First-Line Options in HER2-Positive Metastatic Breast Cancer

The survival outlook for patients with HER2-positive metastatic breast cancer has changed significantly for the better over the last two decades.

For example, a European cohort study showed that overall survival (OS) increased over 10 years, from 30.9 to 57.3 months, for patients diagnosed with de novo HER2-positive metastatic breast cancer, while a retrospective analysis showed that OS now approaches 5 years, regardless of hormone receptor status.

“We have seen the once most aggressive and deadly type of breast cancer become one with the greatest improvements in survival,” Jennifer Litton, MD, of the University of Texas MD Anderson Cancer Center in Houston, told MedPage Today. “Understanding the HER2 receptor and its necessary interactions with other proteins have led to significant breakthroughs.”

“This includes monoclonal antibodies, tyrosine kinase inhibitors, and antibody-drug conjugates, among other targeted therapies in addition to or instead of standard chemotherapies,” she said.

Sara Hurvitz, MD, of the University of Washington and Fred Hutch Cancer Center in Seattle, noted that “it’s only in the last 10 years or so that it’s come to light that if you target the hormone receptors and HER2 in this breast cancer that you can really improve outcomes.”

“I think we haven’t ideally treated HER2-positive, hormone receptor-positive breast cancer in the past, so there’s been some missed opportunity of really taking advantage of receptor status,” she told MedPage Today.

She pointed out that hormone receptor-negative, HER2-positive breast cancer tends to be a little bit more aggressive in terms of the proliferation and grade of the tumor, but also a little bit more responsive. “You see a higher proportion of the cancers shrink or disappear with chemotherapy and HER2-directed therapy than if the hormone receptors are co-expressed,” Hurvitz said.

“There are opportunities to test and use novel targeted therapies that are hormonally directed, or are directed at pathways that are linked to the hormone pathway, and I think we’re just beginning to see this happen clinically,” she added. “I would predict that as we look to the future, we will see more of that sort of separation in the clinical realm that leads to treating it somewhat differently.”

First-Line Approach

For more than a decade, the first-line standard of care for HER2-positive metastatic breast cancer was trastuzumab (Herceptin) plus pertuzumab (Perjeta) and a taxane, based on the landmark CLEOPATRA trial.

First-line treatment with the triplet typically consists of 6 cycles of induction taxane chemotherapy in combination with trastuzumab and pertuzumab, followed by maintenance with the dual antibody therapy, and endocrine therapy if the patient is hormone receptor-positive. In CLEOPATRA, the triplet improved OS by about 16 months compared with trastuzumab and docetaxel plus placebo in patients with HER2-positive metastatic breast cancer, regardless of hormone receptor status.

Two recent studies demonstrated that integrating a HER2-targeted tyrosine kinase inhibitor (TKI) or CDK4/6 inhibitor can optimize antibody-based maintenance in this population.

In the phase III HER2CLIMB-05 trial, the addition of the TKI tucatinib (Tukysa) to first-line maintenance therapy with trastuzumab and pertuzumab significantly improved progression-free survival (PFS). Median PFS was 24.9 months for those who received the three drugs compared with 16.3 months for those who received placebo plus trastuzumab and pertuzumab (P<0.0001), with that PFS benefit observed regardless of hormone receptor status.

For patients with hormone receptor-negative status, median PFS was more than a year longer in the tucatinib arm — 24.9 months versus 12.6 months in the placebo arm (P=0.0002). For those with hormone receptor-positive disease, median PFS was 25 months versus 18.1 months, respectively (P=0.0389).

Then, at the San Antonio Breast Cancer Symposium in 2024, Otto Metzger, MD, of Dana-Farber Cancer Institute and Harvard Medical School in Boston, presented results from the phase III PATINA trial, which showed that the CDK4/6 inhibitor palbociclib (Ibrance) in combination with maintenance anti-HER2 and endocrine therapies, produced a significant and clinically meaningful improvement in PFS among patients with hormone receptor-positive, HER2-positive metastatic breast cancer.

The median PFS was 44.3 months among patients in the palbociclib arm compared with 29.1 months in a control arm of patients treated with anti-HER2 therapy and endocrine therapy alone — a PFS result that Hurvitz, as an invited discussant, called “incredible … and really historic.”

“This was only in hormone receptor-positive patients, so we’re just beginning to see how we treat changes based on the hormone receptor status,” Hurvitz noted. However, “what’s kind of thrown everything up in the air was the DESTINY-Breast09 trial.”

In that trial, first-line trastuzumab deruxtecan (T-DXd, Enhertu) combined with pertuzumab improved PFS in HER2-positive locally advanced or metastatic breast cancer, regardless of hormone receptor status. Patients randomized to T-DXd plus pertuzumab had a median PFS of 40.7 months versus 26.9 months for patients who received a taxane plus trastuzumab and pertuzumab (P<0.00001).

The FDA approved the combination as a first-line treatment for unresectable or metastatic HER2-positive breast cancer in December 2025.

“I think the selection between T-DXd/pertuzumab versus THP [a taxane plus trastuzumab and pertuzumab] as first-line treatment is a bit murky,” Hurvitz said. “While DESTINY-Breast09 was impressive, there are many unanswered questions for all patients, regardless of hormone receptor status.”

For example, “we do not know yet if T-DXd/pertuzumab improves overall survival compared to THP,” she noted, or whether pertuzumab is actually needed, since the T-DXd-alone arm of the trial has yet to be reported.

Additionally, that trial did not take into account any maintenance option.

So, “we do not know how T-DXd/pertuzumab compares to 6 cycles of THP followed by trastuzumab/pertuzumab plus endocrine therapy,” or with the addition of palbociclib as in the PATINA regimen, Hurvitz said.

“Right now, I think clinicians are choosing T-DXd-based therapy for patients with the heaviest disease burden, again regardless of the hormone receptor status,” she added. “So, there’s a little bit of confusion in the field right now as the data continue to evolve.”

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