Human epidermal growth factor receptor 2-positive (HER2+) breast cancer accounts for approximately 15% to 20% of all breast cancer cases,¹ and up to half of these patients will eventually develop brain metastases,² making novel therapies that can improve overall outcomes for metastatic disease especially exciting. Hormone receptor-positive (HR+)/HER2+ disease is the most common form of HER2+ disease.³ Patients with HR+/HER2+ disease have tended to perform better on current therapies than those with HR- disease,⁴ but recent data are shedding light on therapeutic approaches, in both the first-line and first-line maintenance settings, that could improve outcomes for all patients.

In the following Q&A, Drs. Reva Basho and VK Gadi discuss their clinical experience within the current therapeutic landscape for HER2+ disease based on results from the AFT-38 PATINA, DESTINY-Breast09 , and HER2CLIMB-05 trials and on a subsequent regulatory approval from DESTINY-Breast09. During the course of their conversation, they provide insights on how efficacy data translates to real-world application of novel therapies based on patient and disease characteristics, including brain metastases. 

Please set the stage regarding current standard of care for patients with HER2+ metastatic breast cancer. 

Dr. Gadi: We characterize patients with HER2+ disease as having either an immunohistochemistry (IHC) staining score of 3+ or, more commonly in the metastatic setting, amplification as shown by FISH testing. If either of those are the case, then we know, more often than not, the HER2 oncogene is driving the disease. For some of these agents, the benefits vary depending on HER2-expression status. The therapeutic landscape is pretty limited for patients with HER2+ disease outside of these agents.

Prior to now the standard of care in first-line HER2+ disease had been to use a taxane-based chemotherapy with combination trastuzumab and pertuzumab antibody-based therapy (THP), which was established by the CLEOPATRA trial.⁵ Essentially we would often treat these patients with chemotherapy until one of three things happened: intolerance, complete response, or stable disease with eventual progression. Many patients would actually achieve benefit, so we would stop the chemotherapy and use the biologics as maintenance therapy. Patients who had hormone receptor-positive (HR+)/HER2+ disease would also receive endocrine therapy. Although that was not part of CLEOPATRA, we know that tackling both those pathways is important in comprehensively suppressing the drivers for these types of cancers.

So that’s where we were until 2024, when data from the first of a couple transformative trials — the AFT-38 PATINA trial — were presented.

How are these recent trials driving improved outcomes when focusing on the first line and  maintenance therapy settings?

Dr. Basho: In order of release, the AFT-38 PATINA study included patients with treatment-naive metastatic disease. Per the CLEOPATRA regimen, patients received 4 to 8 cycles of induction THP. If there was no disease progression, patients were randomly assigned to receive either anti-HER2 therapy and endocrine therapy alone or in combination with palbociclib. There was a very impressive PFS outcome in this study: 29.1 months in the standard arm versus 44.3 months in the palbociclib arm, with a hazard ratio of 0.74, or a 26% reduction in risk of progression or death.⁶ Both arms compare very favorably to the median PFS of 18.7 months in the THP arm of CLEOPATRA,⁵ really showing us that maintenance approaches — including the addition of endocrine therapy — matters.

The baseline incidence of CNS metastases, presented at the 2025 San Antonio Breast Cancer Symposium® (SABCS® 2025), across both arms was about 4%.⁷ There was a reduced cumulative incidence of CNS progression or death for patients who received palbociclib (13.8% at 36 months) compared with the control arm (20.4% at 36 months). For patients without CNS metastases at baseline, the incidences of CNS progression dropped from 19.0% to 12.8% with the addition of palbociclib. So very impressive and perhaps surprising CNS data.

Dr. Gadi: I agree that this is very impressive, Dr. Basho, and I am pleased that it has recently become part of guideline-driven care.

The next trial, DESTINY-Breast09 (DB09), looked at first-line therapy for patients with newly diagnosed metastatic HER2+ disease. The study had three arms: trastuzumab deruxtecan (T-DXd) plus placebo, T-DXd plus pertuzumab, and THP. Data for T-DXd alone remains unpresented, although we do anticipate it quite soon.

Regarding the primary comparison of T-DXd plus pertuzumab versus THP, there was an improvement in PFS. The median PFS in the THP arm was 26.9 months compared with 40.7 months for T-DXD plus pertuzumab, resulting in a 44% reduction in risk.⁸ The control arm performed very similarly to what we would’ve expected in terms of PFS. The top-line data here are interesting because, not only did we see this really interesting PFS improvement, but there were a lot of patients who were able to achieve complete responses as well — almost one in five or six patients got to that point. So, this seemed to be a very effective frontline option. Because of this, T-DXd plus pertuzumab was recently given an FDA approval in the United States in this setting.

