Search

Objective After temozolomide failure, no evidence-based treatment is available for pituitary carcinomas (PCs) and aggressive pituitary tumors (APTs). To date, only 12 cases treated with immune-checkpoint inhibitors (ICIs) have been published, showing encouraging efficacy. Predictive factors of response are lacking. Here, we aimed to assess the real-life efficacy and predictors of response to ICIs in PCs and APTs. Design and methods This study is a multicentric, retrospective, observational cohort study, including all PCs and APTs treated with ICIs in France up to March 2022. PD-L1 immunohistochemistry and CD8+ T cell infiltration were evaluated centrally. Results Six PCs (four corticotroph and two lactotroph) and nine APTs (five corticotroph and four lactotroph) were included. The real-life efficacy of ICIs was lower than previously published data. Three corticotroph tumors (33.3%) showed partial response, one (11.1%) stable disease, while five (55.6%) progressed. One lactotroph tumor (16.7%) showed partial response, one (16.7%) stable disease, while four (66.7%) progressed. PCs responded far better than APTs, with 4/6 PCs showing partial response compared to 0/9 APTs. Corticotroph tumors responded slightly better than lactotroph tumors. In the four responsive corticotroph tumors, PD-L1 staining was negative and CD8+ T cell infiltration attained a maximum of 1% in the tumor center. Conclusions Confirmation of the presence or absence of metastases is necessary before starting ICIs. After temozolomide failure, ICIs appear as a good therapeutic option for PCs, especially for corticotroph carcinomas. Negative PD-L1 staining and very low CD8+ T cell infiltration in the tumor center should not preclude ICI administration in corticotroph carcinomas. Significance statement This is the first study to assess the real-life efficacy of ICIs in pituitary carcinomas (PCs) and aggressive pituitary tumors. We also assessed potential predictors of response and are the first to assess the predictive value of CD8+ cell infiltration. We identified the tumor type as a major predictor, ICIs proving far more effective in treating PCs. Our study provides evidence that ICIs are a good option after temozolomide failure for PCs (four of six responded), especially for corticotroph carcinomas (three of four responded). We also provide evidence that negative PD-L1 staining and very low CD8+ cell infiltration in the tumor center should not preclude ICI administration in corticotroph carcinomas. Moreover, our findings point toward the need to systematically perform extension workup before starting ICIs.

Supplementary Table 1 from Functional Phosphodiesterase 11A Mutations May Modify the Risk of Familial and Bilateral Testicular Germ Cell Tumors

Inactivating germline mutations in phosphodiesterase 11A (PDE11A) have been implicated in adrenal tumor susceptibility. PDE11A is highly expressed in endocrine steroidogenic tissues, especially the testis, and mice with inactivated Pde11a exhibit male infertility, a known testicular germ cell tumor (TGCT) risk factor. We sequenced the PDE11A gene-coding region in 95 patients with TGCT from 64 unrelated kindreds. We identified 8 nonsynonymous substitutions in 20 patients from 15 families: four (R52T, F258Y, G291R, and V820M) were newly recognized, three (R804H, R867G, and M878V) were functional variants previously implicated in adrenal tumor predisposition, and one (Y727C) was a known polymorphism. We compared the frequency of these variants in our patients to unrelated controls that had been screened and found negative for any endocrine diseases: only the two previously reported variants, R804H and R867G, known to be frequent in general population, were detected in these controls. The frequency of all PDE11A-gene variants (combined) was significantly higher among patients with TGCT (P = 0.0002), present in 19% of the families of our cohort. Most variants were detected in the general population, but functional studies showed that all these mutations reduced PDE activity, and that PDE11A protein expression was decreased (or absent) in TGCT samples from carriers. This is the first demonstration of the involvement of a PDE gene in TGCT, although the cyclic AMP signaling pathway has been investigated extensively in reproductive organ function and their diseases. In conclusion, we report that PDE11A-inactivating sequence variants may modify the risk of familial and bilateral TGCT. [Cancer Res 2009;69(13):5301–6]

