Dramatic response to cyclin D-dependent kinase 4/6 inhibitor in refractory poorly differentiated neuroendocrine carcinoma of the breast.
A 44-year-old Vietnamese woman presented to the emergency department for evaluation of sharp right upper-quadrant abdominal pain. She had no significant past medical, surgical, or family history. She had a 2- to 3-year history of an unevaluated breast mass. Computed tomography of the chest and abdomen showed a 16-mm mass in the left breast, a left hepatic lobe lesion, and metastatic lesions in the thoracic and lumbar spine. Whole-body positron emission tomography (PET) scan was consistent with a fluorodeoxyglucose-avid breast mass as well as left axillary lymph nodes and osseous metastases, but no fluorodeoxy-glucose-avid liver lesions were reported. Ultrasound-guided biopsy of the left breast mass demonstrated high-grade, estrogen receptor-positive, progesterone receptor-positive, Her2-negative breast cancer. Further histochemical analysis revealed a Ki-67 of 80% and positivity for CD56 and synaptophysin diagnostic of high-grade invasive neuroendocrine breast carcinoma (Figure 1).
The patient was started on carboplatin (area under the curve 5) and etoposide (100 mg/[m.sup.2] days 1-3) every 3 weeks. She was also started on zoledronic acid every 4 weeks for her bony metastases. A follow-up PET scan after two cycles of chemotherapy showed a slight reduction of hypermetabolic activity in the tumor in all sites but overall a modest response to therapy. After completing a total of six cycles of carboplatin and etoposide, a follow-up PET scan showed stable response in the breast and bony lesions but revealed two new hypermetabolic liver lesions. Her chemotherapy was stopped and leuprolide and tamoxifen-based endocrine therapy was initiated. Liver magnetic resonance imaging after 1 month of Lupron and tamoxifen showed diffuse metastatic liver disease, so she was started on palbociclib 3 weeks on, 1 week off. After 1 month of follow-up, a new left supraclavicular lymph node was noted on physical exam, and her tamoxifen was changed to fulvestrant and a gonadotropin-releasing hormone agonist while palbociclib was continued.
The patient tolerated this regimen. Her PET scan after
3 months showed improvement in her breast malignancy as well as liver and skeletal metastases (Figure 2). After 18 months of improvement and progression-free survival, she was noted on imaging to have a new left hepatic lobe metastasis, but the remainder of her disease was stable. This new left hepatic lobe metastasis was biopsied for genomic sequencing while on palbociclib therapy. Genomic alterations by next-generation sequencing (Foundation One) on the liver biopsy revealed CCND1 amplification, ESR1 Y537S mutation, ARID1A L1915fs*3 mutation, stable microsatellites, and an intermediate tumor burden (six mutations/Mb). She had no reportable alteration in the ERBB2 gene. She subsequently received stereotactic radiotherapy to her liver lesion and has continued her palbociclib-based therapy.
There are no guidelines for management of neuroendocrine breast carcinomas. Our patient did not respond well to commonly used platinum doublet chemotherapies or tamoxifen and gonadotropin-releasing hormone agonist-based therapy. The best response was mounted to the combination of fulvestrant and palbociclib, with a progression-free survival of 18 months. This appears to be the first case in which palbociclib was used as a primary treatment with positive results for neuroendocrine breast cancer.
