Treatment Strategies for Dopamine Agonist-Resistant and Aggressive Prolactinomas: A Comprehensive Analysis of the Literature

Abstract

Despite most of the prolactinomas can be treated with endocrine therapy and/or surgery, a significant percentage of these tumors can be resistant to endocrine treatments and/or recur with prominent invasion into the surrounding anatomical structures. Hence, clinical, pathological, and molecular definitions of aggressive prolactinomas are important to guide for classical and novel treatment modalities. In this review, we aimed to define molecular endocrinological features of dopamine agonist-resistant and aggressive prolactinomas for designing future multimodality treatments. Besides surgery, temozolomide chemotherapy and radiotherapy, peptide receptor radionuclide therapy, estrogen pathway modulators, progesterone antagonists or agonists, mTOR/akt inhibitors, pasireotide, gefitinib/lapatinib, everolimus, and metformin are tested in preclinical models, anecdotal cases, and in small case series. Moreover, chorionic gonadotropin, gonadotropin releasing hormone, TGFβ and PRDM2 may seem like possible future targets for managing aggressive prolactinomas. Lastly, we discussed our management of a unique prolactinoma case by asking which tumors’ proliferative index (Ki67) increased from 5–6% to 26% in two subsequent surgeries performed in a 2-year period, exerted massive invasive growth, and secreted huge levels of prolactin leading up to levels of 1 605 671 ng/dl in blood.

Dopamine Agonist-Resistant Microprolactinoma—Mechanisms, Predictors and Management: A Case Report and Literature Review

“…The Ki-67 antigen is a protein used as a proliferation marker for human tumour cells. Refractory prolactinomas often show aggressive features and tend to exert higher angiogenesis, cell proliferation, and atypia [ 10 , 20 , 23 , 25 ]. Moreover, the presence of genetic predisposition indicates a poorer prognosis [ 19 , 20 , 23 ].…”

“…Another treatment approach is a stepwise dose escalation beyond conventional doses to the maximally efficient and tolerated dose, as long as the patient responds with some reduction in PRL level to every dose adjustment [ 10 , 16 , 18 ]. It has been reported that 10–20% of the patients require higher than recommended doses of DA to achieve normoprolactinaemia and that DA resistance can be overcome by escalating the dose to a maximal tolerable dose in 75% of the patients [ 6 , 16 ].…”

“…Dopamine reduces PRL synthesis and secretion as well as lactotroph proliferation [ 6 , 7 , 8 , 9 ]. Dopamine agonists (DAs), such as bromocriptine (BRC), cabergoline (CAB) or quinagolide (QUI), are the first-line therapy for prolactinomas since those adenomas express high levels of type 2 dopamine receptors [ 4 , 10 ]. According to most guidelines, CAB is the treatment of choice as it allows the normalisation of PRL serum levels in about 80–90% of the patients at a median weekly dose of 1.0 mg [ 4 , 11 ].…”

“…The majority of prolactinomas are well controlled by DAs and respond to treatment with serum PRL normalisation, tumour volume reduction, and restoration of gonadal function [ 12 , 13 , 14 ]. Nevertheless, about 10–20% of the patients with prolactinomas present resistance to DAs [ 10 , 12 , 15 ]. DA resistance has been observed in less than 10% of patients with microadenomas and in about 15–20% of patients with macroadenomas [ 16 ].…”

“…Those doses vary amongst patients but are usually defined as ≥15 mg of BRC per day, ≥2.0 mg of CAB per week, and ≥225 ug of QUI per day [ 16 ]. Failure to normalise PRL serum levels as a result of primary DA resistance has been observed in up to 20–30% of the patients receiving BRC and in around 10–15% treated with CAB [ 5 , 10 , 16 , 18 ]. Failure to achieve at least a 50% reduction in tumour size occurs in about 30% of the patients treated with BRC and in 10–15% of those treated with CAB [ 18 ].…”