Breast Cancer Targeted Therapies and Guidelines, Part 2
Jun 02, 2025
Photo Credit: iStock.com/Anastasia Usenko
This slideshow highlights some of the latest breakthroughs in breast cancer treatment, spotlighting key molecular pathways—PI3K/AKT/mTOR, RAS/RAF/MEK/ERK, JAK/STAT, and SRC—that are driving innovation in targeted therapy. Explore how cutting-edge agents like alpelisib, capivasertib, MEK and ERK inhibitors, and JAK inhibitors are reshaping the treatment landscape across HR-positive, HER2-positive, and triple-negative subtypes.
From game-changing advances like CDK4/6 inhibitors and adjuvant olaparib in gBRCA1/2-mutated disease to smart strategies for therapy de-intensification in low-risk patients, this presentation delivers a powerful overview of personalized, evidence-based care that’s transforming outcomes—and raising the bar for what’s possible in breast cancer treatment.
Breast Cancer Targeted Therapies and Guidelines
Part 2 JAK/STAT pathway: The JAK/STAT pathway is a critical cell signaling mechanism that transmits information from cytokines, growth factors, and hormones at the cell surface directly to the nucleus to regulate gene expression, affecting tumor immunity and survival. Ruxolitinib, pacritinib, and fedratinib are investigational drugs targeting JAK1/2/3. TSRC: SRC is a non-receptor tyrosine kinase that acts as a critical regulator of multiple signaling pathways involved in cell proliferation, survival, angiogenesis, adhesion, invasion, and metastasis. SRC itself is a single kinase protein, not a complex signaling pathway on its own. It activates the PI3K/AKT, RAS/RAF/MEK/ERK, STAT3, and FAK pathways. Saracatinib, bosutinib, and kaempferol are being studied as agents to target and inhibit SRC.HER2-Positive Breast Cancer Pathways RAS/RAF/MEK/ERK pathway: This pathway controls cell growth, survival, and movement and is overactivated in TNBC, HER2-positive, and HR-positive/HER2-negative breast cancers. Vemurafenib and dabrafenib target the BRAF V600E mutation. Trametinib, cobimetinib, and binimetinib are investigational MEK1/2 inhibitors. Ulixertinib is an ERK1/2 kinase inhibitor and is being studied for resistant tumors that bypass BRAF/MEK inhibition. Balkrishna A et al. Unveiling role of oncogenic signalling pathways in complicating breast cancer. Biomedicine (Taipei). 2025 Mar 1;15(1):13-21. doi:10.37796/2211-8039.1640. Wang P et al. Kaempferol targets Src to exert its chemopreventive effects on mammary tumorigenesis via regulation of the PI3K/AKT pathway. Phytomedicine. 2025 Jun:141:156701. doi:10.1016/j.phymed.2025.156701. References Song Y et al. Targeting RAS–RAF–MEK–ERK signaling pathway in human cancer: Current status in clinical trials. Genes Dis. 2022 May 20;10(1):76-88. doi:10.1016/j.gendis.2022.05.006. PI3K/AKT/mTOR pathway: The PI3K/AKT/mTOR pathway is one of the most frequently altered signaling pathways in breast cancer, especially in HR-positive breast cancer and HER2-positive breast cancer, as well as TNBC. When mutated (eg, PIK3CA mutations), this pathway drives tumor growth, survival, and therapy resistance. Alpelisib (PI3K-alpha isoform), everolimus (mTORC1), and capivasertib (AKT inhibitor) are undergoing trials for HR-positive/HER2-negative advanced breast cancer. ESMO Targeted-Therapy Guidelines Alpelisib with fulvestrant is a treatment option for patients with PIK3CA-mutated tumors previously exposed to an aromatase inhibitor (AI) and with appropriate HbA1c levels. De-intensification of adjuvant treatment can be considered for pathologic stage pT1 pN0 disease, using a regimen of weekly paclitaxel for up to 12 doses along with 12 months of trastuzumab. The addition of trastuzumab to chemotherapy improves OS by approximately one third. The relative magnitude of the survival benefit for patients with HR-positive early breast cancer (EBC) is the same as for those with HR-negative EBC after 10 years of follow-up; however, the latter have earlier recurrences. A CDK4/6 inhibitor combined with endocrine treatment (ET) is the standard of care for patients with ER-positive/HER2-negative advanced breast cancer, because it achieves a substantial progression-free survival (PFS) benefit, significantly increases OS, and either maintains or improves quality of life. The CDK4/6 inhibitor can be combined with an AI or with fulvestrant in de novo or recurrent advanced breast cancer and in cases of primary or secondary resistance.References For patients who were previously treated in the neoadjuvant setting with anti-HER2 therapy, the combination of chemotherapy plus trastuzumab and pertuzumab is an important option for first-line therapy. Note: ESMO is the European Society for Medical Oncology. Cardoso F et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5). Ann Oncol. 2020 Dec;31(12):1623-1649. doi:10.1016/j.annonc.2020.09.010. Loibl S et al. Early breast cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2024 Feb;35(2):159-182. doi:10.1016/j.breast.2024.103756. In patients with gBRCA1/2m and high-risk HER2-negative tumors, adjuvant olaparib for 1 year improves disease-free survival (DFS) and overall survival (OS) regardless of HR status. NCCN Targeted-Therapy Guidelines Adjuvant olaparib may be used concurrently with endocrine therapy. Note: NCCN is the National Comprehensive Cancer Network.References: The addition of adjuvant olaparib for 1 year may be considered for those with germline BRCA1/2 mutations in patients with HR-positive/HER2-negative tumors with greater than or equal to four positive lymph nodes after adjuvant chemotherapy or residual disease following preoperative therapy and a CPS + EG score (clinical stage, pathologic stage, ER status, and tumor grade score) greater than or equal to three. Li Y et al. Recent advances in therapeutic strategies for triple-negative breast cancer. J Hematol Oncol. 2022 Aug 29;15(1):121. doi:10.1186/s13045-022-01341-0. Two years of adjuvant CDK4/6 therapy with abemaciclib should be considered in combination with endocrine therapy in patients with HR-positive/HER2-negative and high-risk breast cancer. Adjuvant capecitabine for 6-8 cycles should be considered in high-risk TNBC patients with residual invasive disease at surgery following standard NAC.SEOM-GEICAM-SOLTI Targeted-Therapy Recommendations For HER2-positive breast cancers, adjuvant trastuzumab is recommended in all patients with a tumor more than 1 cm regardless of nodal status. Note: SEOM-GEICAM-SOLTI is a collaboration of 3 Spanish oncology research groups: Sociedad Española de Oncología Médica, Grupo Español de Investigación en Cáncer de Mama, and Spanish Collaborative Group for the Study, Treatment, and Other Experimental Strategies in Solid Tumors. SEOM-GEICAM-SOLTI clinical guidelines for early-stage breast cancer (2022). Clin Transl Oncol. 2023 Sep;25(9):2647-2664. doi:10.1007/s12094-023-03215-4. The addition of neoadjuvant pembrolizumab to neoadjuvant chemotherapy (NAC) should be considered for TNBC regardless of PD-L1 expression. Adjuvant olaparib for 1 year should be considered in individuals with germline BRCA1/2 mutations and high-risk TNBC with residual invasive disease at surgery following standard NAC. Reference:
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