Antibody-Antineoplastic Conjugates in Gynecological Malignancies: Current Status and Future Perspectives

In the last decade, antibody-drug conjugates (ADCs), normally formed by a humanized antibody and a small drug via a chemical cleavable or non-cleavable linker, have emerged as a potential treatment strategy in cancer disease. They allow to get a selective delivery of the chemotherapeutic agents at the tumor level, and, consequently, to improve the antitumor efficacy and, especially to decrease chemotherapy-related toxicity. Currently, nine antibody-drug conjugate-based formulations have been already approved and more than 80 are under clinical trials for the treatment of several tumors, especially breast cancer, lymphomas, and multiple myeloma. To date, no ADCs have been approved for the treatment of gynecological formulations, but many formulations have been developed and have reached the clinical stage, especially for the treatment of ovarian cancer, an aggressive disease with a low five-year survival rate. This manuscript analyzes the ADCs formulations that are under clinical research in the treatment of gynecological carcinomas, specifically ovarian, endometrial, and cervical tumors.

A case of Carney triad complicated by renal cell carcinoma and a germline SDHA pathogenic variant

Summary Succinate dehydrogenase deficiency has been associated with several neoplasias, including renal cell carcinoma (RCC) and those associated with hereditary paraganglioma (PGL)/ pheochromocytoma (PHEO) syndromes, Carney dyad, and Carney triad. Carney triad is a rare multitumoral syndrome characterized by co-existing PGL, gastrointestinal stromal tumor (GIST), and pulmonary chondroma (CHO). We report a case of a 57-year-old male who presented with para-aortic and gastroesophogeal masses, and a right renal superior pole lesion, which were classified as multiple PGLs, a GIST, and a clear cell renal carcinoma, respectively, on pathology following surgical resection. Additionally, a CHO was diagnosed radiologically, although no biopsy was performed. A diagnosis of Carney triad was made. SDHB immunohistochemical staining was negative for the PGL and the GIST, indicating SDH-deficiency. Interestingly, the renal cell carcinoma (RCC) stained positive for both SDHB and SDHA. Subsequent genetic screening of SDH subunit genes revealed a germline inactivating heterozygous SDHA pathogenic variant (c.91 C>T, p.R31X). Loss of heterozygosity was not detected at the tumor level for the RCC, which likely indicated the SDHA variant would not be causative of the RCC, but could still predispose to the development of neoplasias. To the knowledge of the authors this is the first reported case of an SDHA pathogenic variant in a patient with Carney triad complicated by RCC. Learning points The succinate dehydrogenase enzyme is encoded by four subunit genes (SDHA, SDHB, SDHC, and SDHD; collectively referred to as SDHx), which have been implicated in several neoplasias and are classified as tumor suppressor genes. Carney triad is a rare multiple-neoplasia syndrome presenting as an association of PGLs, GISTs, and CHOs. Carney triad is most commonly associated with hypermethylation of SDHC as demonstrated in tumor tissue, but approximately 10% of cases are due to pathogenic SDHx variants. Although SDHB pathogenic variants are most commonly reported in SDH-deficient renal cell carcinoma, SDHA disease-causing variants have been reported in rare cases.

A Comprehensive Evaluation of Associations Between Routinely Collected Staging Information and The Response to (Chemo)Radiotherapy in Rectal Cancer

Radiotherapy (RT) or chemoradiotherapy (CRT) are frequently used in rectal cancer, sometimes resulting in complete tumor remission (CR). The predictive capacity of all clinical factors, laboratory values and magnetic resonance imaging parameters performed in routine staging was evaluated to understand what determines an excellent response to RT/CRT. A population-based cohort of 383 patients treated with short-course RT (5 × 5 Gy in one week, scRT), CRT, or scRT with chemotherapy (scRT+CT) and having either had a delay to surgery or been entered into a watch-and-wait program were included. Complete staging according to guidelines was performed and associations between investigated variables and CR rates were analyzed in univariate and multivariate analyses. In total, 17% achieved pathological or clinical CR, more often after scRT+CT and CRT than after scRT (27%, 18% and 8%, respectively, p < 0.001). Factors independently associated with CR included clinical tumor stage, small tumor size (<3 cm), tumor level, and low CEA-value (<3.8 μg/L). Size or stage of the rectal tumor were associated with excellent response in all therapy groups, with small or early stage tumors being significantly more likely to reach CR (p = 0.01 (scRT), p = 0.01 (CRT) and p = 0.02 (scRT+CT). Elevated level of carcinoembryonic antigen (CEA) halved the chance of response. Extramural vascular invasion (EMVI) and mucinous character may indicate less response to RT alone.

NCOG-55. HARMONIZING LANGUAGE TO MAXIMIZE IMPACT: AN UPDATE ON COMMON DATA ELEMENTS FOR MENINGIOMA AND REVIEW OF CLINICAL TRIALS IN MENINGIOMA

BACKGROUND With increasing studies reporting on the molecular profiling of meningiomas, there is a need to harmonize language used to capture clinical data across centers to ensure that molecular alterations are appropriately linked to clinical variables of interest. Here the International Consortium on Meningiomas presents a final set of core and supplemental meningioma-specific Common Data Elements (CDEs) to facilitate comparative and pooled analyses. METHODS The generation of CDEs followed the four-phase process similar to other National Institute of Neurological Disorders and Stroke (NINDS) CDE projects: development/discovery based on data from published and ongoing meningioma trials, internal validation, external validation including presentation of our data form at the Society for Neuro-Oncology previously, and distribution. RESULTS We developed a set of CDEs organized into patient- and tumor-level modules. In total, the Consortium identified 16 core CDEs (9 patient-level and 7-tumour-level) e.g. age at index surgery, diagnosis of neurofibromatosis, prior chemotherapy or radiation, tumor location, extent of resection, recurrence, etc. An additional 15 supplemental CDEs were defined and described (8 patient-level and 7 tumour-level) e.g. race, cause of death, multiple tumors, tumor size, Simpson grade, second intervention, etc. These CDES are now made publicly available for dissemination and adoption. We also present a narrative review and analysis of recent and ongoing meningioma trials. CONCLUSIONS These CDEs provide a framework for discussion in the neuro-oncology community that will facilitating data sharing for collaborative research projects and aid in developing a common language for comparative and pooled analyses. The CDEs are intended to be dynamic parameters that evolve with time and The Consortium welcomes international feedback for further refinement and implementation of these CDEs.

