The Evolving Treatment Landscape of Medullary Thyroid Cancer

Genetic assessment is crucial to address the correct treatment for advanced medullary thyroid cancer (MTC). Multi tyrosine kinase inhibitors (mTKIs) cabozantinib and vandetanib are good first line options, even vandetanib prescription is currently limited to RET mutated patients. Selective RET inhibitors such as pralsetinib could be a preferred upfront treatment in case of RET mutated MTC presenting common or gatekeeper RET mutations (e.g. M918T; V804L/M). Selpercatinib, otherwise, can be prescribed as the second line after disease progression to mTKIs. The best option for subsequent lines is to consider inclusion in clinical trials or alternatively other mTKIs such as sunitinib, sorafenib, lenvatinib, or pazopanib could be evaluated. New perspectives include next-generation RET inhibitors able to overcome resistance mechanisms responsible for disease progression to standard mTKIs and RET inhibitors, and immunotherapy for MTC presenting with high tumor mutational burden

Immunotherapy failure in adrenocortical cancer: where next?

Excerpt: Adrenocortical carcinoma (ACC) is a rare endocrine neoplasia, characterized by an overall dismal prognosis and its clinical manifestations are the consequence of either steroid excess or tumor mass progression. Surgery is the mainstay of therapy. For patients with locally advanced or metastatic ACC, not amenable to surgery, Mitotane and cytotoxic chemotherapy (with etoposide, doxorubicin and cisplatin - EDP scheme) are the systemic treatments currently in use

Preclinical Evidence of Progesterone as a New Pharmacological Strategy in Human Adrenocortical Carcinoma Cell Lines

BACKGROUND Adrenocortical cancer (ACC) is a rare malignancy with a dismal prognosis. The treatment includes mitotane and EDP chemotherapy (etoposide, doxorubicin, and cisplatin). However, new therapeutic approaches for advanced ACC are needed, particularly targeting the metastatic process. Here, we deepen the role of progesterone as a new potential drug for ACC, in line with its antitumoral effect in other cancers. METHODS NCI-H295R, MUC-1, and TVBF-7 cell lines were used and xenografted in zebrafish embryos. Migration and invasion were studied using transwell assays, and MMP2 activity was studied using zymography. Apoptosis and cell cycle were analyzed by flow cytometry. RESULTS Progesterone significantly reduced xenograft tumor area and metastases formation in embryos injected with metastatic lines, MUC-1 and TVBF-7. These results were confirmed in vitro, where the reduction of invasion was mediated, at least in part, by the decrease in MMP2 levels. Progesterone exerted a long-lasting effect in metastatic cells. Progesterone caused apoptosis in NCI-H295R and MUC-1, inducing changes in the cell-cycle distribution, while autophagy was predominantly activated in TVBF-7 cells. CONCLUSION Our results give support to the role of progesterone in ACC. The involvement of its analog (megestrol acetate) in reducing ACC progression in ACC patients undergoing EDP-M therapy is now under investigation in the PESETA phase II clinical study

Gastrointestinal Toxicity of Antibody Drug Conjugates (ADCs) in Metastatic Breast Cancer: A Pooled Analysis

: Trastuzumab emtansine (T-DM1), sacituzumab govitecan (SG), and trastuzumab deruxtecan (T-DXd) are three ADCs approved for the treatment of metastatic breast cancer (MBC). Since gastrointestinal toxicities have been commonly observed with these drugs in clinical trials, a pooled analysis evaluating gastrointestinal adverse events (AEs) in patients with MBC treated with ADCs in clinical trials was performed. PubMed, Embase, and the Cochrane Library were searched from inception until May 2023 for phase II and III clinical trials reporting frequency and severity of gastrointestinal AEs during treatment with ADCs. Data were retrieved for nausea, vomiting, diarrhea, constipation, and abdominal pain: overall and grade 3-4 toxicity rates according to NCI-CTCAE were collected and expressed as proportions. A pre-specified subgroup analysis according to the agent was also carried out. Fourteen studies, comprising 5608 patients, were included in the analysis. Gastrointestinal AEs were frequently registered with SG and T-DXd. A significantly higher frequency of nausea (65.6% with SG, 75% with T-DXd), vomiting (43.7% with SG, 45% with T-DXd), and diarrhea (59.7% with SG, 29% with T-DXd) was noticed with these ADCs compared to TDM-1. Furthermore, diarrhea was more frequently associated with SG (grade 3 in 7.5% of patients), while constipation and abdominal pain were less common. Gastrointestinal AEs, notably nausea and diarrhea, were frequently reported by MBC patients treated with SG and T-DXd in clinical trials. Since these ADCs are administered continuously until disease progression or occurrence of unbearable AEs, gastrointestinal toxicity may have a negative impact on patient quality of life. Therefore, appropriate management of gastrointestinal AEs is mandatory to ensure treatment efficacy and adherence

Adrenocortical Carcinoma and CT Assessment of Therapy Response: The Value of Combining Multiple Criteria