Chemotherapy targeted at high-grade neuroendocrine cancers is usually based on drug combinations commonly used for small cell carcinoma of the lung. A similar study that used this treatment plan and then followed up with tamoxifen did not achieve tumor regression, similar to our case. (6) Another reported case of neuroendocrine carcinoma of the breast expressing estrogen receptor, progesterone receptor, and Her2 achieved remission using docetaxel, trastuzumab, and carboplatin. (7) Because most neuroendocrine breast tumors are estrogen receptor and progesterone receptor positive, endocrine-based therapy may be an effective treatment strategy. Tamoxifen as sole therapy as well as adjuvant treatment after surgery has shown good outcomes. (8,9)
In a case report, a neuroendocrine breast cancer that had metastasized to the liver had a promising response to peptide receptor radionuclide therapy. (10) Gene families that could be potential targets include fibroblast growth factor receptor (FGFR), tyrosine kinase KDR (vascular endothelial growth factor receptor 2), and HRAS. (11) The KDR mutation is sensitive to vascular endothelial growth factor receptor kinase inhibitors, and research is ongoing into fibroblast growth factor receptor inhibitors. (11)
Neuroendocrine breast carcinomas harbor an average of 4.5 somatic mutations, similar to luminal B carcinomas but fewer than luminal A carcinomas. (12) The genes that are most frequently associated with neuroendocrine carcinoma are GATA3, FOXA1, TBX3, and ARID1A as well as PIK3CA, AKT1, and CDH1.12 Genomic analysis of the liver lesion noted on progression of palbociclib-based treatment revealed that she had ESR1 Y537S and ARID1A L1915fs*3 mutations as well as CCND1 amplification. Clinically, a CCND1 amplification could predict enhanced sensitivity to cyclin D-dependent kinase (CDK) 4/6 inhibitors, such as palbociclib.13 CDK is important in tumor progression due to its function driving cell cycle proliferation, which is often unregulated and overexpressed in tumor cell lines. (14) Cyclins, such as CCND1, regulate CDKs and specifically when bound to CDK4 and 6 will function as a G1/S transition regulator in the cell cycle. (15) This is in conjunction with what we found clinically, because she responded best to a combination therapy of palbociclib and fulvestrant. Palbociclib was determined to be the best treatment option because she had a modest response to cytotoxic chemotherapy usually directed at small cell carcinomas. Neuroendocrine carcinomas of the breast share a molecular profile similar to that of luminal A and B cancers and may behave like hormone-sensitive carcinomas, which is why the patient was treated with hormone-directed therapy. Further, results from the PALOMA 2 trial failed to demonstrate increased sensitivity to a combination of palbociclib and letrozole based on biomarker analysis of cell cycle-related genes. (16)
ESR1 mutations in breast cancer are related to metastasis, usually while on hormonal therapy. (17,18) The ARID1A gene is a tumor suppressor gene, and an associated mutation or inactivation is reported in many cancers. (19) Preclinical evidence shows that ARID1A inactivation may predict sensitivity to EZH2 inhibitors. (20) Other studies have shown that ARID1A inactivation may relate to the PI3K-AKT pathway activation and therefore may portend sensitivity to drugs that inhibit this pathway. (21) Primary breast neuroendocrine tumors are rare, and limited literature-based therapeutic options are available. Our patient was refractory to chemotherapy and endocrine treatment but had a good response to the combination of palbociclib and endocrine therapy. Further research into CDK4/6 inhibitors in the treatment of neuroendocrine breast cancer is warranted.
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Allison Shanks, BS (a), Julia Choi, MD (a,b), and Vinit Karur, MD, PhD (a,b)
(a) Texas A&M College of Medicine, Temple, Texas; (b) Department of Hematology and Oncology, Baylor Scott and White, Temple, Texas
Corresponding author: Allison Shanks, BS, Texas A&M College of Medicine, 2401 South 31st Street, Temple, TX 76508 (e- mail: email@example.com)
Received January 31,2018; Revised March 18, 2018; Accepted March 22, 2018.
Caption: Figure 1. Synaptophysin staining of breast tumor. Highly positive staining of synaptophysin indicates that the tumor is neuroendocrine based.
Caption: Figure 2. Magnetic resonance images before and after palbociclib therapy. (a, b) Pretreatment scans show diffuse liver and spinal metastases. (c, d) Scans after palbociclib treatment show improved liver and spinal metastasis.
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|Author:||Shanks, Allison; Choi, Julia; Karur, Vinit|
|Publication:||Baylor University Medical Center Proceedings|
|Article Type:||Clinical report|
|Date:||Jul 1, 2018|
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