Elacestrant Provides Treatment Path Forward in Advanced Breast Cancer

CASE SUMMARY

A 52-year-old, postmenopausal woman presents with a palpable right breast mass with no clinically abnormal axillary lymph nodes​.

Diagnostic and Surgical Procedures​

• Diagnostic mammogram: Spiculated mass at 11 o’clock​
• Ultrasound: 1.8 cm solid mass on ultrasound ​
• Core Biopsy: grade II invasive ductal carcinoma (IDC), estrogen receptor positive (ER+) and progesterone receptor positive (PR+), HER2 immunohistochemistry (IHC) 0, Ki-67 20%​
• Lumpectomy and sentinel lymph node (SLN) biopsy: 2.8 cm grade 2 IDC, 2 SLN negative for malignant cells​
• Real-time polymerase chain reaction 21-gene recurrence score: 27​

Adjuvant Therapy​

• Docetaxel and cyclophosphamide given intravenously every 3 weeks for 4 cycles ​
• Radiation therapy​
• Anastrozole for 5 years

3 Years After Completing Anastrozole​

• Patient presented with persistent low back pain radiating to the bilateral hips, which restricted activity​.

Follow-Up Diagnostics​

• Fludeoxyglucose (FDG) 18F PET/CT: FDG uptake seen in multiple vertebrae and bilateral iliac crests​.
• MRI spine: multiple sclerotic vertebral and pelvic bone lesions without cord compromise​
• Bone marrow aspiration: malignant cytokeratin-positive cells​
• ER+/PR+, HER2 IHC 0​
• ECOG performance status: 1​
• Laboratory studies revealed mild anemia but were otherwise normal​.
• Diagnosis: stage IV​ breast cancer

First-Line Therapy​

• She started letrozole and ribociclib (Kisqali) with marked improvement in her pain​.
• Required 1 dose reduction to 400 mg ribociclib due to neutropenia
• Twenty months after starting therapy, routine staging scans showed new FDG avid sclerotic and lytic bone lesions​.
• She noted mild increase in lower back pain​.
• Laboratory studies were normal.
• Routine staging scan revealed new, FDG-avid sclerotic and lytic bone lesions.
• Circulating tumor DNA (ctDNA) analysis confirmed an ESR1 mutation​.

Second-Line Treatment​

• Elacestrant (Orserdu) 345 mg once a day was initiated.
• Mild nausea well controlled when taking elacestrant with food and an occasional ondansetron tablet​.
• Also given low dose olanzapine (2.5 mg) to take at bedtime as needed.
• Her pain improved on therapy with resolution of FDG avidity in bone on PET/CT scan.

Targeted Oncology: What role does the ESR1 mutation play in treating patients with advanced breast cancer?

WILLIAM J. GRADISHAR, MD: The basic [understanding of] ESR1 mutations is that it changes the conformation and makes it...difficult to build habits [based on] fact. Once you have these ESR1 mutations, the efficacy of drugs you might typically use [in a patient case like this] are less effective, and that's been shown in some older trials.... ESR1 mutations tend to occur over time, and they are dominated in a few specific areas, but there can also be more than 1 ESR1 mutation in the same tumor.¹ So, it may not be a single abnormality but more than 1. I think many physicians [treating patients like this] are probably involved in some of the clinical trials with all the oral selective ER degraders [SERDs] that are currently in development.

William J. Gradishar, MD

Chief of Hematology and Oncology in the Department of Medicine

Betsy Bramsen Professor of Breast Oncology

Professor of Medicine

Northwestern Medicine Feinberg School of Medicine

Robert H. Lurie Comprehensive Cancer Center at Northwestern

What therapies are there to consider in this setting?

Elacestrant is the farthest along,² but we have a number of these drugs that are being looked at both in the advanced setting, as well as some that have leapt forward to be looked at in the adjuvant setting. Right now, we don't have any data from those [drugs] other than what's in clinical trials, but…some of these drugs have already been abandoned. It didn't look like they were going to [hit their end points] so they stopped, but we should have more of these drugs available in the next couple of years.

What was the design of the phase 3 EMERALD trial (NCT03778931)?

This is what the approval of elacestrant was based on.² This was a trial that compared elacestrant in patients with metastatic breast cancer who progressed on 1 or 2 lines of prior endocrine therapy, 1 of which had to be a combination with the CD4/6 inhibitor.³ The randomization [for patients] was either elacestrant or treatment of physician’s choice, which could have been any of the endocrine agents [they listed]. The [patient] could have gotten up to 1 prior line of chemotherapy in this setting, but they were also exposed to endocrine therapy. The 2 end points looked at were progression-free survival for everyone and then specifically in those patients whose [disease was positive for an] ESR1 mutation.³ I think the basic message here is, whether you're looking at those patients with ESR1 mutations, which is about half [of the study population], they're comparable results.

What results would you highlight to other physicians?

Specifically in the group [of patients] with an ESR1 mutation [in their disease]...at the landmark time points of 6 months and 12 months [of follow-up], the fraction of patients without disease progression was greater with elacestrant [compared with] fulvestrant.³ Again, there were other choices that patients could have received as treatment, but fulvestrant accounted for the most significant number [of therapies in the physician choice arm].... If [the patient is] particularly endocrine responsive or your duration of time on a CDK4/6 inhibitor, prior to going on this trial [had a longer response].³

^References

^{1. Brett JO, Spring LM, Bardia A, Wander SA. ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer. Breast Cancer Res. 2021;23(1):85. doi:10.1186/s13058-021-01462-3}

^{2. FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. FDA. News release. January 1, 2023. Accessed March 11, 2023. https://tinyurl.com/hxzufufm}

^{3. Bidard FC, Kaklamani VG, Neven P, et al. Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: results from the randomized phase III EMERALD trial. J Clin Oncol. 2022;40(28):3246-3256. doi:10.1200/JCO.22.00338}