New progress and challenges of targeted therapies for breast cancer

Introduction

Breast cancer is a biologically heterogeneous malignancy and remains one of the most frequently diagnosed cancers globally. Despite progress in surgical techniques, radiotherapy, and systemic chemotherapy, metastatic breast cancer continues to present a major clinical challenge due to its capacity for dissemination and therapeutic resistance (1,2). The emergence of targeted therapies has shifted the treatment paradigm by enabling selective inhibition of oncogenic pathways integral to tumor proliferation, survival, and immune evasion. These modalities—including monoclonal antibodies, small-molecule inhibitors, and antibody-drug conjugates (ADCs)—have demonstrated efficacy across molecular subtypes of breast cancer, offering the potential for improved outcomes and reduced systemic toxicity (1,2). However, challenges such as acquired resistance, toxicity management, and the need for predictive biomarkers underscore the complexity of personalized treatment strategies. This mini-review synthesizes current progress in targeted therapy in breast cancer, with emphasis on mechanisms of action, clinical efficacy, limitations, and future direction in optimizing precision oncology approaches.

Human epidermal growth factor receptor 2 (HER2)-targeted therapy

One of the earliest and most influential examples of targeted therapy in breast cancer is the inhibition of HER2. Approximately 15–20% of breast cancers exhibit HER2 gene amplification or overexpression, a characteristic historically associated with higher aggressiveness and poorer prognosis. Trastuzumab, a monoclonal antibody that binds to the extracellular domain of HER2, was the first HER2-targeted agent to demonstrate success in both metastatic and adjuvant settings. By binding to the extracellular domain of HER2, trastuzumab inhibits downstream signaling pathways, such as the phosphoinositide 3-kinase (PI3K) pathway, which is crucial for cell proliferation and survival. Additionally, trastuzumab induces antibody-dependent cellular cytotoxicity (ADCC), enhancing the immune system’s ability to destroy tumor cells (3).

Subsequently, pertuzumab was introduced to further inhibit HER2’s dimerization with other HER family receptors, providing more comprehensive blockade of tumor cell proliferation. By preventing dimerization, pertuzumab effectively disrupts the signaling pathways. The CLEOPATRA study showed that adding pertuzumab to trastuzumab and docetaxel significantly prolonged overall survival in HER2-positive advanced breast cancer patients (4). ADCs, such as trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd), have advanced this field even further, coupling cytotoxic payloads to HER2-specific antibodies for targeted drug delivery, minimizing damage to normal tissues. T-DM1 delivers the cytotoxic agent DM1, a microtubule inhibitor, directly to HER2-overexpressing cells upon internalization, while T-DXd delivers a topoisomerase I inhibitor. T-DM1 has demonstrated survival benefits in HER2-positive breast cancer, both in patients with residual disease following neoadjuvant therapy and in the metastatic setting (5,6). T-DXd has shown significant efficacy in HER2-positive and HER2-low metastatic breast cancer, as reported in the DESTINY-Breast03 and DESTINY-Breast04 trials (7,8).

Despite the substantial impact of HER2-targeted therapies, some patients develop drug resistance and disease progression. Mechanisms include the emergence of p95HER2 (a truncated receptor lacking the trastuzumab-binding site), which allows for continued HER2 signaling independent of trastuzumab binding. Aberrant activation of the PI3K/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway, often due to mutations in PIK3CA, also contributes to resistance by bypassing HER2 blockade. Additionally, alterations in receptor internalization and trafficking can reduce drug efficacy (9). Moreover, toxicities such as cardiotoxicity, bone marrow suppression, gastrointestinal side effects, and, in the case of T-DXd, the potential risk of interstitial lung disease, pose significant clinical challenges (7-9). The cardiotoxicity associated with HER2-targeted therapies relates to the inhibition of the HER2 receptor in cardiac cells, as HER2 signaling is involved in maintaining cardiac myocyte survival and function. T-DXd-induced interstitial lung disease is believed to be related to the drug’s cytotoxic payload, which can cause inflammatory damage to lung tissue. In palliative care contexts, careful cardiac monitoring and symptom management are essential to maintain both extended survival and quality of life.

