Abstract
Abemaciclib is approved for use in the adjuvant setting in combination with endocrine therapy for patients with high-risk, hormone receptor-positive, HER2-negative early-stage breast cancer based on the monarchE trial. Options for endocrine therapy for premenopausal women include an aromatase inhibitor with ovarian function suppression or tamoxifen with or without ovarian suppression. We describe a unique case of a premenopausal woman with early-stage breast cancer receiving adjuvant abemaciclib and an aromatase inhibitor with elevated estradiol levels as measured by the Abbott Alinity chemiluminescent immunoassay despite chemical and surgical ovarian function suppression. Given low estradiol levels using liquid chromatography-mass spectrometry testing following a bilateral salpingo-oopherectomy, our case report suggests an interference of abemaciclib with the Abbott Alinity immunoassay. This possible interference has significant impacts on clinical care as false elevations in estradiol levels measured by immunoassays can lead to unnecessary treatment changes, including surgery.
1. Introduction
Abemaciclib, a selective cyclin-dependent kinase 4 and 6 inhibitor, is approved for use in the adjuvant setting for patients with high-risk, hormone receptor-positive (HR+) breast cancer. The monarchE study, a phase III trial of patients with HR+, HER2-negative early-stage breast cancer, included patients with four or more positive lymph nodes, or patients with one to three nodes and high-risk features (tumor size ≥ 5 cm, histologic grade 3, or Ki-67 ≥ 20%) (Johnston et al., 2020). The study demonstrated superior invasive disease-free survival with abemaciclib when added to endocrine therapy (ET) compared to ET alone in the adjuvant setting. As per the study protocol, patients received standard adjuvant ET per physician’s choice, which included aromatase inhibitors (AI) or antiestrogens with or without ovarian function suppression (OFS).
The use of an AI in premenopausal women is predicated on suppressing ovarian function. OFS can be accomplished chemically with the use of gonadotropin-releasing hormone (GnRH) agonists, or surgically with a bilateral oophorectomy. Serial estradiol levels are commonly used to confirm menopausal status in women receiving concurrent OFS and AI.
We describe a unique case of a premenopausal woman with early-stage HR+ breast cancer receiving adjuvant abemaciclib with elevated estradiol levels as measured by the Abbott Alinity assay utilizing chemiluminescent microparticle immunoassay (CMIA) technology despite OFS. Due to concern for inadequate OFS, the patient underwent a bilateral salpingo-oophorectomy. Although post-operative estradiol levels remained elevated as measured by the Abbott Alinity assay, estradiol levels using liquid chromatography-mass spectrometry (LC-MS) testing were appropriately low following surgery.
2. Case presentation
A 44-year-old premenopausal woman with no significant past medical history was diagnosed with clinical stage III HR+ breast cancer and treated with neoadjuvant doxorubicin and cyclophosphamide every two weeks for four cycles followed by paclitaxel every two weeks for four cycles. The patient underwent a left mastectomy with a left axillary lymph node dissection as well as a prophylactic right mastectomy. Pathology revealed residual invasive poorly differentiated ductal carcinoma spanning 8 mm in greatest dimension in the breast tissue and three of ten lymph nodes with scattered foci of tumor in a background of treatment-related changes.
She began monthly subcutaneous goserelin 3.6 mg followed by oral anastrozole 1 mg daily one month later. After two months of goserelin, estradiol levels as measured by the Abbott Alinity assay [Chicago, IL, USA] were noted to be in the menopausal range of < 24 pg/mL (reference range for postmenopausal female: < 41 pg/mL). Following radiation therapy, she began adjuvant abemaciclib 150 mg twice daily as per the monarchE study. She continued to receive monthly goserelin as well as anastrozole. Two months after beginning abemaciclib, estradiol levels as measured by the Abbott Alinity assay increased to 68 pg/mL, at which time anastrozole was discontinued and she started tamoxifen due to concern for failure of adequate OFS with goserelin. The following month, she underwent a laparoscopic bilateral salpingo-oophorectomy. Pathology confirmed removal of benign ovaries and fallopian tubes. She resumed anastrozole after surgery. Following surgery, estradiol levels continued to rise to a maximum estradiol level of 122 pg/mL three months after surgery. She was not taking any other medications or supplements. Anastrozole was again discontinued, and she was resumed on tamoxifen while continuing abemaciclib. She was referred to endocrinology, at which time estradiol was rechecked by LC-MS testing with a value of 2.2 pg/mL (reference range for postmenopausal female: < 15 pg/mL). Given menopausal range estradiol levels, anastrozole was resumed and she has continued on anastrozole and abemaciclib for the last two months.