Dr. Basho: Switching now to HER2CLIMB-05, which, like PATINA, focused on the maintenance setting. This trial evaluated maintenance HP plus placebo or HP plus tucatinib, a small molecule inhibitor of the HER2 kinase. Endocrine therapy was allowed in patients with HR+/HER2+ disease. The addition of tucatinib to maintenance therapy improved PFS from 16.3 to 24.9 months, resulting in a 36% reduction in risk of progression or death. PFS was assessed by hormone receptor status. For HR- patients, PFS improved from 12.6 to 24.9 months with the addition of tucatinib, and in the HR+ subgroup analysis the PFS improved from 18.1 to 25.0 months.⁹

Interestingly enough, tucatinib did not reduce the CNS progression events in the ITT population, but in an exploratory analysis looking at patients with baseline brain metastases (about 12% per arm), median CNS-PFS was improved from 4.3 to 8.5 months for patients who received tucatinib.⁹

Regarding maintenance therapy, do you have any thoughts about why the control arm did better in PATINA versus HER2CLIMB-05? 

Dr. Basho: That’s a really important question because of course we don’t like those cross-trial comparisons, but we tend to do them anyway. Although both trials focus on post-THP induction maintenance therapy, they include fundamentally different groups of patients. PATINA was limited to HR+/HER2+ patients, who we know tend to have longer disease control compared with HR- patients. In addition, regardless of arm, all patients in PATINA received endocrine therapy as part of their maintenance regimen, which, in some sense, is adding maintenance therapy for all patients compared to our historic data from CLEOPATRA. And of course we are adding two agents on top of the historical CLEOPATRA regimen in the experimental arm. I think these are the reasons we see such a big difference numerically, but it’s most important to look at the difference between the two arms within each study because this difference is really our driving factor for the decisions that we’re making.

The PFS in the control arm for PATINA was 29 months, which improved to 44 months once palbociclib was added.⁶ The control arm in HER2CLIMB-05 had a PFS of about 16 months, which improved to about 25 months for the overall study population.⁹ The hazard ratio in PATINA for PFS improvement with palbociclib was 0.74⁶; the hazard ratio in HER2CLIMB-05 for the primary endpoint of investigator-assessed improvement in PFS with tucatinib was 0.641.⁹ Based on just hazard ratios, we see a slightly greater effect for tucatinib, which might be because that trial included a higher-risk population overall.

Thinking about maintenance approaches, what comments can be made about selection between palbociclib and tucatinib? 

Dr. Basho: Of course PATINA was limited to HR+/HER2+ metastatic breast cancer, and HER2CLIMB-05 included all comers with HER2+ metastatic breast cancer. PATINA showed very impressive numeric improvement in PFS, highlighting the importance of maintenance endocrine therapy for these patients, and making palbociclib the likely choice here. We may be more inclined to look at tucatinib as a treatment option in the maintenance setting for the HR- patients based on the subgroup analysis in HER2CLIMB-05.

Toxicity is always a concern when choosing a therapy, but both of these agents are relatively well tolerated. The safety profile of tucatinib was consistent with what we’ve seen in the past. It was well tolerated, with the majority of adverse events being grade 1/2. We did see some grade 3 diarrhea and liver function abnormalities. Diarrhea can have a profound impact on quality of life, but the median time to resolution after its onset was 8 days,⁹ showing that this can be managed.

Dr. Gadi: I agree, Dr. Basho. One thing I want to mention is that patients on DB09 had nausea, vomiting, and fatigue that was more prolonged than what you would see with the taxane-based regimen where most of the toxicities are upfront, but, in my experience, once the taxane drops, life gets pretty manageable for those patients. Even on PATINA and HER2CLIMB-05, however, we saw manageable expected toxicity profiles. Palbociclib in particular is manageable once you figure out the neutropenia rhythm of that agent. We did see more transaminitis toxicities with tucatinib but once you know what to look for, it’s a very feasible regimen as evidenced by few permanent discontinuations. Whereas with T-DXd, patients seem to have a hard time being on it for a long period of time.

Dr. Basho: CNS metastases also are a big concern, and I think we did expect to see some CNS prevention data with maintenance tucatinib in HER2CLIMB-05 It was somewhat surprising that we did not see the CNS-PFS improve in the ITT population. We did, however, see an improvement in CNS-PFS for patients who had baseline brain metastases so it will be important to consider tucatinib in that setting.

Dr. Gadi: In theory, I think both of these agents will be very CNS active, which is exciting, although we don’t have the full PATINA data for this yet. One of the raison d’êtres for even pursuing a drug like tucatinib in the first place, however, is its activity for brain and CNS metastases. As you mentioned Dr. Basho, we certainly want to see the same CNS penetration in the first line that we see in the second line and beyond with tucatinib.

