Experts Preview Anticipated HER2-Positive Breast Cancer Data Ahead of SABCS 2025

As anticipation builds for this year’s San Antonio Breast Cancer Symposium (SABCS), OncLive® asked leading breast cancer specialists to share the HER2-positive research topics they are most eager to follow at this year’s meeting.

We gathered exclusive insights from:

• Kelly McCann, MD, PhD, an assistant clinical professor of medicine at the UCLA Health David Geffen School of Medicine
• Jason Mouabbi, MD, an assistant professor in the Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center
• Elizabeth Sakach, MD, an assistant professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine

Several key HER2-targeted studies will be in focus at this year’s SABCS, offering new insights that may shape both early-stage and metastatic treatment paradigms. These include HER2CLIMB-05 (NCT05132582), evaluating tucatinib (Tukysa) as part of a maintenance strategy in metastatic HER2-positive disease;1 the phase 3 DESTINY-Breast11 (NCT05113251), investigating neoadjuvant trastuzumab deruxtecan (T-DXd; Enhertu)–based approaches in high-risk early-stage HER2-positive breast cancer;2 and DESTINY-Breast09 (NCT04784715), examining first-line T-DXd regimens compared with standard trastuzumab and taxane combinations in metastatic settings.3 Together, these trials are expected to clarify optimal sequencing, inform personalization of HER2-directed therapy, and potentially redefine standards across the continuum of HER2-positive breast cancer care.

OncLive: How do you anticipate the HER2CLIMB-05 results will refine maintenance treatment strategies and influence long-term management for patients with HER2-positive metastatic breast cancer?

McCann: Treatment in the first-line metastatic setting for HER2-postive breast cancer is a rapidly-changing space. HER2CLIMB05 evaluated the addition of tucatinib to trastuzumab and pertuzumab maintenance after induction therapy with the [phase 3] CLEOPATRA [NCT00567190] regimen of a taxane, trastuzumab, and pertuzumab (THP) in the first-line metastatic setting for HER2-positive breast cancer. This trial was designed and enrolled before results from two relevant clinical trials: [the phase 3] AFT-38 PATINA [NCT02947685] and DESTINY-Breast07 [NCT04538742] trials.

AFT-38 PATINA established a role for the addition of endocrine therapy and palbociclib [Ibrance] to trastuzumab and pertuzumab maintenance for metastatic hormone receptor–positive/HER2-positive breast cancer. DESTINY-Breast07 demonstrated the potential for T-DXd plus pertuzumab to replace the CLEOPATRA regimen. However, several years of cytotoxic therapy with T-DXd vs approximately 4.5 months of cytotoxic therapy with THP may not represent a desirable trade-off for all patients.

The [phase 2] DEMETHER trial [NCT06665768] is enrolling patients into a CLEOPATRA-like induction strategy using 6 cycles of T-DXd followed by subcutaneous trastuzumab plus pertuzumab.

With so many options for metastatic HER2-positive breast cancer in the first-line metastatic setting, T-DXd induction for a set number of cycles or to maximal response followed by maintenance with HP with or without additional oral therapies according to estrogen receptor positivity, patient preference, and with the purpose of toxicity avoidance, may be an attractive strategy by extrapolation.

Such a strategy could incorporate rechallenge with T-DXd at the time of progression. There is a strong drive to de-escalate therapy for patients with HER2-positive breast cancer in the curative setting because we know that we overtreat some patients. It is important that we give the same consideration in the metastatic setting. However, with these new tools and combinations at our disposal, it may also be that we actually cure more patients in the metastatic setting with a more aggressive approach.

Mouabbi: In the metastatic setting, I am keenly anticipating the full data readout for HER2-CLIMB05. The recent announcement that this trial met its primary end point of progression-free survival [PFS] is incredibly encouraging for our [patients with] first-line HER2-positive [disease]. We have long sought strategies to de-escalate therapy while maintaining control, and the prospect of a chemotherapy-free maintenance phase using tucatinib added to trastuzumab and pertuzumab is very attractive. If the data confirms we can extend the time before disease progression without the cumulative toxicity of continued chemotherapy, this could represent a new standard of care for maintenance therapy following induction.

Sakach: Results of HER2-CLIMB05 could change the treatment landscape as another and/or better maintenance therapy option for [patients with] metastatic disease after 4 to 8 cycles of SOC [THP] to prolong PFS. It will be interesting to see if the addition of tucatinib also prolongs time to central nervous system metastases.

How could the patient-reported outcomes (PROs) from DESTINY-Breast11 inform clinical decision-making around neoadjuvant therapy selection for high-risk, HER2-positive early-stage breast cancer, particularly when comparing T-DXd–based strategies with more traditional approaches?

Sakach: With positive results of DESTINY-Breast05 and DESTINY-Breast11 revealed at the 2025 ESMO Congress, these are highly awaited SABCS abstracts to discuss which patients we may consider an escalation approach both in the neoadjuvant and adjuvant settings—keeping in mind that the neoadjuvant approach with T-DXd for 4 cycles followed by THP, if patients do achieve pathological complete response, will allow patients with high-risk HER2-positive breast cancer to have less time on T-DXd. However, it is yet to be determined whether this will lead to an overall survival benefit. The escalated neoadjuvant and adjuvant approach with T-DXd is an important awaited discussion at SABCS to determine for whom we should be considering this treatment switch, and PRO data will be helpful in determining our best approach.

How do you interpret the PROs from DESTINY-Breast09 comparing T-DXd plus pertuzumab with THP in the first-line metastatic setting, and how might these data influence treatment selection for patients with HER2-positive advanced breast cancer?

Sakach: As we discuss best approaches in the first-line HER2-positive metastatic setting, given positive data from DESTINY-Breast09, it is important to review and discuss PRO data, as the control arm of THP followed by HP maintenance is overall well-tolerated in the maintenance phase, whereas T-DXd often comes with more toxicity than HP alone.

References

1. Tucatinib in combination with trastuzumab and pertuzumab as maintenance therapy for HER2-positive metastatic breast cancer. ClinicalTrials.gov. Updated July 15, 2025. Accessed December 2, 2025. https://clinicaltrials.gov/study/NCT05132582
2. Trastuzumab deruxtecan (T-DXd) alone or followed by paclitaxel, trastuzumab, and pertuzumab versus ddAC-THP in high-risk HER2-positive early breast cancer. ClinicalTrials.gov. Updated August 3, 2025. Accessed December 2, 2025. https://clinicaltrials.gov/study/NCT05113251
3. Trastuzumab deruxtecan (T-DXd) with or without pertuzumab versus taxane plus trastuzumab and pertuzumab for first-line HER2-positive metastatic breast cancer. ClinicalTrials.gov. Updated September 12, 2025. Accessed December 2, 2025. https://clinicaltrials.gov/study/NCT04784715