HRness in Breast and Ovarian Cancers

Ovarian and breast cancers are currently defined by the main pathways involved in the tumorigenesis. The majority are carcinomas, originating from epithelial cells that are in constant division and subjected to cyclical variations of the estrogen stimulus during the female hormonal cycle, therefore being vulnerable to DNA damage. A portion of breast and ovarian carcinomas arises in the context of DNA repair defects, in which genetic instability is the backdrop for cancer initiation and progression. For these tumors, DNA repair deficiency is now increasingly recognized as a target for therapeutics. In hereditary breast/ovarian cancers (HBOC), tumors with BRCA1/2 mutations present an impairment of DNA repair by homologous recombination (HR). For many years, BRCA1/2 mutations were only screened on germline DNA, but now they are also searched at the tumor level to personalize treatment. The reason of the inactivation of this pathway remains uncertain for most cases, even in the presence of a HR-deficient signature. Evidence indicates that identifying the mechanism of HR inactivation should improve both genetic counseling and therapeutic response, since they can be useful as new biomarkers of response.

The Osteosarcoma Microenvironment: A Complex but Targetable Ecosystem

Osteosarcomas are the most frequent primary bone sarcomas, affecting mainly children, adolescents, and young adults, and with a second peak of incidence in elderly individuals. The current therapeutic management, a combined regimen of poly-chemotherapy and surgery, still remains largely insufficient, as patient survival has not improved in recent decades. Osteosarcomas are very heterogeneous tumors, both at the intra- and inter-tumor level, with no identified driver mutation. Consequently, efforts to improve treatments using targeted therapies have faced this lack of specific osteosarcoma targets. Nevertheless, these tumors are inextricably linked to their local microenvironment, composed of bone, stromal, vascular and immune cells and the osteosarcoma microenvironment is now considered to be essential and supportive for growth and dissemination. This review describes the different actors of the osteosarcoma microenvironment and gives an overview of the past, current, and future strategies of therapy targeting this complex ecosystem, with a focus on the role of extracellular vesicles and on the emergence of multi-kinase inhibitors.

OR24-06 USP8 Genetic Variants May Contribute to the Development of Bilateral Adrenal Hyperplasia and ACTH-Independent Cushing Syndrome

Background: Bilateral adrenocortical hyperplasias (BAHs), including primary pigmented nodular adrenocortical disease (PPNAD), isolated micronodular adrenocortical disease (iMAD) and primary macronodular adrenocortical hyperplasia (PMAH), are rare causes of ACTH-independent Cushing syndrome (CS). PPNAD and iMAD usually present in children or adolescents as multiple small (&lt;1cm), cortisol-producing adrenocortical nodules. On the other hand, PMAH is most frequently identified in older patients with multiple large adrenal nodules. Most patients with PPNAD have PRKAR1A mutations whereas patients with PMAH may harbor variants in other genes (ARMC5, MC2R, GNAS, APC, MEN1). Even though several genes have been associated with ACTH-independent CS, there are still cases that the genetic cause has not been elucidated. Clinical cases: Herein, we present two unrelated patients with ACTH-independent CS that harbor USP8 gene variants. USP8 is mainly known for being mutated in Cushing disease but as a deubiquitinase it may be involved into the Wnt/β-Catenin signaling pathway. The first patient was diagnosed with BAH on prenatal ultrasound (26 gestational week) and subsequently required bilateral adrenalectomy for CS as she had virilization, hirsutism, hypertension and cardiac hypertrophy 9 weeks old. Adrenalectomy revealed that she had iMAD. She also presented with hemihypertrophy of the right leg, labia and mild newborn hypoglycemia, however she was negative for Beckwith-Wiedemann mutation. Gene analysis of PRKAR1A did not reveal any mutations. After whole exome sequencing (WES), we found a novel heterozygous USP8 variant (c.1387_1393delinsT, p.Ala463_Ile465delinsPhe) at germline level and loss of heterozygosity (LOH) at tumor level. Immunohistochemistry showed significantly lower expression of USP8 protein in both of her adrenals compared to a control tissue. The second case is a 59-year old female with osteoporosis who failed to suppress cortisol levels after low dose dexamethasone administration. MRI revealed an adenoma on the right adrenal (2.6cm). She underwent right adrenalectomy and was found to have PMAH. We performed WES in germline level and we detected a novel heterozygous missense USP8 variant (c.287A&gt;G, p.Lys96Arg) that is present also at tumor level. Immunohistochemistry showed significantly lower expression of USP8 protein in her adrenal tumor compared to the control tissue. No LOH was identified. Conclusion: This is the first report of the association of USP8 in ACTH-independent CS and the preliminary findings support UPS8 involvement in the development of adrenocortical disease. We are currently performing further in vitro studies to evaluate the effect of these two USP8 variants into the canonical Wnt pathway which is commonly involved in adrenocortical disorders.