to be acceptable and similar to the overall patient population.
The data presented in their article highlights an important assessment of the efficacy of T-DXd on breast cancer BM, showing an improvement over comparable HER2-targeted drugs used for these patients. Dr. Hurvitz emphasized their initial concerns that they believed that, like other antibody therapeutics, the drug would have difficulty crossing the blood-brain-barrier due to its size. However, the team was excited to see that “45% of patients with brain metastases treated with T-DXd had shrinkage or disappearance of their brain metastases.” The team also emphasized that many of their cohort had recurrent breast cancer disease, which is often associated with BM. Yet screening for BM is not routine until symptoms occur, at which time they often respond poorly to treatment. They proposed that early screening and BM-directed treatment might further enhance progression-free disease and survival rates among this population. Since these patients are so often challenging to treat, the team pointed out that it is important to include, rather than exclude, patients with BM in clinical trials such as these, “so that we know whether the new agents are benefitting them,” added Dr. Hurvitz. While there is still a long way to go in ensuring that everyone diagnosed with breast cancer can be cured of this disease, continued medical advances encourage hope that we are moving in the right direction.
André F, Cortés J, Curigliano G, Modi S, Li W, Park YH, Chung WP, Kim SB, Yamashita T, Pedrini JL, Im SA, Tseng LM, Harbeck N, Krop I, Nakatani S, Tecson K, Ashfaque S, Egorov A, Hurvitz SA. A pooled analysis of trastuzumab deruxtecan in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer with brain metastases. Ann Oncol. 2024 Sep 5:S0923-7534(24)03928-0. doi: 10.1016/j.annonc.2024.08.2347. Epub ahead of print. PMID: 39241960.
This spotlighted work was funded by Daiichi Sankyo Co, Ltd. and AstraZeneca
Fred Hutch/University of Washington/Seattle Children's Cancer Consortium member Dr. Sara Hurvitz contributed to this work.