<p>Despite major advances with endocrine therapy, CDK4/6 inhibitors, and ADCs, treatment resistance remains a significant clinical challenge in HR+/HER2- metastatic breast cancer. At the <strong>2025 San Antonio Breast Cancer Symposium (SABCS 2025)</strong>, multiple translational and clinical studies were presented, shedding light on resistance pathways and potentially informing future therapeutic development for metastatic breast cancer.</p> <p><br></p> <p><em>Following these presentations, featured expert Sonya Reid, MD, MPH, was interviewed by </em>Conference Reporter<em> Associate Editor-in-Chief Christopher Ontiveros, PhD. Clinical perspectives from Dr Reid on these findings are presented here.</em></p>

In the later-line setting, we know that patients with HR+/HER2- metastatic breast cancer can become resistant to targeted therapies, including CDK4/6 inhibitors and ADCs. However, we are still trying to understand what is driving some of the resistance to these newer agents. We do know that the PI3K-AKT-mTOR (PAM) pathway can lead to endocrine and CDK4/6 inhibitor resistance, with one major driver being a PIK3CA mutation. Patients who have a PIK3CA mutation benefit from treatment with a PI3K inhibitor. Most of these therapies (eg, alpelisib, capivasertib, and inavolisib) are only indicated for patients with a mutation in this pathway, but data suggest that even patients with wild-type (WT) tumors have some resistance to CDK4/6 inhibitors, likely from this same pathway.

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There were several interesting studies presented at SABCS 2025 on this topic. One notable presentation was by Barbara Pistilli, MD, who reported updated results for the PIK3CA WT cohort from the phase 3 VIKTORIA-1 trial (abstract RF7-04). The VIKTORIA-1 trial evaluated the safety and efficacy of gedatolisib-based regimens in patients with HR+/HER2- advanced breast cancer whose disease progressed during or after CDK4/6 inhibitor and nonsteroidal aromatase inhibitor therapy. The primary progression-free survival (PFS) results were previously presented at the European Society for Medical Oncology (ESMO) Congress 2025.

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VIKTORIA-1 was developed based on the premise that patients without a driver mutation may still develop resistance through activation of the PAM pathway and that the addition of gedatolisib, a multitarget PAM pathway inhibitor, may restore endocrine sensitivity and prevent adaptive pathway activation. In this analysis, patients with PIK3CA WT tumors with a time to progression of more than 18 months on their most recent prior therapy achieved a median PFS of 12.4 months with the gedatolisib, palbociclib, and fulvestrant triplet and 10 months with the gedatolisib and fulvestrant doublet, compared with 1.9 months with fulvestrant alone.

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These results are quite impressive because we have always seen, on average, a 6-month PFS in the second-line setting for our patients after they become CDK4/6 inhibitor resistant. So, seeing that 10-month PFS was definitely exciting. I think that conducting more trials testing additional drugs that target the PAM pathway is leading us in the right direction to overcome treatment resistance. Even in the PIK3CA WT group, we are seeing significant results. We are eagerly anticipating results from the VIKTORIA-1 trial in the PIK3CA-mutated group. Perhaps we are going to see an even larger improvement in PFS in this subgroup.

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Also discussed at SABCS 2025, a study from the AURORA US Network by Ana C. Garrido-Castro, MD, and colleagues characterized potential mechanisms of resistance to ADCs in patients with metastatic breast cancer (poster PD3-09). Investigators performed whole exome and genome sequencing on paired tumor samples (primary vs metastatic tumors) to compare mutational profiles and to better understand the drivers of disease progression. Because many patients developed metastatic disease maybe 10 years after their initial diagnosis, archived primary tumor samples were frequently used for this analysis.

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Although the subgroup sizes were small, I think that this analysis provides an important launching pad for future breast cancer research. For example, among the 35 patients with HER2+ disease who were treated with trastuzumab deruxtecan, investigators examined mutation patterns based on treatment sequencing (ie, whether patients received trastuzumab deruxtecan as the first ADC therapy or following prior ADC exposure) to explore potential molecular differences associated with treatment line and resistance.

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Another retrospective study by Elie Rassy, MD, MSc, MPH, and colleagues presented at this year’s SABCS meeting explored biomarkers associated with primary resistance to sacituzumab govitecan in 55 patients with triple-negative metastatic breast cancer in a real-world cohort (poster PD3-10). In this small study, 13 patients (23.6%) had more than 3 lines of therapy prior to sacituzumab govitecan; 36 samples (65.5%) were taken from metastatic sites and 19 (34.5%) from primary tumors. A differential analysis of patients with a PFS of more than 3 months compared with those with a PFS of 3 months or less showed that the top 5 genes were IGLV2-23, IGLV3-19, IGLV4-60, SFTPB, and IGHV1-2.

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None of these genes are targetable, but, similar to the last study I shared, I think that this study is also important because I believe that this is the direction in which we need to go for translational breast cancer research. We need to figure out how we should target mutations going forward, and we need to think about next-line treatment. So, what do we do with this information? If we have all these data on novel therapies pre- and posttreatment, it will help inform what is driving treatment resistance. I think that this is going to be a way to not only understand what is driving this resistance but also inform novel therapies in the future.