Advancements in HER2-positive breast cancer are shifting towards personalized, less toxic treatments that improve patient outcomes and quality of life. Clinical trials are exploring de-escalation strategies, novel agents, and combination therapies to address specific challenges like CNS recurrences and treatment resistance.
De-escalation in Early-Stage HER2-Positive Breast Cancer
In early-stage HER2-positive breast cancer, trials like APT (paclitaxel and trastuzumab) and ATEMPT (trastuzumab emtansine or T-DM1) have demonstrated promising results with de-escalated treatments. The APT trial's final analysis showed a 10-year invasive disease-free survival of 91.3% with trastuzumab. The ATEMPT trial, though not designed to compare efficacy, showed a 5-year IDFS of 97% with T-DM1 and 91.1% with trastuzumab, with T-DM1 generally better tolerated.
Naomi Dempsey, MD, a breast medical oncologist at Baptist Health Miami Cancer Institute, noted that these trials indicate patients can achieve optimal outcomes with reduced toxicity. The ATEMPT 2.0 trial is currently randomizing patients with stage I HER2-positive breast cancer to T-DM1 followed by subcutaneous trastuzumab versus trastuzumab alone, aiming to omit cytotoxic chemotherapy.
Anthracycline Omission in Stage II and III Disease
The TRAIN-2 trial, a randomized phase 3 study, demonstrated that omitting anthracycline from neoadjuvant chemotherapy in stage II and III HER2-positive breast cancer does not compromise efficacy but reduces cardiotoxicity. The pathologic complete response rates were similar in both arms (67% with anthracycline vs. 68% without), and 3-year overall survival was 97.7% and 98.2%, respectively. These results have led many oncologists to omit anthracycline in this setting.
Addressing Residual Disease and CNS Recurrences
The KATHERINE trial showed a 13.7% invasive disease-free survival benefit with T-DM1 at 7 years in patients with residual disease after neoadjuvant chemotherapy. However, a disproportionate number of recurrences on T-DM1 were CNS recurrences. Ongoing trials like CompassHER2 RD (T-DM1 vs. T-DM1 plus tucatinib) and DESTINY-Breast05 (T-DM1 vs. trastuzumab deruxtecan or T-DXd) are evaluating treatments with CNS activity to address this unmet need.
Combination Therapies and Novel Agents in Metastatic Settings
In the metastatic setting, combination therapies remain crucial. The CLEOPATRA trial established the standard of care as taxane chemotherapy with trastuzumab and pertuzumab. The DESTINY-Breast03 trial demonstrated the superiority of T-DXd over T-DM1 as second-line therapy, with a median progression-free survival of 28.8 months versus 6.8 months. The HER2CLIMB regimen (tucatinib, trastuzumab, and capecitabine) has shown efficacy systemically and in the CNS, making it a consideration in the second line for patients with brain metastases.
Personalizing Treatment Plans
Treatment plans are increasingly personalized based on factors like age, overall health, and tumor biology. Less toxic approaches are favored for older or frailer patients. The TRAIN-3 trial evaluated an MRI-directed approach to determine whether chemotherapy could be ended early. In unique cases with tumor heterogeneity, such as HER2-positive and triple-negative components, treatment may be adjusted accordingly.
Overcoming Resistance and Managing Adverse Effects
Resistance to HER2-targeted therapies remains a challenge. Novel agents like T-DXd and tucatinib have shown promise in overcoming resistance and improving outcomes, including in the CNS. Managing adverse effects is crucial, with strategies tailored to each agent. For example, trastuzumab can cause reversible cardiac function suppression, pertuzumab can cause diarrhea, and T-DXd requires vigilance for pneumonitis. Tucatinib is generally well-tolerated but can cause diarrhea and transaminitis.
Future Directions
The future of HER2-positive breast cancer lies in personalized medicine, understanding resistance mechanisms, and developing more active agents in the CNS space. Ongoing research aims to identify patients who can achieve equal outcomes with less intensive treatments and to address the unmet need of preventing CNS recurrences.