Supplementary Table 2 from Functional Phosphodiesterase 11A Mutations May Modify the Risk of Familial and Bilateral Testicular Germ Cell Tumors

Purpose Adrenocortical carcinoma (ACC) is a rare endocrine malignancy, whose diagnosis is suspected by conventional radiology and hormonal investigations. 18F-fluorodeoxyglucose positron emission tomography ([18F]-FDG PET) could help predict malignancy, but more consistent data are necessary to support future guidelines.MethodsA cohort of 63 patients with histologically proven ACC (n=55) or metastatic ACC with steroid oversecretion (n=8) was assembled. All patients underwent a [18F]-FDG PET and the maximum Standardized Uptake Value (SUVmax) and the adrenal-to-liver SUVmax ratio were calculated. The [18F]-FDG PET parameters were compared with clinical, pathological and outcome data.ResultsA positive correlation between [18F]-FDG PET parameters (SUVmax and adrenal-to-liver SUVmax ratio) and tumor size, ENSAT (European Network for the Study of Adrenal Tumors) staging, total Weiss score and the proliferation marker Ki67 was found. The strong correlation between SUVmax and Ki67 (r=0.47, p=0.0009) suggests a relationship between FDG uptake levels and tumor proliferation. Associations between outcome parameters (progression free or overall survival) and [18F]-FDG PET parameters were weaker. Fifty-six out of 63 patients (89%) had an adrenal-to-liver SUVmax >1.45, a previously defined cutoff value to predict malignancy. Seven ACC (11%) had a lower uptake, with a Ki67 expression level statistically lower compared to other ACC.ConclusionThis large cohort study shows that most ACC demonstrate high [18F]-FDG uptake. However, the positive correlation observed between SUVmax and Ki67 expression levels seems to explain the possibility of identifying some ACC with a low [18F]-FDG uptake and Ki67 ≤ 10%.

Design Molecular classification is important for the diagnosis and prognosis of adrenocortical tumors (ACT). Transcriptome profiles separate adrenocortical adenomas ‘C2’ from carcinomas, and identify two groups of carcinomas ‘C1A’ and ‘C1B’, of poor and better prognosis respectively. However, many ACT cannot be profiled because of improper or absent freezing procedures, a mandatory requirement so far. The main aim was to determine transcriptome profiles on formalin-fixed paraffin-embedded (FFPE) samples, using the new 3’-end RNA-sequencing technology. A secondary aim was to demonstrate the ability of this technique to explore large FFPE archives, by focusing on the rare oncocytic ACT variants. Methods We included 131 ACT: a training cohort from Cochin hospital and an independent validation cohort from Wuerzburg hospital. The 3’ transcriptome was generated from FFPE samples using QuantSeq (Lexogen, Vienna, Austria) and NextSeq500 (Illumina, San Diego, CA, USA). Results In the training cohort, unsupervised clustering identified three groups: ‘C1A’ aggressive carcinomas (n = 28, 29%), ‘C1B’ more indolent carcinomas (n = 28, 29%), and ‘C2’ adenomas (n = 39, 41%). The prognostic value of FFPE transcriptome was confirmed in the validation cohort (5-year OS: 26% in ‘C1A’ (n = 26) and 100% in ‘C1B’ (n = 10), P = 0.003). FFPE transcriptome was an independent prognostic factor in a multivariable model including tumor stage and Ki-67 (OS HR: 7.5, P = 0.01). Oncocytic ACT (n = 19) did not form any specific cluster. Oncocytic carcinomas (n = 6) and oncocytic ACT of uncertain malignant potential (n = 4) were all in ‘C1B’. Conclusions The 3’ RNA-sequencing represents a convenient solution for determining ACT molecular class from FFPE samples. This technique should facilitate routine use and large retrospective studies.