3. Discussion
We report a unique case of elevated estradiol as measured by the Abbott Alinity assay utilizing CMIA technology despite chemical and surgical OFS. Given post-operative estradiol levels using LC-MS were appropriately low, this suggests an interference of abemaciclib with the immunoassay. A review of the package insert for the Abbott immunoassay did not reveal verified cross reactivity of abemaciclib with the assay. Of note, this patient was not taking any medications known to interfere with the assay.
In the monarchE trial, 43.5% of patients were premenopausal. Patients received standard adjuvant ET as per physician’s choice. In 14.2% of the study population, AI in combination with OFS was prescribed as the first ET on study treatment and 7.6% of the study population was prescribed tamoxifen or tamoxifen with OFS. There was no mention of serial estradiol monitoring in premenopausal women receiving OFS by the authors. The National Comprehensive Cancer Network guidelines recommend serial assessment of estradiol levels in premenopausal patients who have become amenorrheic with chemotherapy and receiving adjuvant AI therapy (National Comprehensive Cancer Network (NCCN) Guidelines, 2022). The American Society of Clinical Oncology guidelines also recommend attention to possible incomplete ovarian suppression in premenopausal women with GnRH agonist therapy (Burstein et al., 2019).
The possible interference of abemaciclib with estradiol immunoassays has profound implications for patient care. It is unknown if this interference is unique to the Abbott Alinity immunoassay. Detailed studies would need to be conducted running the same sample concurrently across several estradiol immunoassays along with the LC-MS assay to determine which assays are affected by abemaciclib. We recommend that clinicians be mindful if they receive unexpected results on an estradiol immunoassay in patients taking abemaciclib and run the sample on the LC-MS assay before making clinical decisions based on the immunoassay results. It is crucial to recognize and identify the mechanism in which abemaciclib may interfere with immunoassays given the repercussions, including significant treatment delays and unnecessary surgery, in women receiving abemaciclib and OFS.
Acknowledgments
Dr. Gallagher serves as a consultant for Seagen and SynDevRx and serves on the advisory board for Novartis. Dr. Fasano serves on the advisory board for Magellan Health.
Funding
Dr. Gallagher is supported by the National Institutes of Health/National Cancer Institute [grant R37CA266853].
Biographies
Dr. Alaina J. Kessler is an Assistant Professor of Medicine in the Division of Hematology and Medical Oncology at the Icahn School of Medicine at Mount Sinai. She serves as Assistant Director of Oncology Quality and Safety at the Tisch Cancer Institute at Mount Sinai. She provides medical oncology services to patients with breast cancer.
Dr. Rima Patel is Chief Fellow of the Hematology and Medical Oncology Fellowship Program at the Icahn School of Medicine at Mount Sinai. She is interested in caring for patients with breast and gynecological cancers.
Dr. Emily Jane Gallagher is an Associate Professor of Medicine in the Division of Endocrinology, Diabetes, and Bone Disease at the Icahn School of Medicine at Mount Sinai. She serves as Associate Program Director for the Internal Medicine Residency Program and Director of the Internal Medicine ABIM Research Pathway at Mount Sinai. She provides medical care for oncology patients with endocrinology disorders.
Dr. Theresa Shao is an Assistant Professor of Medicine in the Division of Hematology and Medical Oncology at the Icahn School of Medicine at Mount Sinai. She provides medical oncology services to patients with breast and gynecological cancers.
Dr. Julie Fasano is an Assistant Professor of Medicine in the Division of Hematology and Medical Oncology at the Icahn School of Medicine at Mount Sinai. She provides medical oncology services to patients with breast cancer.
Footnotes
CRediT authorship contribution statement
Alaina J. Kessler: Conceptualization, Writing – original draft. Rima Patel: Conceptualization, Writing – original draft. Emily Jane Gallagher: Conceptualization, Supervision, Writing – review & editing. Theresa Shao: Conceptualization, Supervision, Writing – review & editing. Julie Fasano: Conceptualization, Supervision, Writing – review & editing.
References
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