The most interesting molecule in some respects — and I was a doubter, but now I’m a believer — is T-DXd. It’s a big bulky monoclonal antibody. With the chemotherapy payload, we were taught conventionally, these are drugs that just don’t get into the CNS yet, when we looked at the combined analysis of DESTINY-Breast01, DESTINY-Breast02, and DESTINY-Breast03 in the later-line setting,¹⁰ we saw what looked like CNS activity. We later confirmed that in the DESTINY-Breast12 study.¹¹ I think it just makes me feel very confident that, for patients who may have CNS involvement, T-DXd is a very reasonable, fair option.

Which first-line approach do you choose for your patients: THP or T-DXd plus pertuzumab?

Dr. Gadi: So now that we do have the DB09 regimen approved in the United States, I suspect we’re going to see accelerating usage of T-DXd plus pertuzumab in many circumstances. We know that T-DXd used alone in the second line is quite effective and, at least in the United States, most patients who complete any first-line therapy will probably go on to the second, third, and even fourth lines. I think it is fully justified to start with taxane-based chemotherapy and HP together, follow with maintenance therapy, and then, if there’s a progression event, pull in the T-DXd by itself. But starting with T-DXd and pertuzumab is also justified, as practitioners can then employ other strategies that are becoming more compelling. For example, some of my colleagues are thinking about using T-DXd to induce a good response, dropping it, and then moving over to HP plus a maintenance strategy with either palbociclib or tucatinib. Obviously, we have no data for that, but the phase 2 DEMETHER study¹² in Europe is currently enrolling and will be very important, as the European regulatory system only approves agents in precisely the way they were studied on the trials. There is just less latitude in those countries for providers to exercise judgment freely.

Dr. Basho: I agree that practitioners are thinking about maintenance treatments for patients treated with T-DXd, Dr. Gadi, and that we are all very excited about DEMETHER. As you mentioned, this trial is looking at an induction maintenance approach with T-DXd followed by HP maintenance, and that data might significantly impact our decisions around these induction approaches.

In this context, I did want to mention the patient-reported outcome data presented from DB09 at SABCS® 2025, which generally showed us that T-DXd plus pertuzumab had a favorable PRO profile, but there was increased incidents of nausea, vomiting, appetite loss, and constipation symptoms in patients treated with T-DXd plus pertuzumab.¹³

I think a lot of our decisions will depend on the extent of disease. For patients with high-volume disease, a lot of visceral disease, we may choose the option with a higher response rate and higher rates of complete response — T-DXd plus pertuzumab. On the flip side, if we have a patient with HER2 3+ disease or de novo metastatic disease, we might tend to use THP with the option of an induction maintenance approach.

Dr. Gadi: We’re going to be able to walk our patients through those pros and cons regarding toxicities, but one of the things that was very clear is that the experience of being on the CLEOPATRA regimen was very different from that with the DB09 regimen.

If you are seeing a patient who is in dire straits where their disease is imminently threatening their lives, going with a strategy that incorporates T-DXd makes a lot of sense. It’s a very active drug. As mentioned earlier, the rate of complete responses was almost double times higher than what we saw with the taxane-based strategy in DB09. For patients who have more indolent disease, could you use HP with a non-taxane-based chemotherapy? Maybe that’s okay. Or maybe if you have a frail patient or a patient who is going to be prone to complications from T-DXd, such as pulmonary issues or nausea, you may favor a different first-line strategy in those patients. So at least we have ways to tailor care for each patient rather than select therapies simply based on a single clinical trial.

What are your main takeaways about the importance of endocrine therapy for patients with HR+/HER2+ disease and in general about the overall HER2+ therapeutic landscape?

Dr. Basho: The numerically longer PFS we’re seeing in the maintenance setting compared with historical data really highlights the strides we have made in treating HER2+ disease. It also highlights the importance of adopting endocrine therapy as part of maintenance for patients whose disease is also HR+. I think this is particularly highlighted in the PATINA study, where we saw that impressively long median PFS both in the standard arm, which incorporated endocrine therapy into maintenance, as well as in the palbociclib-treated arm.

In general, we have not changed frontline management of HER2+ metastatic breast cancer in about a decade, and now we have several practice-changing studies that open the door to even more questions to explore. It’s very exciting to see the profound improvement in outcomes that we saw with these three studies.

Dr. Gadi: I agree, and I would add that the story isn’t done. We’re going to see more insights emerge from formal data publications and then the National Comprehensive Cancer Network has already begun to adjust guidelines, and the overall picture is going to get clearer. Having said that, there also are additional agents in the pipeline that look equally or more exciting for this space. So, although we had success with the CLEOPATRA regimen for nearly 15 years, these newer regimens may flip over even more rapidly. And these strategies, of course, are being incorporated into the early-stage breast cancer setting, which will create opportunities for us to improve outcomes even further for patients with metastatic disease. We must keep paying attention — we are not done.

References:

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