International audience; P826The French COMETE-Cancer network for adrenal cancer: 10 years of activity as part of a national plan for clinical care of rare cancersIntroductionThe French National Institute of Cancer (INCa) launched supported by the Ministry of Health in 2008 a program for the recognition of national networks for the management of rare cancers. Among the 23 selected networks COMETECancer was recognized by INCa in 2009 for Adrenocortical carcinoma (ACC) and malignant pheochromocytoma/paraganglioma (MPP). At that time 60–120 new ACC/year and 30 new MPP/year were expected at the national level.AimTo describe the general activities of COMETE-cancer after 10-years of activity.Materials and methodsINCa list 7 tasks for the national rare cancer networks: 1) Expertise: double reading of tumor samples, Referral National Multisciplinary Staff (RNMS); 2) Care practice: national best practice guidelines release; 3) Referral: patient access to highly specialized/innovative treatments (clinical trial); 4) Observation: exhaustive recording of national cases in registries; 5) Clinical and translationalresearch; 6) Healthcare professional training; 7) Role of patient associations. TheFrench COMETE-K network is coordinated by two-sites Centers (Cochin andGustave Roussy). Ten Regional Experts Centers have been recognized for anational geographical coverage.ResultsA double reading is done in about 200 cases of ACC/MPP tumor samples/year. A RNMS is organized twice a month (web based system): about 170 ACC and MPP patients/year are discussed. The coverage rate of ‘new’ patients reviewed in RNMS/‘estimated’ total number cases was 68%. The consistency between treatment proposed in RNMS and treatment administered was of 84%. Since2010, 958 ACC and 384 MPP have been entered in the ENSAT database. Two National best practice guidelines for ACC/MPP were released. About 70 ACC/MPP have been referred to the COMETE-Cancer centers for highly specialized and innovative treatment (phase II-III trial, radiofrequency/cryotherapy, liver chimioembolisation). COMETE-Cancer participated in two international trials (ADIUVO in ACC and FIRSTMAPP in MPP) and more than 20 translational studies. Every year more than 500 healthcare professional (student, endocrinologists, surgeons, pathologist, oncologists) are trained. Moreover, it strongly collaborates with the patients ‘Association Surre´nale’ by writing specific documents on the clinical ACC/MPP management.ConclusionsCOMETE-cancer has led to a homogenous national organization for clinical care of ACC and MPP. The RNMS proved to be very efficient for that. Links with the ENSAT, ENDO-ERN and EURACAN networks will allow further progress at the European level.DOI: 10.1530/endoabs.63.P826

Adrenocortical carcinoma is a rare cancer with a poor but heterogeneous prognosis. These tumours are more frequently encountered in women, sometimes very young and may be diagnosed in women in their child bearing years or already pregnant. Several clinical data have indicated that the secretion and or proliferation of adrenocortical tumors may be affected by the hormonal context of pregnancy. In this review, we will examine the link between ACC and pregnancy in two main aspects. We will first consider the situation of a pregnant woman with a clinical suspicion of adrenocortical carcinoma: which diagnostic procedures will be useful and safe for the foetus? What are the therapeutic options? What is the prognosis if the diagnosis is confirmed? In a second part, we will examine the possible risk of mothering a child in a patient previously treated for an ACC. The data shown here were obtained from studies carried out in a tertiary reference medical centre in Paris (Hopital Cochin) and from the European Network for the Study of Adrenal Tumor (ENS@T) database of adrenocortical carcinoma.

Recent developments in the treatment of adrenocortical carcinoma (ACC) include diagnostic and prognostic risk stratification algorithms, increasing evidence of the impact of historical therapies on overall survival, and emerging targets from integrated epigenomic and genomic analyses. Advances include proper clinical and molecular characterization of all patients with ACC, standardization of proliferative index analyses, referral of these patients to large cancer referral centers at the time of first surgery, and development of new trials in patients with well-characterized ACC. Networking and progress in the molecular characterization of ACC constitute the basis for significant future therapeutic breakthroughs.

