How Modern Research Is Transforming Metastatic HER2+ Breast Cancer Care

There has been an explosion of newer HER2-directed therapies, including monoclonal antibodies, novel antibody-drug conjugates (ADCs) and oral tyrosine kinase inhibitors (TKIs) designated for patients with HER2-positive breast cancer that are already significantly improving the outcomes of this population.

“Patients with HER2-positive metastatic breast cancer are living longer, sometimes extending life expectancy for several years,” Dr. Katherine Crew said. “When we see these drugs are showing promising activity in the metastatic setting, we start testing them in patients with early-stage disease to improve cure rates. As you can see, the rapid progress and treatment of HER2-positive breast cancer is directly related to clinical trial participation by these brave patients who contributed to these studies.”

Crew, the Avon Products Foundation Professor of Breast Cancer Research at Columbia University Irving Medical Center in New York, New York, led the discussion on current and evolving management of patients with HER2-positive metastatic breast cancer during a CURE Educated Patient® Lung Cancer Summit, held virtually on December 20.

Breast cancer that is HER2 (human epidermal growth factor receptor 2)–positive comprises 15% to 20% of all breast cancer cases, with a median survival of 5 years. Main systemic therapies comprise chemotherapy, endocrine therapy, and HER2-directed treatment. Healthcare professionals measure HER2 overexpression via immunohistochemistry; a score of 3+ would categorize a breast cancer as HER2 positive, while a score of 0 or 1+ would be HER2 negative, Crew explained. A score of 2+ would lead to fluorescence in situ hybridization (FISH) testing.

“If the FISH testing is positive, then the tumor is considered HER2 positive,” she added.

HER2-directed therapies are broken down as:

1. Monoclonal antibodies: Herceptin (trastuzumab) and Perjeta (pertuzumab)
2. Antibody-drug conjugates: Kadcyla (ado-trastuzumab emtansine; T-DM1) and Enhertu (fam-trastuzumab deruxtecan-nxki; T-DXd)
3. Tyrosine kinase inhibitors: Tykerb (lapatinib), Nerlynx (neratinib) and Tukysa (tucatinib)

In her presentation, Crew zeroed in on the CLEOPATRA, DESTINY-Breast01, DESTINY-Breast03, and HER2CLIMB trials, that led to the metastatic breast cancer indications for Perjeta, Enhertu, and Tukysa, respectively.

In CLEOPATRA:

• The median progression-free survival (PFS) was 18.5 months with the addition of Perjeta to Herceptin and Taxotere in patients with treatment-naive, metastatic HER2-positive breast cancer compared with 12.4 months with placebo/Herceptin with Taxotere (HR, 0.62).2
• Overall survival (OS) was also significantly improved with the addition of Perjeta (HR, 0.64).

The most common, all-grade side effects for the Perjeta combination versus placebo/Herceptin with docetaxel included diarrhea (60.9% vs 46.3%, respectively), alopecia (60.9% vs 60.5%) and rash (33.7% vs 24.2%). A common grade 3 or higher side effect included neutropenia (48.9% vs 45.8%).

In DESTINY-Breast01:

• Enhertu was evaluated in patients with HER2-positive metastatic breast cancer previously treated with Kadcyla. Results showed a 60.9% objective response rate, with 11 complete responses.
• The median PFS was 16.6 months, and the median OS was not reached.

Enhertu was also compared with Kadcyla in the second-line setting for patients with advanced HER2-positive breast cancer in the DESTINY-Breast03 study.

In DESTINY-Breast03

• The median PFS was not reached in the Enhertu arm compared with 6.8 months with the Kadcyla arm (HR, 0.28).
• The median OS was NE in both arms (HR, 0.55).

As it relates to safety, the most common any-grade treatment-related side effects with Enhertu compared with Kadcyla is neutropenia (42.8% vs 11.1%), anemia (30.4% vs 14.2%), nausea (72.8% vs 27.6%), diarrhea (23.7% vs 3.8%) and adjudicated drug-related interstitial lung disease or pneumonitis (10.5% vs 1.9%).

