Ana C. Garrido-Castro, MD, on Managing Metastatic Breast Cancer in 2024

Over the past decade, the treatment of metastatic breast cancer has clearly shifted towards a more individualized care. We now have multiple treatment options that are available in biomarkers selected patient populations, and several of these have overlapping indications. It has become imperative to understand how to, optimally, sequence these agents. When making decisions about treatment options for patients with metastatic breast cancer, it is important to carefully weigh what are the potential benefits from treatment, including the impact on survival, tumor growth, quality of life, and symptom management, against the potential risks of therapy. In essence, the side effects, and financial toxicity, also, time and resources from patients, while also taking into consideration individual factors including tumor burden, comorbidities, and patient preference when it comes to potential side effects, and route, and schedule of administration of these agents. There are key questions across each breast cancer subtype that, I think, are important to highlight. In the HER2-positive metastatic breast cancer setting, after first line taxane, trastuzumab, and pertuzumab-based therapy, the HER2 directed antibody drug conjugate trastuzumab deruxtecan has established itself as a preferred second line regimen in this space. I think a key question is among the patients who have CNS metastases, what is the optimal selection of agent for those with HER2-positive CNS disease, in particular, those patients with active CNS disease in whom there are limited data for TDXD in that setting. We also have available a HER2 tyrosine kinase inhibitor to CATNIB in combination with capecitabine and trastuzumab. I think it's important to carefully weigh what are some of the individual factors, including whether there is predominant intracranial/extracranial disease, whether the CNS lesions are asymptomatic or progressing after prior therapy when making decisions about the preferred regimen in this space. In the hormone receptor positive HER2-negative setting, one of the key questions after is what to do after first line endocrine therapy and CDK4/6 inhibitor. Treatment options there depend on the results of somatic NGS testing. For patients with ESR1 mutant hormone receptor positive HER2-negative metastatic breast cancer, elacestrant, an oral selective estrogen receptor degrader is an option. In the Emerald trial we saw that in fact, the patients who appear to derive most benefit from elacestrant were those who had received a prior CDK4/6 inhibitor for at least 12 months. For patients who have alterations in the PiK3 kinase pathway, there are two targeted agents that are currently available. The PI-III kinase inhibitor alpelisib in combination with endocrine therapy for those patients with activating PiK3CA mutations, and the AKT inhibitor capivasertib in combination with fulvestrant for patients with activating PiK3 or AKT1 mutations or alterations in activating alterations in P10. Both of these agents carry toxicities that are important to take into account when making decisions about the optimal agent and sequence of therapies. For those patients who do not have actionable alterations, genomic alterations after progression on endocrine therapy and CDK4/6 inhibition, there are combinations available with everolimus. At ASCO, there were data presented also from the post-monarch trial, the first phase 3 study evaluating the continuation of CDK4/6 inhibition after progression on prior CDK4/6 inhibitors. For patients with metastatic triple negative breast cancer in the first line setting, we know that immune checkpoint inhibition has demonstrated to significantly improve outcomes when added to chemotherapy in patients with PD-L1 positive tumors. For patients with PD-L1 negative triple negative breast cancer, the standard of care remains chemotherapy, single agent chemotherapy for most patients or for those with germline BRCA1 or 2 mutations, a PARP inhibitor, either olaparib or talazoparib. At ASCO, there were also data presented from the Olaparib Expanded trial looking at the activity of PARP inhibition in patients who carry germline PALB2 or somatic BRCA 1 or 2 mutations, also suggesting activity of PARP inhibitors in these patient populations. And then both for hormone receptor positive HER2-negative and triple negative breast cancer, in the hormone receptor positive setting in an endocrine refractory setting and for patients in the metastatic triple negative setting who have received at least one prior chemotherapy regimen, there are multiple chemotherapy options and antibody drug conjugates now available. Currently, there are two FDA approved antibody drug conjugates for patients with metastatic HER2-negative breast cancer, the TROP-2 directed ADC sacituzumab govitecan. And also, for patients for the approximately 50% of patients who have HER2-low breast cancer defined by IHC 1+ or 2+ without amplification by ISH, the HER2 directed ADC trastuzumab deruxtecan is also available. At ASCO, we saw data presented from the Destiny-Breast06 trial for T-DXd in patients with hormone receptor positive HER2-low or ultra low breast cancer who had received prior endocrine therapy and no prior chemotherapy in the advanced setting. So now as we have multiple ADC options available for these patients, it is key to understand how to optimally sequence these agents. Having a better understanding of the mechanisms that drive response and resistance to these treatments will be key to help inform the optimal sequencing, duration and potential combination strategies of these treatments.