Cyclin dependent kinase 4/6 (CDK4/6) inhibitors in hormone receptor-positive breast cancer

Around 70% to 80% of breast cancers are estrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive, particularly within the HER2-negative subtype, where CDK4/6 inhibitors have demonstrated significant efficacy and are a standard of care (10). Additionally, mTOR and PI3K inhibitors are currently being explored for efficacy in specific subsets, with some already approved. Traditional endocrine therapies—such as tamoxifen or aromatase inhibitors—remain foundational but face de novo or acquired resistance. With growing insights into cell-cycle regulation, CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) emerged as a major breakthrough for overcoming endocrine resistance in ER-positive breast cancer (11). These agents selectively halt tumor-cell cycle progression by inhibiting the G1 to S phase transition. CDK4/6 kinases phosphorylate retinoblastoma (RB) protein, allowing for the release of E2F transcription factors, which drive cell cycle progression. By inhibiting CDK4/6, these drugs prevent RB phosphorylation, halting the cell cycle in the G1 phase (12).

Multiple phase III trials (PALOMA-2, MONALEESA-2, MONARCH-3) have demonstrated that combination of CDK4/6 inhibitors with endocrine therapy significantly extends progression-free survival compared with endocrine therapy alone. For example, the PALOMA-2 trial, which compared palbociclib plus letrozole versus letrozole alone, demonstrated a median progression-free survival of 24.8 months in the combination arm compared to 14.5 months in the letrozole alone arm (13-15). Moreover, the toxicity profiles—commonly including grade 3–4 neutropenia, fatigue, and diarrhea—are generally manageable with dose modifications and supportive care.

Nevertheless, resistance remains a central issue. RB protein normally acts as a tumor suppressor by binding to E2F transcription factors and preventing cell cycle progression. However, loss of RB function can render cells incapable of effective cell-cycle arrest, thus diminishing the impact of CDK4/6 inhibitors (16). Abnormalities in cyclin E1, CDK2, and fibroblast growth factor receptor (FGFR) pathways also contribute to resistance. Strategies to overcome these challenges, such as combining CDK4/6 inhibitors with mTOR or PI3K inhibitors, are under active investigation. Recent trials, such as EMERALD and INAVO120, have explored combining CDK4/6 inhibitors with novel endocrine agents or PI3K inhibitors to enhance treatment effectiveness and address resistance mechanisms (17,18). Additionally, the substantial cost of CDK4/6 inhibitors raises concerns for both healthcare systems and patients. When considering these therapies for palliative care, balancing the medication’s expense against potential benefits in disease control, symptom relief, and prolonged survival is crucial.

PARP inhibitors in BRCA-mutated breast cancer

Around 5–10% of breast cancer patients carry germline mutations in breast cancer gene 1 (BRCA1) or gene 2 (BRCA2), which play a central role in homologous recombination repair. Homologous recombination is a high-fidelity DNA repair pathway that corrects double-strand DNA breaks, maintaining genomic stability. BRCA1 and BRCA2 proteins play a central role in this process by facilitating DNA strand invasion and repair synthesis. When BRCA1 or BRCA2 is mutated, homologous recombination is impaired, leading to the accumulation of DNA damage and increased genomic instability. Consequently, cancer cells with BRCA mutations become dependent on poly (ADP-ribose) polymerase (PARP)-mediated single-strand DNA break repair. PARP is an enzyme that repairs single-strand DNA breaks. When PARP is inhibited in cells with BRCA mutations, single-strand DNA breaks accumulate and are converted into double-strand DNA breaks, which cannot be repaired due to the deficiency in homologous recombination. This results in the buildup of lethal double-strand DNA breaks, resulting in cell death through a mechanism known as synthetic lethality

