Assessing NCCN Guidelines for Endocrine-Refractory Breast Cancer

Megan Kruse, MD

Associate Staff, Hematology and Medical Oncology

Cleveland Clinic

Member, Developmental Therapeutics Program

Case Comprehensive Cancer Center

Cleveland, OH

This article is part 1 of a 2-part series from a Case-Based Roundtable event.

CASE SUMMARY

• A 52-year-old postmenopausal woman with endocrine-refractory, metastatic (bone only), hormone receptor (HR)–positive, HER2 immunohistochemistry (IHC) 2+/in situ hybridization (ISH)–negative breast cancer had progression 14 months after starting first-line fulvestrant plus ribociclib.
  • Initial response to fulvestrant plus ribociclib noted on imaging at 3 months.
  • Progression:
    • New areas of bone involvement in T-spine, left ribs, and L2
    • Circulating tumor DNA showed no actionable alterations.

Targeted Oncology: What are some recommendations the NCCN guidelines make about the different lines of therapy for a patient such as this with HR-positive metastatic breast cancer?

Megan Kruse, MD: Systemic chemotherapy is preferred in the first-line setting.¹ This is for endocrine-refractory disease. I think we know that we don't recommend chemotherapy anymore in first-line HR-positive metastatic breast cancer in general. That's really been put to bed.

But in the footnotes of the NCCN guidelines, they're saying, whether you choose chemotherapy or trastuzumab deruxtecan [Enhertu; T-DXd], it's [dependent on clinical features and patient preference]. It leads to that whole conversation of, how do you feel about it, how does the patient feel about it, and what are the disease characteristics? There's a call out for pneumonitis monitoring; T-DXd has a pneumonitis risk. We don't have a standard way we all do this. It’s more about being aware, watching for it, and being vigilant of it. I've yet to see any good published studies that show that if you monitor in a particular way, patients have better outcomes from a pneumonitis standpoint. I think that's still a gap in our literature.

Sacituzumab govitecan [Trodelvy] is reserved right now for patients who are more heavily pretreated with 2 or more lines of prior chemotherapy. This may evolve in the near future. Then datopotamab deruxtecan [Datroway; Dato-DXd] from TROPION-Breast01 [NCT05104866]...had a slightly more treatment-exposed population than some of the T-DXd studies but limited to a progression-free survival [PFS] advantage without an overall survival [OS] advantage. So that leads to some confusion of how we are going to use it, when we are going to use it, and how strongly we feel about it. Then, there are no data about [sequencing] antibody-drug conjugate [ADC] after ADC.

As a category 1 regimen in the NCCN, what data back up the use of T-DXd in this setting?

DESTINY-Breast06 [NCT04494425] was an HR-positive, metastatic breast cancer trial.² The patients were allowed to have up to 2 lines of prior endocrine therapy and no prior chemotherapy for metastatic disease. This is where we were first introduced to that ultra-low HER2 category. It included the population we were used to seeing from DESTINY-Breast04 [NCT03734029] with IHC 1+ or 2+, but [those with] also essentially any HER2 positivity. Patients were randomly assigned to T-DXd or physician's choice of chemotherapy. Most of the physician's choice of chemotherapy here, about 60%, was capecitabine.

The primary end point was PFS in the HER2-low population, but then they reported out the whole trial population, the intent-to-treat, and then the HER2 low specifically. Across all of those subgroups, the PFS favored T-DXd by a magnitude of about 5 to 6 months, depending on what subgroup you're looking at. The OS is immature, because this is first-time chemotherapy, so these patients are doing very well for a long time. We know the response rate was also higher with T-DXd. I think this leads to some of the inevitable questions, such as, where do we go from here?

CASE UPDATE

• T-DXd was initiated.
  • The patient experienced moderate diarrhea and fatigue, with 2 temporary holds for neutropenia.

After 11 Months of T-DXd

• Chest/abdomen/pelvis CT and bone scan: 2 liver lesions, 1.8 cm and 2.4 cm; persistent bony metastases consistent with progressive disease; lung lesions too small to characterize, but in setting of other findings concerning for metastatic disease

Follow-Up Diagnostic Tests

• ECOG performance status: 1
• Laboratory profile: within normal limits

Next-Line of Therapy

• Sacituzumab govitecan was initiated.
  • Best response of partial response observed, with further symptomatic improvement
  • Patient maintained an absolute neutrophil count of 3,900/μL and white blood cell count of 7,800/μL.

Is this sequence of therapies appropriate for this patient?

When you look at TROPiCS-02 [NCT03901339], which was the study that got sacituzumab approved in HR-positive disease, everybody in this study had a [prior] taxane. So if you're going to go by the book, you would use the taxane first. I think there was a lot of enthusiasm in the early time of ADCs asking, do we need to sandwich treatments? Do we do ADC, then chemotherapy, then ADC? That hasn't really played out to be that impactful, although the amount of data we have on that question is small. But I keep that in mind when I'm thinking about sacituzumab for patients. Who were the patients in TROPiCS-02? They were treatment refractory, so they had at least 1 endocrine therapy with a CDK4/6 inhibitor, and not only had a taxane, but they also had a second chemotherapy, and up to 4 lines of chemotherapy for their disease. These are later-line patients that we're all talking about.

DISCLOSURE: Kruse previously reported honoraria from Curio Science; a consulting or advisory role for AstraZeneca/Daiichi Sankyo, GE Healthcare, Genentech, and Gilead Sciences; and research funding from AstraZeneca.

REFERENCES:

1. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer; version 3.2025. Accessed March 31, 2025. https://tinyurl.com/mwe5ca6e

2. Bardia A, Hu X, Dent R, et al. Trastuzumab deruxtecan after endocrine therapy in metastatic breast cancer. N Engl J Med. 2024;391(22):2110-2122. doi:10.1056/NEJMoa2407086