Therapy Type and Site of Metastases Factor into HR+, HER2+ mBC Treatment

Ian Krop, MD, PhD (Moderator)

Professor of Internal Medicine (Medical Oncology)

Yale School of Medicine

Director, Clinical Trials Office

Chief Clinical Research Officer

Associate Director, Clinical Sciences

Yale Cancer Center

New Haven, CT

CASE SUMMARY

• A 39-year-old premenopausal woman underwent bilateral mastectomy with reconstruction for ypT1b, ypN2a, grade 2 invasive ductal carcinoma (IDC), hormone receptor (HR) positive, HER2 positive (immunohistochemistry [IHC] 3+)
• Germline testing results showed no actionable/pathogenic alterations​.
• She received adjuvant TCHP (docetaxel, carboplatin, trastuzumab [Herceptin], and pertuzumab [Perjeta]) for 6 cycles, with trastuzumab/pertuzumab for 1 year; leuprolide plus aromatase inhibitor (AI) was initiated​.
• Three years later: metastatic recurrence in the vertebral spine​
• Bone biopsy confirms relapse, HR+, HER2+ (IHC 3+) IDC​
• Next-generation sequencing: no actionable mutations identified ​
• ECOG performance status: 1​
• She received first-line THP (docetaxel, trastuzumab, and pertuzumab) for 6 cycles plus denosumab​.
• Excellent radiographic response​
• Transitions to HP (trastuzumab plus pertuzumab)

DISCUSSION QUESTIONS

• What is your preferred frontline therapy for HR-positive, HER2-positive metastatic breast cancer (mBC)? ​
• Are you using endocrine therapy for patients with HR-positive, HER2-positive mBC? ​

Ian Krop, MD: This is a pretty straightforward case. What do people think? What's your usual practice for a patient who now has metastatic HER2-positive, HR-positive disease and have not received any other treatment for the metastatic setting?

Anusha Madadi, MD: I usually start out with THP in the first-line setting, and after finishing paclitaxel with HP, add something like ovarian suppression plus AI. If they have progressed on an AI, I consider fulvestrant.

Krop: Does anybody do anything different? Does anyone use a different chemotherapy? Does everyone use paclitaxel?

Kelly Westbrook, MD: I usually use docetaxel with HP.

Krop: Both are very reasonable. The original study with HP [CLEOPATRA; NCT00567190] used docetaxel. Some of us have switched to use paclitaxel instead because, in some patients, it's a little better tolerated, but it does require more visits. But both are appropriate.

Does anybody not use chemotherapy up front? There are some data using endocrine therapy alone with HP with some good outcomes, but that hasn't been compared with chemotherapy.¹ Given the fairly substantial survival benefit seen with THP for most patients, most physicians are using chemotherapy, at least as an induction.

Dr Madadi already talked about using endocrine therapy once you drop the chemotherapy. Does everybody tend to do that for an ER-positive, HER2-positive patient once you've stopped the chemotherapy?

Louay Hanna, MD: The problem in this case is that the patient was already on AI. It doesn't hurt to add it if you want to stop or hold the chemotherapy, so to speak. But that's the only thing here. She was on AI, and she experienced progression. That's what makes me think, “Would there be any benefit here?” But it doesn't hurt. The downside is pretty low here in this case.

Krop: Yes, and as was brought up, you could use fulvestrant. If you wanted to do endocrine therapy, you could use fulvestrant if you were worried. It's a good point. This [disease] developed on AI. Are you going to get much mileage out of putting her back on an AI vs giving her fulvestrant? I think that's very reasonable. Unfortunately, this hasn't been tested in a definitive way, because the original CLEOPATRA trial did not allow any endocrine therapy. All the data we have on THP, at least right now, were in the absence of endocrine therapy. But for all the reasons you've all mentioned, it seems pretty reasonable. I think most of us end up doing it, whether it's an AI or fulvestrant, depending on the situation.

DISCUSSION QUESTION

• How do site(s) of progression and tumor burden factor into your decision making at this point?​ For example:
  • Liver involvement instead of bone?​
  • Liver plus bone involvement?​
  • Brain-only metastasis?​
  • Progression limited to 1 or 2 small sites?​

Krop: What’s important to you? What sites would change your thinking on using trastuzumab deruxtecan [Enhertu; T-DXd] vs something else?

Madadi: [It would be] concern about brain metastases because if there are extensive brain metastases, we have some data on the tucatinib [Tukysa] and capecitabine combination being more effective.² Otherwise, systemically, I would say a majority of the time [I would use] T-DXd.

Krop: Fair enough. What about the people who said doesn't matter? Why doesn't it matter? I am one of the people who says doesn't matter, and until recently, I would have said it does matter for the same reason that Dr Madadi just said. But some of the data that have come in more recently suggest that maybe it's not so important to use presence or absence of brain metastases in your treatment decision.³

Are there any other site issues? It sounds like most of the importance was because of brain metastases. Are there any other factors, like comorbidities or safety issues; to whom would you not give T-DXd to in the second line?

Westbrook: I would be concerned about someone who already has interstitial lung disease.

Krop: Yes, in somebody who already had pneumonitis. Would you think about trying something different [based on] performance status? This patient was doing well, but [what about] for somebody who was debilitated, with a lot of comorbidities? [What if they had], not necessarily lung issues, but were someone who's pretty limited.

Westbrook: I think that for somebody with a limited performance status, maybe we would be thinking something gentle, like vinorelbine plus trastuzumab, and neither the [tucatinib] nor T-DXd. But for me, somebody has to have pretty limited performance status to not want to at least try T-DXd, especially if I think their performance status is limited because of their disease burden.

Krop: Fair enough, and you also don't have to use full dose in that patient if you're concerned.

_References:

_{1. Arpino G, de la Haba Rodríguez J, Ferrero JM, et al. Pertuzumab, trastuzumab, and an aromatase inhibitor for HER2-positive and hormone receptor-positive metastatic or locally advanced breast cancer: PERTAIN final analysis. Clin Cancer Res. 2023;29(8):1468-1476. doi:10.1158/1078-0432.CCR-22-1092}

_{2. Lin NU, Borges V, Anders C, et al. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial. J Clin Oncol. 2020;38(23):2610-2619. doi:10.1200/JCO.20.00775}

_{3. Hurvitz SA, Modi S, Li W, et al. 377O A pooled analysis of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-positive (HER2+) metastatic breast cancer (mBC) with brain metastases (BMs) from DESTINY-Breast (DB) -01, -02, and -03. Ann Oncol. 2023;34(suppl 2):S335-S336. doi:10.1016/j.annonc.2023.09.554}