Two PARP inhibitors—olaparib and talazoparib—have been approved for metastatic BRCA-mutated breast cancer, demonstrating significant improvements in progression-free survival compared with chemotherapy (19,20). For example, the EMBRACA trial demonstrated a median progression-free survival of 8.6 months with talazoparib compared to 5.6 months with chemotherapy (20). Similarly, the OlympiAD trial, which compared olaparib with chemotherapy, showed a median progression-free survival of 7.0 months in the olaparib group versus 4.2 months in the chemotherapy group (21). The convenience of oral PARP inhibitors, which reduces the need for frequent hospital visits, offers a potential benefit in the palliative setting. However, patient selection, guided by BRCA mutation testing, must also consider the significant financial burden these drugs impose. Common adverse events, such as anemia and neutropenia, can impact quality of life, potentially leading to fatigue, increased risk of infections, and the need for blood transfusions or growth factor support (21).

Despite the clinical benefits, tumors can develop resistance to PARP inhibitors through mechanisms such as restoration of homologous recombination via secondary mutations that restore BRCA function, or through upregulated drug efflux pumps, which reduce intracellular drug concentrations (21). Restored homologous recombination allows cancer cells to repair double-strand DNA breaks, bypassing the synthetic lethality induced by PARP inhibition.

PI3K/AKT/mTOR pathway inhibitors

Aberrant activation of the PI3K/AKT/mTOR signaling pathway is frequently observed in breast cancer, particularly in the hormone receptor-positive subtype. This pathway plays a crucial role in cell proliferation, survival, and metabolism. Approximately 40% of ER-positive tumors harbor activating PIK3CA mutations, which lead to constitutive activation of the PI3K pathway, fostering tumor proliferation and resistance to therapy. Alpelisib emerged as the first PI3K inhibitor approved for PIK3CA-mutated hormone receptor-positive metastatic breast cancer, demonstrating significant progression-free survival benefits in combination with fulvestrant (22). In the phase III SOLAR-1 trial, which compared alpelisib plus fulvestrant versus fulvestrant alone, the median progression-free survival was 11.0 months in the alpelisib arm compared to 5.7 months in the fulvestrant alone arm (23).

Yet, PI3K inhibitors present notable challenges, including hyperglycemia—a dose-limiting toxicity—since PI3K signaling helps regulate glucose metabolism. Additional adverse events include rash, which can be severe and require dose modifications, and diarrhea, which can lead to dehydration and electrolyte imbalances. Clinical teams must closely monitor metabolic parameters and manage hyperglycemia promptly. Meanwhile, feedback loops and alternative signaling activation limit the long-term efficacy of PI3K inhibitors. Therefore, balancing tumor control with toxicity management and financial considerations is critical in palliative care. The elevated cost of these inhibitors can pose a financial burden for patients, potentially leading to treatment discontinuation or non-adherence, and therefore needs to be considered in patient management. Multiple combination trials exploring PI3K inhibitors with CDK4/6 inhibitors and other targeted agents are currently underway.

Immunotherapy for triple-negative breast cancer (TNBC)

TNBC lacks ER, PR, and HER2 expression, traditionally affording fewer treatment options and carrying a poorer prognosis (24,25). In recent years, immune checkpoint inhibitors [anti-programmed cell death protein 1 (anti-PD-1)/programmed death-ligand 1 (PD-L1)] have offered new possibilities for metastatic TNBC. PD-1 and PD-L1 are checkpoint proteins that regulate T-cell activity. By inhibiting this pathway, anti-PD-1/PD-L1 antibodies enhance T-cell-mediated antitumor immunity. The tumor microenvironment of the TNBC is often characterized by high levels of tumor-infiltrating lymphocytes (TILs) and PD-L1 expression, making it potentially susceptible to immunotherapy.

The IMpassion130 trial revealed that atezolizumab combined with nab-paclitaxel significantly improved progression-free survival in patients with PD-L1-positive TNBC. Specifically, the trial demonstrated a median progression-free survival of 7.5 months in the atezolizumab plus nab-paclitaxel arm compared to 5.0 months in the nab-paclitaxel alone arm (26). Pembrolizumab has also shown some efficacy in both early-stage and advanced TNBC. In early-stage TNBC, the KEYNOTE-522 trial demonstrated a significantly increased pathological complete response (pCR) rate with pembrolizumab plus chemotherapy in the overall population; however, the magnitude of benefit varied across patient subgroups (27).