Most recently, in December 2025, the FDA approved Enhertu in combination with Perjeta for the first-line treatment of adults with unresectable or metastatic HER2-positive breast cancer as approved by an FDA-approved test.

In HER2CLIMB:

• Patients with HER2-positive metastatic breast cancer who were previously treated with Herceptin, Pertuzumab, and Kadycla were randomly assigned to receive third-line treatment with Tukysa plus Herceptin and Xeloda or a placebo with Herceptin and Xeloda. Results showed to a median PFS of 7.8 months with Tukysa compared with 5.6 months of patients on the placebo combination (HR, 0.54).
• The median OS was 21.9 months compared with 17.4 months, respectively (HR, 0.66).

“A unique aspect of the HER2CLIMB trial is that they allowed patients with active brain metastases,” Crew explained. “Oftentimes, these patients are excluded from participation in clinical trials due to their poor prognosis. In particular, patients with HER2-positive breast cancer have an increased likelihood of developing brain metastases; of all the patients with metastatic breast cancer that have spread to the brain, nearly half have HER2-positive breast cancer.”

In a subgroup of patients with brain metastases, the median PFS with tucatinib was 7.6 months compared with 5.4 months with the placebo regimen (HR, 0.48).

The most common any-grade side effects from the Tukysa and placebo groups, respectively, included diarrhea (80.9% vs 53.3%), hand-foot syndrome (63.4 vs 52.8%), nausea (58.4% vs 43.7%), fatigue (45.0% vs 43.1%), vomiting (35.9% vs 25.4%), stomatitis (25.5% vs 14.2%), decreased appetite (24.8% vs 19.8%), headache (21.5% vs 20.3%), increased aspartate aminotransferase (21.3% vs 11.2%) and increased alanine aminotransferase (20.0% vs 6.6%).

How Does HER2-Low or HER2-Ultralow Breast Cancer Fit In?

“HER2-low and ultra-low disease represents an additional 55% to 60% of breast cancers, including aggressive triple-negative breast cancers, which generally have more limited treatment options,” Crew said.

In January 2025, the FDA approved Enhertu for patients with unresectable or metastatic hormone receptor–positive, HER2-low or HER2-ultralow breast cancer that has progressed on one or more endocrine therapies in the metastatic setting. The results were based on the DESTINY-Breast06 (NCT04494425) trial.

“Antibody-drug conjugate, [Enhertu] was recently approved for HER2-low and ultra-low breast cancer which is greatly expanded. The use of this drug [was also studied] in the DESTINY-Breast04 [NCT03734029] and DESTINY-Breast06 trials, where Enhertu was compared to standard-of-care chemotherapy in patients with metastatic HER2-low or ultralow breast cancer.”

Most recently, Enhertu has been approved for patients in HER2-low breast cancer, based on results from these trials.

The Full Circle With HER2-Positive Breast Cancer Treatment

To demonstrate the long-term effects and survival outcomes of some of the more modern HER2-directed therapies, Crew referenced the landmark analysis of the CLEOPATRA trial with Perjeta and Herceptin. Data showed that at 8 years, the PFS was 16% with the addition of pertuzumab compared with 10%; the median OS was 37% versus 23%, respectively.

“Does this mean that some patients with metastatic breast cancer are cured? Typically, we treat metastatic breast cancer like a chronic disease, where we continue the same treatment until progression or intolerable side effects. But if these patients have no evidence of disease, does that mean we can stop their HER2-directed therapy after several years, particularly since these drugs are associated with some side effects, including financial toxicity,” Crew concluded. “Since these since these drugs are quite expensive, these are still some unanswered questions in the field.”

References

1. “Management of HER2-Positive Metastatic Breast Cancer,” by Dr. Katherine Crew. Presented at: CURE Educated Patient Summit on Metastatic Breast Cancer; December 20, 2025.
2. "Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer," by Dr. José Baselga, et al. The New England Journal of Medicine.
3. "Trastuzumab deruxtecan in previously treated HER2-positive breast cancer," by Dr. Shanu Modi. The New England Journal of Medicine.
4. "Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer," by Dr. Javier Cortés. The New England Journal of Medicine.
5. "Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer," by Dr. Rashmi K Murthy. The New England Journal of Medicine.

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