Introduction to Post-CDK4/6 Inhibitor Treatment
Treating hormone receptor-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer (MBC) has improved with CDK4/6 inhibitors like palbociclib. However, progression after this therapy creates challenges for clinicians. This guide to post-CDK4/6 inhibitor treatment explores the latest strategies, based on Teysir et al. (2025) in the ASCO Educational Book [link: https://ascopubs.org/doi/pdf/10.1200/EDBK-25-473372]. Moreover, we cover resistance, new therapies, and global access to help oncologists and researchers.
Understanding Resistance Mechanisms
Genomic Drivers of Resistance
Resistance often stems from genomic changes. ESR1 mutations in 20-50% of cases, causing endocrine resistance. Furthermore, PI3K/AKT pathway shifts affect over 50% of tumors, per a PubMedCentral [link: https://pmc.ncbi.nlm.nih.gov/articles/PMC6366304/. Hence, factors like RB loss and cyclin E-CDK2 growth also play a role.
Detecting Resistance Early
Molecular profiling is key for post-CDK4/6 inhibitor treatment. The PADA-1 trial [link: https://www.thelancet.com/article/S1470-2045(22)00555-1/abstract shows liquid biopsies spot ESR1 mutations early. As a result, this guides switches to fulvestrant, boosting PFS. Likewise, timely detection improves outcomes.
Emerging Therapeutic Options
Selective Estrogen Receptor Degraders (SERDs)
The EMERALD trial highlights elacestrant, an oral SERD, lifting PFS to 3.8 months in ESR1-mutant patients versus 1.9 months with standard therapy (Teysir et al., 2025). Furthermore, this improves post-CDK4/6 inhibitor treatment for resistant cases. On the other hand, side effects need monitoring.
PI3K/AKT/mTOR Inhibitors
PI3K inhibitors like alpelisib and capivasertib target PIK3CA mutations. The SOLAR-1 trial [link: https://clinicaltrials.gov/study/NCT02437318 reports alpelisib’s PFS at 11 months. Besides, capivasertib adds 7.2 months in biomarker-selected patients.
Antibody-Drug Conjugates (ADCs)
Trastuzumab deruxtecan, an ADC, offers PFS up to 13.2 months in HER2-low disease. The DESTINY-Breast04 trial link: https://dailynews.ascopubs.org/do/destiny-breast04-establishes-trastuzumab-deruxtecan-new-standard-care-her2-low supports this for post-CDK4/6 inhibitor treatment, changing options after endocrine failure. Subsequently, this expands treatment choices.
Ongoing Research and Trials
Novel SERDs and Combinations
Trials like SERENA-6 and ELEVATE test new SERDs and combos for post-CDK4/6 inhibitor treatment. These are steps toward better precision medicine in HR+/HER2- MBC. Moreover, results may improve care significantly.
Tailored Treatment Approaches
Response varies in ER-independent tumors benefit from ADCs, while ER-dependent cases do well with prolonged endocrine therapy. Furthermore, the Teysir review offers a framework using biomarkers. Hence, personalization is key.
Global Access and Equity Challenges
Disparities in Low-Resource Areas
Access to post-CDK4/6 inhibitor treatment lags in low- and middle-income countries (LMICs). An article from PubMed point out the high cost of drugs like capivasertib. Therefore, this is a major hurdle.
Ways to Boost Access
HHS [link: https://telehealth.hhs.gov/providers/best-practice-guides/telehealth-and-cancer-care promotes generics and tele-oncology to improve access. As a result, more patients may benefit.
Practical Applications for Clinicians
Sequencing Diagnostics and Therapies
In post-CDK4/6 inhibitor treatment, use liquid biopsies and ctDNA monitoring, per PADA-1. Sequencing based on ESR1 and PIK3CA status can lift PFS. Consequently, this approach saves effort and time.
Supporting Patient Understanding
Educate patients about post-CDK4/6 inhibitor treatment options. Mayo Clinic Press [link: https://mcpress.mayoclinic.org/cancer/hormone-receptor-positive-her2-negative-breast-cancer-what-to-expect/ provides resources for shared decisions. Besides, this builds trust and confidence.
Conclusion and Future Directions
Post-CDK4/6 inhibitor treatment is heading toward precision medicine for HR+/HER2- MBC. The Teysir et al. (2025) review [link: https://ascopubs.org/doi/pdf/10.1200/EDBK-25-473372] is a foundation. Moreover, future trials and equity efforts will drive progress. Explore more on ASCO’s Educational Book [link: https://ascopubs.org/journal/edbk and OncologyTube.com.
References
- Teysir et al. (2025). After a CDK4/6 Inhibitor: State of the Art in Hormone Receptor-Positive Metastatic Breast Cancer. ASCO Educational Book. https://ascopubs.org/doi/pdf/10.1200/EDBK-25-473372]
- Turner, N. C., et al. (2020). ESR1 Mutations and Resistance to CDK4/6 Inhibitors. NEJM. https://www.nejm.org/doi/full/10.1056/NEJMoa1810527
- André, F., et al. (2019). Alpelisib for PIK3CA-Mutated Breast Cancer. NEJM. https://www.nejm.org/doi/full/10.1056/NEJMoa1813904
- Modi, S., et al. (2022). Trastuzumab Deruxtecan in HER2-Low Breast Cancer. NEJM. https://www.nejm.org/doi/full/10.1056/NEJMoa2203690