However, only a subset of patients experience meaningful benefits, and the duration of response varies widely. Severe immune-related adverse events (irAEs)—including pneumonitis, hepatitis, colitis, and endocrine disorders—can be life-threatening and require high-dose steroids or immunosuppressive therapy, potentially compromising immunotherapy’s effectiveness (28). Moreover, predictive markers such as PD-L1 expression and tumor mutational burden (TMB) are imperfect. PD-L1 expression can be highly variable and influenced by factors such as tumor heterogeneity and has not been consistently validated across all TNBC subtypes. This emphasizes the need for more reliable biomarkers.

When considering immunotherapy in palliative care, clinicians must carefully select patients due to the modest survival gains and risk of severe toxicity. For patients with limited anticipated benefit based on tumor biology or clinical presentation, the toxicities may outweigh the potential advantages. PD-L1-positive patients could experience meaningful survival extensions with manageable side effects, leading to improved symptom control and overall well-being. Nonetheless, the substantial cost of immunotherapy must also be factored into treatment decisions.

ADCs and other emerging targets

Beyond T-DM1, other ADCs are transforming the treatment landscape. For instance, sacituzumab govitecan, targeting Trop-2, has been approved for refractory metastatic TNBC, providing a significant survival advantage over chemotherapy (29). Trop-2 is a transmembrane glycoprotein overexpressed in various cancers, including TNBC. Sacituzumab govitecan delivers the topoisomerase I inhibitor SN-38 directly to Trop-2 expressing tumor cells. This targeted delivery minimizes systemic toxicity while maximizing antitumor activity. The ASCENT trial demonstrated a significant improvement in overall survival with sacituzumab govitecan compared to chemotherapy in pretreated metastatic TNBC.

Meanwhile, T-DXd has shown remarkable efficacy not only in HER2-positive patients but also in those with lower levels of HER2 expression (“HER2-low”), broadening the reach of HER2-targeted therapy (30). HER2-low breast cancer, defined as immunohistochemistry (IHC)1+ or IHC2+ with in situ hybridization (ISH)-negative, represents a significant proportion of breast cancer previously considered HER2-negative. The DESTINY-Breast04 trial demonstrated significant improvements in progression-free and overall survival with T-DXd in HER2-low metastatic breast cancer. Despite their promise, ADCs can still cause toxicities such as bone marrow suppression, which can lead to neutropenia and increased risk of infection, and gastrointestinal disturbances, including nausea, vomiting, and diarrhea.

Additional ADCs targeting LIV-1, TROP-2 variants, and B7-H4 are in various stages of clinical development. For example, datopotamab deruxtecan, targeting Trop-2, and ladiratuzumab vedotin, targeting LIV-1, are being investigated in ongoing clinical trials. Next-generation small-molecule inhibitors against mutant ER1, FGFR, and Kristen rat sarcoma virus (KRAS) are also being explored in preclinical or early-phase clinical trials. These inhibitors aim to target specific oncogenic drivers and overcome resistance mechanisms. At the same time, new drug development coupled with companion diagnostic requirements can substantially increase treatment costs, limiting global accessibility.

Consequently, for patients in palliative care, ADCs may represent a middle ground between broad-spectrum chemotherapy and highly selective targeted agents, potentially yielding sustained responses with fewer systemic toxicities.