We evaluated tumor response at Computed Tomography (CT) according to three radiologic criteria: RECIST 1.1, CHOI and tumor volume in 34 patients with metastatic adrenocortical carcinoma (ACC) submitted to standard chemotherapy. These three criteria agreed in defining partial response, stable or progressive disease in 24 patients (70.5%). Partial response (PR) was observed in 29.4%, 29.4% and 41.2% of patients according to RECIST 1.1, CHOI and tumor volume, respectively. It was associated with a favorable prognosis, regardless of the criterion adopted. The concordance of all the 3 criteria in defining the disease response identified 8 patients (23.5%) which displayed a very good prognosis: median progression free survival (PFS) and overall survival (OS) 14.9 and 37.7 months, respectively. Seven patients (20.6%) with PR assessed by one or two criteria, however, still had a better prognosis than non-responding patients, both in terms of PFS: median 12.3 versus 9.9 months and OS: 21 versus 12.2, respectively. In conclusions, the CT assessment of disease response of ACC patients to chemotherapy with 3 different criteria is feasible and allows the identification of a patient subset with a more favorable outcome. PR with at least one criterion can be useful to early identify patients that deserve continuing the therapy

Germline NGS targeted analysis in adult patients with sporadic adrenocortical carcinoma

Background: Adrenocortical carcinoma (ACC) is a rare cancer that arises sporadically or due to hereditary syndromes. Data on germline variants (GVs) in sporadic ACC are limited. Our aim was to characterize GVs of genes potentially related to adrenal diseases in 150 adult patients with sporadic ACC. Methods: This was a retrospective analysis of stage I-IV ACC patients with sporadic ACC from two reference centers for ACC in Italy. Patients were included in the analysis if they had confirmed diagnosis of ACC, a frozen peripheral blood sample and complete clinical and follow-up data. Next generation sequencing technology was used to analyze the prevalence of GVs in a custom panel of 17 genes belonging to either cancer-predisposition genes or adrenocortical-differentiation genes categories. Results: We identified 18 GVs based on their frequency, enrichment and predicted functional characteristics. We found six pathogenic (P) or likely pathogenic (LP) variants in ARMC5, CTNNB1, MSH2, PDE11A and TP53 genes; and twelve variants lacking evidence of pathogenicity. New unique P/LP variants were identified in TP53 (p.G105D) and, for the first time, in ARMC5 (p.P731R). The presence of P/LP GVs was associated with reduced survival outcomes and had a significant and independent impact on both progression-free survival and overall survival. Conclusions: GVs were present in 6.7 % of patients with sporadic ACC, and we identified novel variants of ARMC5 and TP53. These findings may improve understanding of ACC pathogenesis and enable genetic counseling of patients and their families

Cytotoxic Effect of Progesterone, Tamoxifen and Their Combination in Experimental Cell Models of Human Adrenocortical Cancer

Progesterone (Pg) and estrogen (E) receptors (PgRs and ERs) are expressed in normal and neoplastic adrenal cortex, but their role is not fully understood. In literature, Pg demonstrated cytotoxic activity on AdrenoCortical Carcinoma (ACC) cells, while tamoxifen is cytotoxic in NCI-H295R cells. Here, we demonstrated that in ACC cell models, ERs were expressed in NCI-H295R cells with a prevalence of ER-β over the ER-α.Metastasis-derived MUC-1 and ACC115m cells displayed a very weak ER-α/β signal, while PgR cells were expressed, although at low level. Accordingly, these latter were resistant to the SERM tamoxifen and scarcely sensitive to Pg, as we observed a lower potency compared to NCI-H295R cells in cytotoxicity (IC50: MUC-1 cells: 67.58 µM (95%CI: 63.22-73.04), ACC115m cells: 51.76 µM (95%CI: 46.45-57.67) and cell proliferation rate. Exposure of NCI-H295R cells to tamoxifen induced cytotoxicity (IC50: 5.43 µM (95%CI: 5.18-5.69 µM) mainly involving ER-β, as their nuclear localization increased after tamoxifen: Δ A.U. treated vs untreated: 12 h: +27.04% (p < 0.01); 24 h: +36.46% (p < 0.0001). This effect involved the SF-1 protein reduction: Pg: -36.34 ± 9.26%; tamoxifen: -46.25 ± 15.68% (p < 0.01). Finally, in a cohort of 36 ACC samples, immunohistochemistry showed undetectable/low level of ERs, while PgR demonstrated a higher expression. In conclusion, ACC experimental cell models expressed PgR and low levels of ER in line with data obtained in patient tissues, thus limiting the possibility of a clinical approach targeting ER. Interestingly, Pg exerted cytotoxicity also in metastatic ACC cells, although with low potency. Keywords: ACC cell lines; ACC primary cells; adrenocortical carcinoma; estrogen receptors; progesterone receptors; tamoxifen

Taste Alterations Do Not Affect Change in Food Habits and Body Weight in Breast Cancer Patients

Background/Aim: Chemotherapy-induced taste alterations (TAs) affect approximately 53-84% of breast cancer patients with significant consequences on flavor perception, possibly leading to food aversion and changes in daily dietary habits. The aim of this study was to investigate the relationship between TAs and changes in food habits and body weight among early breast cancer (EBC) patients undergoing adjuvant chemotherapy. Patients and Methods: TAs were prospectively evaluated in 182 EBC patients from April 2014 to June 2018. TAs, dietary habits, and body weight were collected by a trained dietician. TAs were classified into different subtypes according to the following basic taste perception: metallic, sweet, bitter, salty, sour, and umami taste. Results: During adjuvant chemotherapy, a significant reduction in the consumption of bread, breadsticks, red meat, fat salami, snacks, added sugar, milk, and alcoholic beverages was observed, regardless of TAs onset. No correlation between these dietary changes and different TAs subtypes was found. Body weight remained stable in most EBC patients (71.4%) and was not influenced by TAs onset and by different TAs subtypes. Conclusion: EBC patients change their dietary habits during adjuvant chemotherapy, mostly following the World Cancer Research Fund recommendations, irrespective of TAs onset and without affecting body weight