Updates in HER2-Positive Breast Cancer From SABCS 2025

Vaishali Deenadayalan, MD Roswell Park Comprehensive Cancer Center

December 30, 2025

HER2-positive breast cancer updates from SABCS 2023, featuring expert Vaishali Deenadayalan at Roswell Park, emphasizing advancements in treatment and research in oncology for improved patient outcomes.
Copy Link Share
Key Points

  • Trastuzumab deruxtecan (T-DXd) is moving earlier across treatment lines, supported by data in the neoadjuvant (DESTINY-Breast11), postneoadjuvant (DESTINY-Breast05), and first-line metastatic settings (DESTINY-Breast09).

  • First-line metastatic therapy is evolving, with DESTINY-Breast09 showing improved progression-free survival (PFS) and preserved quality of life, leading to recent FDA approval of T-DXd plus pertuzumab (P).

  • Maintenance and central nervous system (CNS)–directed strategies are expanding, supported by the PATINA and HER2CLIMB-05 trials.

Data presented at the 2025 San Antonio Breast Cancer Symposium continue to reshape treatment paradigms in both early-stage and metastatic HER2-positive breast cancer. Central themes included antibody–drug conjugates (ADCs), chemotherapy-sparing approaches, and increasingly nuanced sequencing strategies, with T-DXd emerging as a cornerstone therapy across disease stages.

Early-Stage HER2-Positive Breast Cancer

DESTINY-Breast05 showed that in patients with high-risk residual invasive disease following neoadjuvant therapy, T-DXd demonstrated a statistically significant improvement in invasive disease-free survival at 3 years compared with ado-trastuzumab (92.4% vs 83.7%, respectively) across all prespecified subgroups. Updated safety data presented at SABCS noted interstitial lung disease (ILD), mostly grade 1 or 2, in 9.6% of patients in the T-DXd group; grade 5 ILD occurred in 0.2% of patients.1 

DESTINY-Breast11, a neoadjuvant study, explored T-DXd alone or followed by paclitaxel plus trastuzumab plus pertuzumab (THP) versus dose-dense doxorubicin plus cyclophosphamide (ddAC) followed by THP for high-risk (≥ cT3cN0 or cT0-4cN1-3) HER2-positive disease. Neoadjuvant T-DXd–THP demonstrated a statistically significant pathologic complete response (pCR) and improved safety versus ddAC-THP (67.3% vs 56.3%; absolute pCR rate difference, 11.2% [95% CI, 4.0-18.3; P = .003]), with benefit observed in both hormone receptor (HR)–positive and HR-negative subgroups.2 It is important to note that the control arms did not include docetaxel plus carboplatin plus trastuzumab plus pertuzumab, the commonly used neoadjuvant standard of care in the United States.

Clinical Implications 

Together, DESTINY-Breast05 and DESTINY-Breast11 raise important sequencing questions. If T-DXd is used in the neoadjuvant setting and residual disease persists, should clinicians continue ADC therapy postoperatively or switch strategies? Until longer-term outcomes mature, shared decision-making, individualized recurrence risk assessment, and careful consideration of ILD risk remain essential. During the OncUpdates forum, Susan Dent, MD, noted that DESTINY-Breast11 “meaningfully improved pCR, and we are all waiting for longer-term follow-up to determine how this should change practice.”

Metastatic HER2-Positive Breast Cancer

DESTINY-Breast09 evaluated first-line treatment in metastatic HER2-positive breast cancer, randomizing patients to T-DXd plus P, T-DXd plus placebo (blinded), or standard THP.  T-DXd plus P demonstrated a statistically significant improvement in median PFS compared with THP (40.7 vs 26.9 months [hazard ratio, 0.56; 95% CI, 0.44-0.71; P < .00001]).3 Patient-reported outcomes presented at SABCS showed higher gastrointestinal symptom burden with T-DXd plus P, although overall patient-reported treatment impact was similar between regimens.

On December 15, 2025, the FDA approved T-DXd plus P for first-line treatment of adults with unresectable or metastatic HER2-positive breast cancer, marking a major shift in frontline management.

HER2CLIMB-05 evaluated the addition of tucatinib to THP as maintenance therapy in patients who had not progressed following induction treatment. Updated SABCS data demonstrated a significant improvement in median PFS with tucatinib compared with placebo (24.9 vs 16.3 months [hazard ratio, 0.64; 95% CI, 0.5-0.80; P < .0001]), regardless of HR status or presence of brain metastases. Overall survival data remain immature but highly anticipated.4

The PATINA trial established the role of adding a CDK4/6 inhibitor to HER2-targeted maintenance therapy plus endocrine therapy in improving PFS following induction chemotherapy. Updated SABCS 2025 analyses showed sustained benefit, with a median PFS of 44.3 months versus 29.1 months at 60 months (hazard ratio, 0.74; 95% CI, 0.58-0.94; P = .01). Importantly, the cumulative incidence of CNS progression at 36 months was lower in the CDK4/6 inhibitor arm (13.8% vs 20.4%), suggesting a potential protective effect that warrants further validation.

Clinical Implications

Brain metastases continue to drive outcomes in HER2-positive metastatic breast cancer, and T-DXd–based regimens can be favored in those with brain metastasis, visceral disease, PIK3CA mutation, quick relapse, and HER2 heterogeneity. THP may remain appropriate for select patients with de novo–metastatic, oligometastatic, and HER2 immunohistochemistry 3+ disease. Emerging data support personalized maintenance strategies, incorporating palbociclib for HR-positive disease and tucatinib for HR-negative disease with HP.

References

  1. Loibl S, Park YH, Shao Z, et al; DESTINY-Breast05 trial investigators. Trastuzumab deruxtecan in residual HER2-positive early breast cancer. N Engl J Med. Published online December 10, 2025. doi:10.1056/NEJMoa2514661
  2. Harbeck N, Modi S, Pusztai L, et al; DESTINY-Breast11 trial investigators. Neoadjuvant trastuzumab deruxtecan alone or followed by paclitaxel, trastuzumab, and pertuzumab for high-risk HER2-positive early breast cancer (DESTINY-Breast11): a randomised, open-label, multicentre, phase III trial. Ann Oncol. Published online October 21, 2025. doi:10.1016/j.annonc.2025.10.019
  3. Tolaney SM, Jiang Z, Zhang Q, et al; DESTINY-Breast09 trial investigators. Trastuzumab deruxtecan plus pertuzumab for HER2-positive metastatic breast cancer. N Engl J Med. Published online October 29, 2025. doi:10.1056/NEJMoa2508668
  4. Dieras V, Curigliano G, Martin M, et al. HER2CLIMB-05: A phase 3 study of tucatinib versus placebo in combination with trastuzumab and pertuzumab as first-line maintenance therapy for HER2+ metastatic breast cancer. J Clin Oncol. Published online December 10, 2025. doi:10.1200/JCO-25-02600