Limitations and challenges of targeted therapies

Despite the remarkable progress of targeted therapies, numerous limitations remain in clinical practice. Tumor cells often evade targeted inhibition through various resistance mechanisms, including pathway reactivation, mutations in the drug-binding site, activation of bypass pathways, or phenotype changes. Elucidating these mechanisms is key to designing next-generation inhibitors and novel combinations. Additionally, while targeted drugs are generally more selective than conventional chemotherapy, they can still be associated with significant toxicity, such as cardiotoxicity from HER2-targeted drugs, hyperglycemia from PI3K inhibitors, and life-threatening immune reactions from immunotherapies. These toxicities can necessitate dose reductions or treatment discontinuation, potentially compromising efficacy. Moreover, the high cost of most targeted therapies poses a substantial financial burden on patients and healthcare systems, making the balance between financial toxicity and quality of life particularly critical in a palliative setting. Additionally, while established biomarkers like HER2, BRCA, PIK3CA, and PD-L1 guide therapy selection, many patients do not fit these classifications, highlighting the need for more accurate and reliable biomarkers. The integration of targeted agents with other modalities, such as radiation or surgery, can improve outcomes but may also exacerbate toxicity, requiring careful planning of sequencing and combinations. Finally, clinical trials often enroll relatively homogeneous patient populations, which may not reflect real-world diversity, particularly in older patients or those with multiple comorbidities. Therefore, registries and real-world studies are crucial for accurately evaluating risk-benefit profiles in broader populations.

Palliative perspective and quality-of-life considerations

In palliative care, therapeutic objectives center on symptom control, functional maintenance, and enhancing quality of life. Targeted therapies often align with these objectives by providing more precise tumor control and potentially reducing systemic toxicity compared to conventional chemotherapy. Symptom control can include managing pain, nausea, and other distressing symptoms, while functional maintenance focuses on preserving mobility, cognitive function, and the ability to perform activities of daily living. Nonetheless, any treatment plan must carefully weigh the potential for meaningful benefit against the risks of adverse events, the need for ongoing monitoring, and the psychological toll of continuous therapy. Early involvement of palliative care teams can facilitate symptom management, provide psychosocial support such as counseling, support groups, and spiritual care, and engage in advanced care planning. Patient-centered decision-making is essential. Patients should receive clear, comprehensive information regarding anticipated outcomes, potential side effects, and financial implications, including the risk of financial toxicity that may lead to treatment discontinuation. This enables them to align treatment strategies with their personal values and preferences. As regimens become more complex, a compassionate, tailored multidisciplinary approach is necessary to safeguard patients’ overall well-being. Furthermore, the discussion of advanced directives is important, to ensure that the patient’s wishes are known, and followed.

Conclusions

Targeted therapies have significantly shaped breast cancer treatment by enabling subtype-specific interventions and improving patient outcomes. Yet despite these advances, numerous challenges persist—including therapeutic resistance, biomarker limitations, and treatment-associated toxicities—that continue to drive research and clinical innovation. The future of precision oncology lies in refining current tools and incorporating novel technologies. Widespread adoption of next-generation sequencing—via multigene panels, circulating tumor DNA assays, and transcriptomic profiling—holds promise for identifying actionable targets and tailoring treatment strategies. Innovations such as bispecific antibodies, improved ADC linker technologies, and highly selective kinase inhibitors aim to overcome resistance and enhance therapeutic specificity. Parallel efforts to integrate targeted therapies with immunomodulatory agents, guided by biomarkers like TMB and TILs, may expand their reach and clinical utility.

Furthermore, real-time monitoring of tumor evolution through tools like liquid biopsy and adaptive treatment strategies could enable earlier intervention against resistance. Prioritizing patient-centered outcomes such as quality of life, financial toxicity, and accessibility through real-world studies and pragmatic trials will be key to translating advances into equitable care. Emerging technologies such as artificial intelligence and patient-derived xenograft modeling further support individualized treatment planning. Ultimately, the success of targeted therapies in breast cancer depends on continued scientific rigor, innovation, and a holistic commitment to tailoring care. With sustained investment in research and clinical translation, personalized and compassionate cancer therapy may become the standard rather than the aspiration.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://apm.amegroups.com/article/view/10.21037/apm-25-30/prf

Funding: This study was supported by the National Institutes of Health (Nos. R01HL157456 and R01HL168464 to Y.W.) and American Heart Associate (No. 968781 to J.L.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-25-30/coif). J.L. reports that this study was supported by American Heart Associate (No. 968781). Y.W. reports that this study was supported by the National Institutes of Health (Nos. R01HL157456 and R01HL168464). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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