HER2-positive breast cancer treatment is rapidly evolving, with growing emphasis on de-escalation strategies in early-stage disease and personalized therapy across the continuum of care. At the Best of Hematology & Breast Cancer 2026 conference, Dr. Vidhya Nair reviewed pivotal trials including NEON-CARB, CompassHER2 pCR, DESTINY-Breast11, DESTINY-Breast05, DESTINY-Breast09, and HER2CLIMB-05. These studies are reshaping how clinicians approach neoadjuvant, adjuvant, and metastatic HER2-positive breast cancer, balancing efficacy, toxicity, and patient-reported outcomes while moving toward more individualized treatment algorithms.

Dr. Vidhya Nair is Medical Director of Adult Cancer Survivorship at Fred Hutch and Assistant Professor in the Clinical Research Division at Fred Hutch and the Division of Hematology and Oncology at the University of Washington School of Medicine. She is a breast cancer physician who sees patients at the Sloan Clinic. At the Best of Hematology & Breast Cancer 2026 conference in Seattle, Dr. Nair presented an overview of recent advances in HER2-positive breast cancer treatment, with emphasis on de-escalation strategies in early-stage disease and personalized approaches across the treatment continuum.

The transcript report below has not been reviewed by the speaker and may contain errors.

Overview of Recent HER2-Positive Disease Updates

The past year has brought numerous studies in HER2-positive disease with a particular focus on potential de-escalation options. The discussion encompasses updates from early-stage through metastatic settings, highlighting key trials that may reshape treatment paradigms.

Early-Stage Disease: The NEON-CARB Study

The NEON-CARB study represents the first trial incorporating a potential de-escalation strategy in early-stage HER2-positive breast cancer. Presented at ASCO, this Chinese study enrolled over 700 patients with stage 2-3 HER2-positive disease. Patients were randomized to receive standard neoadjuvant TCHP for three cycles versus omission of carboplatin with THP for six cycles, followed by six cycles in each arm every three weeks.

The study uniquely allowed physician choice of taxane, which could be Q3 week docetaxel, Q3 week paclitaxel, or nab-paclitaxel, though the latter is not commonly used. The primary endpoint was pathologic complete response. Results showed similar pCR rates between the THP and TCHP arms at 64 to 65%. pCR rates were also similar when comparing ER-negative versus ER-positive groups, with ER-negative patients performing better as expected.

Importantly, toxicity was reduced for those who did not receive carboplatin, with fewer rates of hematologic toxicity, specifically neutropenia and thrombocytopenia. Neuropathy, nausea, and increased creatinine were also less frequently observed when carboplatin was omitted.

The CompassHER2 pCR Study

A similar study presented at ASCO was the CompassHER2 pCR study, a much larger trial of 2,000 patients conducted by Alliance. This study included patients with stage 2 or stage 3 HER2-positive disease, all receiving only four cycles of THP. The study demographics showed the majority of patients were stage 2, 75% had T2 disease, and only 46% were node positive, representing a slightly lower risk group.

The pCR rate for all patients was significantly lower compared to the NEON-CARB study at 43.8%. This was slightly improved for ER-negative patients at 63.7%, but only 32.5% of the ER-positive group achieved pCR. Clinical and pathologic features associated with higher pCR rates included higher grade disease, lower ER expression, HER2 positivity by IHC rather than FISH, and use of paclitaxel.

The study also examined HER2DX, a genomic score for HER2-positive disease. Results showed an association where patients with higher HER2DX scores had a higher absolute pCR rate of over 40%, compared to those with low HER2DX scores.

Higher Risk Disease: DESTINY-Breast11

Moving to a higher risk neoadjuvant population, DESTINY-Breast11 examined incorporating the use of T-DXd. This was not strictly a de-escalation study, as the control arm consisted of dose-dense AC followed by THP, a choice that drew some criticism since anthracyclines are not commonly used with HER2-directed therapy in the neoadjuvant setting currently.

This higher risk group required at least T3 disease if not node positive, and importantly allowed inclusion of inflammatory breast cancer. The study initially had three arms but prematurely closed the T-DXd alone arm, leaving results for two arms. Patients in the T-DXd arm received 4 cycles of T-DXd followed by 4 cycles of THP, while the standard chemotherapy arm received 4 cycles of dose-dense AC followed by 4 cycles of THP.

The primary endpoint was pathologic complete response. The pCR rate for T-DXd was quite high at 67.3%, with improvement regardless of hormone receptor positivity. The HR-negative group achieved a particularly impressive 80.3% pCR. Residual cancer burden outcomes also showed patients who received T-DXd in the neoadjuvant setting were more likely to be categorized as RCB0 or RCB1 compared to the ACTHP group.

Safety and Patient-Reported Outcomes in DESTINY-Breast11

Safety and tolerability showed interesting differences between groups. Higher amounts of adverse events occurred with ACTHP, leading to more dose reductions in that group. However, the T-DXd arm had more treatment discontinuation. ILD rates were similar between groups, likely because T-DXd patients only received four cycles. Cardiac dysfunction and left ventricular effects were higher with ACTHP. Other adverse events included higher nausea rates with T-DXd and higher neutropenia and anemia rates with ACTHP.

