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Dramatic response to cyclin D-dependent kinase 4/6 inhibitor in refractory poorly differentiated neuroendocrine carcinoma of the breast.

Neuroendocrine carcinoma of the breast is an aggressive tumor that has a higher local recurrence rate and inferior survival than invasive ductal carcinoma. (1,2) Neuroendocrine breast cancers also present on average 10 years later and with a higher T stage than invasive ductal carcinomas. (1,3) Poor prognostic factors for neuroendocrine breast carcinoma include advanced TNM stage, increased expression of Ki-67, the absence of progesterone expression, high nuclear grade, large tumor size, and regional lymph node metastasis. (4) Neuroendocrine tumors of the breast commonly are estrogen receptor (100%) and progesterone receptor (50%) positive and human epidermal growth factor receptor 2 (Her2) negative, although Her2-positive cases have been reported. (5) A few reviews have explored the different treatment options for primary neuroendocrine tumors of the breast. This case report examines the different types of systemic therapies that can be used to target neuroendocrine breast carcinomas.


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.

(1.) Wang J, Wei B, Albarracin CT, Hu J, Abraham SC, Wu Y. Invasive neuroendocrine carcinoma of the breast: a population-based study from the Surveillance, Epidemiology and End Results (SEER) database. BMC Cancer. 2014; 14:147-157. doi:10.1186/1471-2407-14147. PMID:24589259.

(2.) Wei B, Ding T, Xing Y, et al. Invasive neuroendocrine carcinoma of the breast: a distinctive subtype of aggressive mammary carcinoma. Cancer. 2010; 116:4463-4473. doi:10.1002/cncr.25352. PMID:20572042.

(3.) Zhang Y, Chen Z, Bao Y, et al. Invasive neuroendocrine carcinoma of the breast: a prognostic research of 107 Chinese patients. Neoplasma. 2013; 60:215-222. doi:10.4149/neo_2013_029. PMID:23259792.

(4.) Tian Z, Wei B, Tang F, et al. Prognostic significance of tumor grading and staging in mammary carcinomas with neuroendocrine differentiation. Hum Pathol. 2011; 42:1169-1177. doi:10.1016/j.humpath.2010.11.014. PMID:21334720.

(5.) Yavas G, Karabagli P, Araz M, Yavas C, Ata O. HER-2 positive primary solid neuroendocrine carcinoma of the breast: a case report and review of the literature. Breast Cancer. 2015; 22:432-436. doi:10.1007/s12282-012-0382-x. PMID:22711316.

(6.) Lee DH, Park AY, Seo BK, Kim YS, Lee KY, Cha SH. Primary neuroendocrine carcinoma of the breast with clinical features of inflammatory breast carcinoma: a case report and literature review. J Breast Cancer. 2015; 18:404-408. doi:10.4048/jbc.2015.18.4.404. PMID:26770249.

(7.) Tato-Varela S, Albalat-Fernandez R, Pabon-Fernandez S, Zarco ER, Calle-Marcos ML. Primary neuroendocrine tumour of the breast: a case report and review of the literature. Ecancermedicalscience. 2015; 9:607.

doi:10.3332/ecancer.2015.607. PMID:26798407.

(8.) Shin SJ, DeLellis RA, Ying L, Rosen PP. Small cell carcinoma of the breast: a clinicopathologic and immunohistochemical study of nine patients. Am J Surg Pathol. 2000; 24:1231-1238. doi:10.1097/00000478-200009000-00006. PMID:10976697.

(9.) Jochems L, Tjalma WA. Primary small cell neuroendocrine tumour of the breast. Eur J Obstet Gynecol Reprod Biol. 2004; 115:231-233. doi:10.1016/j.ejogrb.2003.12.013. PMID:15262362.

(10.) Savelli G, Zaniboni A, Bertagna F, et al. Peptide receptor radionuclide therapy (PRRT) in a patient affected by metastatic breast cancer with neuroendocrine differentiation. Breast Care (Basel). 2012; 7:408-410. doi:10.1159/000343612. PMID:24647781.

(11.) Ang D, Ballard M, Beadling C, et al. Novel mutations in neuroendocrine carcinoma of the breast: possible therapeutic targets. Appl Immunohistochem Mol Morphol. 2015; 23:97-103. doi:10.1097/PDM.0b013e3182a40fd1. PMID:25679062.

(12.) Marchio C, Geyer FC, Ng CK, et al. The genetic landscape of breast carcinomas with neuroendocrine differentiation. J Pathol. 2017; 241:405-419. doi:10.1002/path.4837. PMID:27925203.

(13.) Juric D, Ismail-Khan R, Campone M, et al. Phase Ib/II study of ribociclib and alpelisib and letrozole in ER+, HER2- breast cancer: safety, preliminary efficacy and molecular analysis [abstract]. Cancer Res. 2016; 76. doi:10.1158/1538-7445.SABCS15-P3-14-01.

(14.) Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009; 9:153-166. doi:10.1038/nrc2602. PMID:19238148.

(15.) Rocca A, Schirone A, Maltoni R, et al. Progress with palbociclib in breast cancer: latest evidence and clinical considerations. Ther Adv Med Oncol. 2017; 9:83-105. doi:10.1177/1758834016677961. PMID:28203301.

(16.) Finn F, Jiang Y, Rugo H, et al. Biomarker analyses from the phase 3 PALOMA-2 trial of palbociclib (P) with letrozole (L) compared with placebo (PLB) plus L in postmenopausal women with ER+/HER2-advanced breast cancer (ABC). Ann Oncol. 2016; 27(Suppl 6):1-36.

(17.) Robinson DR, Wu YM, Vats P, et al. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet. 2013; 45:1446-1451. doi:10.1038/ng.2823. PMID:24185510.

(18.) Toy W, Shen Y, Won H, et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet. 2013; 45:1439-1445. doi:10.1038/ng.2822. PMID:24185512.

(19.) Mamo A, Cavallone L, Tuzmen S, et al. An integrated genomic approach identifies ARID1A as a candidate tumor-suppressor gene in breast cancer. Oncogene. 2012; 31:2090-2100. doi:10.1038/ onc.2011.386. PMID:21892209.

(20.) Bitler BG, Aird KM, Garipov A, et al. Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. Nat Med. 2015; 21:231-238. doi:10.1038/nm.3799. PMID:25686104.

(21.) Samartzis EP, Gutsche K, Dedes KJ, Fink D, Stucki M, Imesch P. Loss of ARID1A expression sensitizes cancer cells to PI3K- and AKT-inhibition. Oncotarget. 2014; 5:5295-5303. doi:10.18632/oncotarget.2092. PMID:24979463.

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:

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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