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Background: Bone health management in premenopausal women with breast cancer (BC) under hormone-deprivation therapies (HDTs) is often challenging, and the effectiveness of bone-active drugs is still unknown., Methods: This retrospective multicenter study included 306 premenopausal women with early BC undergoing HDTs. Bone mineral density (BMD) and morphometric vertebral fractures (VFs) were assessed 12 months after HDT initiation and then after at least 24 months., Results: After initial assessment, bone-active drugs were prescribed in 77.5% of women (151 denosumab 60 mg/6 months, 86 bisphosphonates). After 47.0 ± 20.1 months, new VFs were found in 16 women (5.2%). Vertebral fracture risk was significantly associated with obesity (odds ratio [OR] 3.87, P = .028), family history of hip fractures or VFs (OR 3.21, P = .040], chemotherapy-induced menopause (OR 6.48, P < .001), preexisting VFs (OR 25.36, P < .001), baseline T-score less than or equal to -2.5 standard deviation (SD) at any skeletal site (OR 4.14, P = .036), and changes at lumbar and total hip BMD (OR 0.94, P = .038 and OR 0.88, P < .001, respectively). New VFs occurred more frequently in women untreated compared to those treated with bone-active drugs (14/69, 20.8% vs 2/237, 0.8%; P < .001) and the anti-fracture effectiveness remained significant after correction for BMI (OR 0.03; P < .001), family history of fractures (OR 0.03; P < .001), chemotherapy-induced menopause (OR 0.04; P < .001), and preexisting VFs (OR 0.01; P < .001)., Conclusions: Premenopausal women under HDTs are at high risk of VFs in relationship with high BMI, densitometric diagnosis of osteoporosis, preexisting VFs, and family history of osteoporotic fractures. Vertebral fractures in this setting might be effectively prevented by bisphosphonates or denosumab., Competing Interests: Conflict of interest: R.P. received consultancy fees from Roche, Novartis, Eli Lilly, Daiichi Sankyo, Gilead, Eisai, and Accord, outside the submitted work. A.P. reports lecture fees from Amgen, Theramex, and UCB, outside the submitted work. A.N. reports lecture fees from Theramex, outside the submitted work. G.T. reports lectures fees from Theramex and Abiogen, outside the submitted work. R.T. received research grants from Pfizer, consultancy fees from MSD, and lecture fees from Pfizer, Eli Lilly, Eisai, and Genomic Health outside the submitted work. A.Z. received consultancy fees from Roche, Novartis, Pfizer, Eli Lilly & Co., AstraZeneca, and Genomic Health outside the submitted work. L.C. received consultancy fees from UCB and lecture fees from Abiogen Pharma and Bruno Farmaceutici, outside the submitted work. A.C. Bossi reports research grants from Bayer SA, Lilly Italia SpA, MSD USA, and Novo Nordisk Italia SpA and personal fees from Sanofi Italia SpA, Boehringer Ingelheim Italia SpA, and AstraZeneca Italia SpA, outside the submitted work. A.L. received grants from Pfizer and lecture fees from Recordati, outside the submitted work. A.B. reports receiving grants and personal fees from Janssen Cilag, grants and personal fees from Astellas, and personal fees from Bayer outside the submitted work. G.M. received consultancy fees and preceptorship from Amgen–UCB and Sanofi and lectures fees from Theramex and Recordati. The other authors have nothing to declare., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Context: Patients with adrenocortical carcinoma (ACC) are frequently on mitotane therapy for a long time period. The drug exerts adrenolytic activity requiring glucocorticoid supplementation, which can be potentially detrimental for bone., Objective: To explore whether mitotane with/without chemotherapy is associated with an increased proportion of morphometric vertebral fractures (VFs) in ACC patients. Secondary objectives were proportion of patients with VF progression, or worsening of the spinal deformity index (SDI) during mitotane therapy; and to explore predictive factors of VF progression and a prognostic role of VF progression., Methods: Multicenter, retrospective cohort study of patients with ACC who received mitotane alone or in association to chemotherapy, recruited from January 2010 to January 2020 in 2 reference centers in Italy and France., Results: A significant increase in the frequency of VFs before and after mitotane therapy was seen both in Italian (28.3% vs 47.8%, P = .04) and French (17.8% vs 35.6%, P = .04) series. VF progression was observed in 39.1%, and 28.9% of patients, respectively. Baseline VFs and increased patient body mass index, but not the dose of cortisol supplementation, showed an independent association with VF progression at multivariate analysis. Among the 72 advanced ACC patients, progression of VFs was associated with a poorer survival., Conclusion: The administration of mitotane with/without chemotherapy in ACC patients impairs bone health independently from cortisol supplementation. Appropriate preventive measures to decrease the fracture risk should be implemented in these patients., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Mitotane is the only approved drug for treating adrenocortical carcinoma (ACC). The regimen added to mitotane is chemotherapy with etoposide, doxorubicin, and cisplatin. This pharmacological approach, however, has a limited efficacy and significant toxicity. Target-therapy agents represent a new promising approach to cancer therapy. Among these, a preeminent role is played by agents that interfere with cell-cycle progression, such as CDK4/6-inhibitors. Here, we investigate whether ribociclib could induce a cytotoxic effect both in ACC cell line and patient-derived primary cell