International audience; Context:Adrenocortical cancer (ACC) is an aggressive tumor with a heterogeneous outcome. Prognostic stratification is difficult even based on tumor stage and Ki67. Recently integrated genomics studies have demonstrated that CpG islands hypermethylation is correlated with poor survival.Objective:The goal of this study was to confirm the prognostic value of CpG islands methylation on an independent cohort.Design:Methylation was measured by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA).Setting:MS-MLPA was performed in a training cohort of 50 patients with ACC to identify the best set of probes correlating with disease-free survival (DFS) and overall survival (OS). These outcomes were validated in an independent cohort from 21 ENSAT centers.Patients:The validation cohort included 203 patients (64% women, median age 50 years, 80% localized tumors).Main Outcome Measures:DFS and OS.Results:In the training cohort, mean methylation of 4 genes (PAX5, GSTP1, PYCARD, PAX6) was the strongest methylation marker. In the validation cohort, methylation was a significant prognostic factor of DFS (P < 0.0001) and OS (P < 0.0001). Methylation, Ki67, and ENSAT stage were combined in multivariate models. For DFS, methylation (P = 0.0005) and stage (P < 0.0001) but not Ki67 (P = 0.19) remained highly significant. For OS, methylation (P = 0.0006), stage (P < 0.0001), and Ki67 (P = 0.024) were independent prognostic factors.Conclusions:Tumor DNA methylation emerges as an independent prognostic factor in ACC. MS-MLPA is readily compatible with clinical routine and should enhance our ability for prognostication and precision medicine.

Adrenocortical carcinoma is a rare cancer with a poor but heterogeneous prognosis. These tumours are more frequently encountered in women, sometimes very young and may be diagnosed in women in their child bearing years or already pregnant. Several clinical data have indicated that the secretion and or proliferation of adrenocortical tumors may be affected by the hormonal context of pregnancy. In this review, we will examine the link between ACC and pregnancy in two main aspects. We will first consider the situation of a pregnant woman with a clinical suspicion of adrenocortical carcinoma: which diagnostic procedures will be useful and safe for the foetus? What are the therapeutic options? What is the prognosis if the diagnosis is confirmed? In a second part, we will examine the possible risk of mothering a child in a patient previously treated for an ACC. The data shown here were obtained from studies carried out in a tertiary reference medical centre in Paris (Hôpital Cochin) and from the European Network for the Study of Adrenal Tumor (ENS@T) database of adrenocortical carcinoma.

Publisher Summary This chapter reviews the genetic aspects of adrenocortical tumors (ACT) and hypersecretory syndromes. The advances in research on the molecular mechanisms of ACT and study of rare genetic syndromes associated with ACT has facilitated in understanding the genetic alterations involved in both benign and malignant ACT. A detailed analysis of the various genetic syndromes and the concerned genes are described. In Li-Fraumeni syndrome, germline mutation of the tumor suppressor gene TP53 occurs in 70% of cases. This syndrome displays dominant inheritance and causes susceptibility to breast carcinoma, soft tissue sarcoma, adrenocortical carcinoma (ACC) and brain tumors among others. The loss of heterozygosity at locus (LOH) 17p13 occurs in ACC but not in adrenocortical adenoma and increased prevalence of LOH is correlated with pathological alterations that determine malignancy of ACT. The other syndromes discussed include Beckwith-Wiedemann syndrome IGF-II, multiple endocrine neoplasia type 1 and congenital adrenal hyperplasia. The study of hereditary neoplasia syndromes is stated to have led to identification of various loci or chromosomal regions and gene responsible for ACT development.

Adrenal cortical carcinoma is a rare malignancy, with only one or two new cases being diagnosed per million subjects per year. The prognosis is dismal, with less than 30% survival at five years. The best chances of cure are obtained when a "localized" tumor can undergo "complete" surgical removal. Most often, however, the diagnosis is made when the tumor is already invasive and non secretory Clinical, hormonal and imaging features, including 18-fluorodeoxyglucose PET scan, can provide strong evidence of malignancy and indicate open surgical excision in expert hands. Recent advances in the genetics of adrenal cortical carcinomas have identified molecular factors that can be used as diagnostic and prognostic markers. These markers are more valuable than classical staging and histology (Weiss score). A better understanding of the pathophysiology of these tumors is required in order to develop targeted therapies.