Patient-reported outcomes presented at San Antonio included physical function data showing both arms experienced initial decline in physical function early on for the first few cycles. For T-DXd, this decline recovered later in treatment and appeared sustained. Overall treatment tolerability showed more patients in the ACTHP arm reported symptoms or side effects as very bothersome or quite a bit bothersome, while T-DXd patients more frequently reported side effects as not at all bothersome.

Adjuvant Setting: DESTINY-Breast05

DESTINY-Breast05, presented at ESMO, examined a potential new option for patients with residual disease in the HER2-positive state after neoadjuvant chemotherapy. This very high-risk population included patients considered inoperable at diagnosis or operable patients with residual disease specifically in lymph nodes to be eligible.

Patients were randomized to receive 14 cycles of either T-DXd or T-DM1, with invasive disease-free survival as the primary endpoint. The study met its primary endpoint, showing the 3-year IDFS rate was better with T-DXd versus T-DM1 at 80%. CNS events were numerically less with T-DXd, though this involved only a small number of patients. Overall survival data remain immature. Toxicity was substantially higher with T-DXd, with 9.6% ILD rates versus 1.6% with T-DM1. Discontinuation rates were also higher with T-DXd at 17.9% versus 12.9%, with patients receiving 14 cycles.

Metastatic Disease: DESTINY-Breast09

DESTINY-Breast09, presented at ASCO, examined what has now received FDA approval for first-line treatment of metastatic HER2-positive breast cancer. The study randomized patients to receive T-DXd alone, T-DXd with pertuzumab, or THP, the regimen known from the CLEOPATRA trial used for many years. Results were reported for T-DXd with pertuzumab, showing remarkable progression-free survival exceeding 40 months, favoring T-DXd and pertuzumab over TCHP. This ultimately led to FDA approval for the combination therapy.

However, concerns arose regarding study design given the absence of maintenance therapy options. Questions about patient quality of life prompted presentation of patient-reported outcomes at San Antonio. Overall tolerability showed higher proportions of patients reporting being very much or somewhat bothered by treatment in the T-DXd arm, whereas more patients in the THP arm reported being not at all or just a little bit bothered by symptoms. Interestingly, there appeared to be some symptom improvement after cycle seven of T-DXd, though data only extended to cycle nine while some patients received up to 40 months of treatment.

Other treatment-related symptoms of interest included fatigue, which was actually similar between arms. Nausea and vomiting were reported at higher rates with T-DXd, as was patient-reported appetite loss.

HER2CLIMB-05: Maintenance Strategy

The final study in the HER2-positive metastatic space was HER2CLIMB-05, presented at San Antonio and generating considerable discussion post-meeting as a potential new maintenance strategy option. This trial enrolled patients who had already received induction chemotherapy with THP for 4 to 8 cycles and had no evidence of disease progression. Patients with asymptomatic brain metastases were allowed. Randomization assigned patients to receive tucatinib in addition to HP maintenance versus placebo with HP.

Progression-free survival for tucatinib with HP was 24.9 months versus 16.3 months with HP alone, representing an 8.6-month PFS benefit. PFS was similar for hormone receptor-negative and hormone receptor-positive patients. An exploratory analysis examined CNS PFS in patients with baseline brain metastases. This involved only 80 patients as an exploratory endpoint and did not reach statistical significance, but showed numeric improvement. This represents an important endpoint for HER2-positive patients, especially those with brain metastases.

Safety and tolerability showed more grade 3 adverse events with tucatinib at 42% versus 24%. Discontinuation from tucatinib occurred mainly due to hepatic events, which are characteristic of this drug.

Future Directions in HER2-Positive Disease

Looking forward in the HER2-positive space, early-stage treatment should focus not just on de-escalation but treatment optimization. This includes determining whether de-escalation can be guided by treatment response using ctDNA, imaging, or genomic testing, and identifying opportunities to escalate with T-DXd or other therapies when response is lacking.

In the adjuvant setting for patients with residual disease, T-DXd may provide a new option, potentially for highest risk patients or those who received escalated treatment upfront. In the metastatic setting, the key question involves applying DESTINY-Breast09 results given the absence of data for an induction regimen with T-DXd followed by maintenance. Guidance is anticipated from the DENVER study investigating this approach.

Current Treatment Algorithms

Current practice for very early-stage HER2-positive disease continues using the APT regimen of adjuvant taxane with trastuzumab. In the neoadjuvant setting, TCHP remains standard for stage 2 and stage 3 disease, though opportunity exists to de-escalate carboplatin if patients experience significant treatment toxicities. In the adjuvant setting for patients with residual disease, T-DM1 remains standard of care, but a future role for T-DXd may emerge for the highest risk group.

For metastatic patients in the first-line setting, treatment should be personalized. Highest risk patients with high visceral disease burden, quick relapse from early-stage treatment, or brain metastases should be considered for first-line T-DXd with pertuzumab. Patients with de novo metastatic disease, long survival, or oligometastatic disease may still benefit from the CLEOPATRA regimen, now with additional maintenance therapy options including tucatinib based on PATINA and HER2CLIMB-05.