cultures, alone or in combined settings. Cell viability was determined by 3-(4,5-dimethyl-2-thiazol)-2,5-diphenyl-2H-tetrazolium bromide assay, whereas cell proliferation was evaluated by direct count. Binary combination experiments were performed using Chou and Talalay method. Gene expression was analyzed by quantitative RT-PCR, whereas protein expression was evaluated by immunofluorescence. A double staining assay revealed that ribociclib induced a prevalent apoptotic cell death. Cell-cycle analysis was performed to evaluate the effect of ribociclib treatment on cell-cycle progression in ACC cell models. Our results indicate that ribociclib was cytotoxic and reduced the cell proliferation rate. The effect on cell viability was enhanced when ribociclib was combined with progesterone and/or mitotane. The effect of ribociclib on cell-cycle progression revealed a drug-induced cell accumulation in G2 phase. The positive relationship underlined by our results between ribociclib, progesterone, and mitotane strengthen the clinical potential of this combination., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Adrenocortical carcinoma (ACC) has an aggressive but variable clinical course. Prognostic stratification based on the European Network for the Study of Adrenal Tumours stage and Ki67 index is limited. We aimed to demonstrate the prognostic role of a points-based score (S-GRAS) in a large cohort of patients with ACC., Design: This is a multicentre, retrospective study on ACC patients who underwent adrenalectomy., Methods: The S-GRAS score was calculated as a sum of the following points: tumour stage (1-2 = 0; 3 = 1; 4 = 2), grade (Ki67 index 0-9% = 0; 10-19% = 1; ≥20% = 2 points), resection status (R0 = 0; RX = 1; R1 = 2; R2 = 3), age (<50 years = 0; ≥50 years = 1), symptoms (no = 0; yes = 1), and categorised, generating four groups (0-1, 2-3, 4-5, and 6-9). Endpoints were progression-free survival (PFS) and disease-specific survival (DSS). The discriminative performance of S-GRAS and its components was tested by Harrell's Concordance index (C-index) and Royston-Sauerbrei's R2D statistic., Results: We included 942 ACC patients. The S-GRAS score showed superior prognostic performance for both PFS and DSS, with best discrimination obtained using the individual scores (0-9) (C-index = 0.73, R2D = 0.30, and C-index = 0.79, R2D = 0.45, respectively, all P < 0.01vs each component). The superiority of S-GRAS score remained when comparing patients treated or not with adjuvant mitotane (n = 481 vs 314). In particular, the risk of recurrence was significantly reduced as a result of adjuvant mitotane only in patients with S-GRAS 4-5., Conclusion: The prognostic performance of S-GRAS is superior to tumour stage and Ki67 in operated ACC patients, independently from adjuvant mitotane. S-GRAS score provides a new important guide for personalised management of ACC (i.e. radiological surveillance and adjuvant treatment).

Context: We investigated the role of Gallium 68 dodecanetetraacetic acid Tyr3-octreotide (68Ga-DOTATOC) positron emission tomography/computed tomography (PET/CT) in detecting somatostatin receptors (SSTRs) in 19 patients with metastatic adrenocortical carcinoma (ACC) and explored the activity of yttrium-90/lutetium-177 (90Y/177Lu-DOTATOC) peptide receptor radionuclide therapy (PRRT)., Case Description and Methods: 68Ga uptake in metastatic sites was scored in terms of intensity and anatomical uptake distribution of standard uptake value (SUV). Tissue expression of SSTR2A and SSTR5 was also evaluated by immunohistochemistry (IHC) on primary tumors. Eight (42%) patients displayed radiometabolic uptake of any-grade intensity with focal and limited distribution. Two (11%) patients displayed strong uptake in multiple lesions and were treated with PRRT. Both obtained an overall disease control lasting 4 and 12 months, respectively., Conclusions: ACC can express SSTRs as detected by IHC and 68Ga-DOTATOC PET. SSTRs-based PRRT may represent a potential treatment opportunity for a minority of patients with advanced ACC. This treatment modality deserves further investigation., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Temozolomide has shown a significant anti-proliferative activity on adrenocortical cancer (ACC) cells in vitro., Design: On the basis of these results the drug was prescribed as second/third line in advanced metastatic ACC patients in four referral centers in Italy., Methods: We retrospectively collected anagraphic, clinical and pathological data of patients with advanced ACC with disease progression to standard chemotherapy plus mitotane who were treated with temozolomide at the dose of 200 mg/m2/die given for 5 consecutive days every 28 days. The primary endpoint was the disease control rate, defined as objective response or disease stabilization after 3 months. Secondary endpoints were overall survival (OS), progression-free survival (PFS) and drug safety., Results: Twenty-eight patients have been included in the study. Ten patients (35.8%, 95% CI: 17.8-53.8) obtained a disease control from temozolomide treatment. In particular, 1 patient had a complete response, 5 patients a partial response and 4 patients stable disease. Median PFS was 3.5 months and median OS was 7.2 months. Disease response was more frequently observed in patients with methylation of O6-methylguanine-DNA methyltransferase (MGMT) gene. Temozolomide therapy was well tolerated and most toxicities were limited to grade G1-2 according to WHO criteria., Conclusion: Temozolomide was found active in the management of advanced ACC patients. The disease control rate obtained, however, was short-lived and the prognosis of treated patients was poor.