In the ever-evolving field of cancer treatment, the progress of breast cancer therapy has unfolded like a fierce contest, with new advancements rising ever higher in response to the challenges posed by each breakthrough. Every step forward not only improves survival outcomes but also uncovers deeper, more complex biological hurdles.   The story of breast cancer treatment is one of continuous adaptation—a battle against resistance and an ongoing search for innovative therapies. One significant development in this journey has been the role of HER2, a receptor that is abnormally overexpressed in certain cancers, including breast cancer. In fact, HER2 is found in approximately 20-30% of breast cancer tumors and is a key driver in HER2-amplified cancers.   In HER2-positive breast cancer, the HER2 receptor triggers downstream signaling pathways, such as RAS-RAF-ERK and PI3K-PTEN-AKT, which fuel cancer cell proliferation. As a result, HER2 has become an essential biomarker for diagnosis and a prime therapeutic target, leading to the development of antibody-drug conjugates (ADCs) that aim to treat these tumors more effectively.   Take hormone receptor-positive (HR+) breast cancer, for example. Endocrine therapy used to be the standard treatment. However, as tumors found ways to bypass drug inhibition by activating the CDK4/6 signaling pathway, resistance to treatment became a growing issue. The introduction of CDK4/6 inhibitors provided new hope for patients and catalyzed a multibillion-dollar market.   Yet, over time, resistance emerged again. Tumors began activating the PI3K-AKT-mTOR signaling pathway, creating a new hurdle for treatment. Recent studies have intensified the focus on this pathway, particularly on AKT, the core node that plays a pivotal role in tumor cell proliferation, immune evasion, and angiogenesis.   Despite extensive research into PI3K and mTOR inhibitors, they each come with drawbacks. mTOR inhibitors, for example, have yielded poor results, with an objective response rate (ORR) of just 9.5%. PI3K inhibitors, though effective, cause significant side effects, such as high blood sugar, with severe adverse events occurring in up to 76% of patients. This has led to growing interest in AKT inhibitors, which are seen as a promising avenue for overcoming these challenges.   At the same time, bispecific HER2-targeted ADCs have gained increasing attention. These therapies combine the precision of anti-HER2 monoclonal antibodies with the potent cytotoxic effect of ADCs. The bispecific design aims to tackle the issue of tumor heterogeneity, providing new hope for patients with hard-to-treat breast cancer.   Innovative ADCs like DS8201 are already transforming treatment for HER2-positive breast cancer patients. The rapid development of bispecific HER2-targeted ADCs is expected to push the boundaries of current therapies, offering more targeted treatments for patients with low or even negative HER2 expression.   For HR+ breast cancer, the continued evolution of CDK4/6 inhibitors and the development of novel first-line combination therapies are providing patients with more treatment options. In the case of triple-negative breast cancer, ADCs targeting TROP2 and other biomarkers are emerging as key research focuses, offering fresh hope to patients. Additionally, advances in immunotherapy, including the increasing use of PD-1/PD-L1 inhibitors, are expanding treatment options for breast cancer patients.   The trajectory of breast cancer treatment highlights the rise of "dark horse" drugs: those that begin by addressing resistance and evolve through a deeper understanding of signaling pathways. Whether it’s the much-discussed AKT inhibitors or the rapid emergence of bispecific HER2-targeted ADCs, these new therapies are paving the way for a more dynamic future in breast cancer treatment. In this ongoing race, scientists and pharmaceutical companies are injecting fresh possibilities into the extension of life through continuous innovation.

In HER2-positive breast cancer, HER2 stimulates downstream signaling pathways such as RAS-RAF-ERK and PI3K-PTEN-AKT, promoting cancer cell proliferation. As a result, HER2 has become a crucial biomarker for cancer diagnosis and a major therapeutic target in treatments such as antibody-drug conjugates (ADCs).