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Pancreatic cancer (PC) is a recalcitrant disease characterized by high incidence and poor prognosis. The extremely complex genomic landscape of PC has a deep influence on cultivating a tumor microenvironment, resulting in the promotion of tumor growth, drug resistance, and immune escape mechanisms. Despite outstanding progress in personalized medicine achieved for many types of cancer, chemotherapy still represents the mainstay of treatment for PC. Olaparib was the first agent to demonstrate a significant benefit in a biomarker-selected population, opening the doors for a personalized approach. Despite the failure of a large number of studies testing targeted agents or immunotherapy to demonstrate benefits over standard chemotherapy regimens, some interesting agents, alone or in combination with other drugs, have achieved promising results. A wide spectrum of therapeutic strategies, including immune-checkpoint inhibitors tyrosine kinase inhibitors and agents targeting metabolic pathways or the tumor microenvironment, is currently under investigation. In this review, we aim to provide a comprehensive overview of the current landscape and future directions of personalized medicine for patients affected by PC.

e20515 Background: Large cell neuroendocrine carcinoma of the lung (LCNEC) is a rare tumor, with clinical and molecular features between non-small cell and small-cell lung cancer (NSCLC and SCLC, respectively). To date, little is known about factors able to predict clinical outcome of these patients. We sought to identify prognostic factors in LCNEC. Methods: We retrospectively collected pathologically-confirmed LCNEC patients treated at the S. Orsola Malpighi Hospital of Bologna between 01/01/2009 and 31/12/2020. LCNEC was defined as tumor with neuroendocrine morphology, expression of ≥2 neuroendocrine markers (including chromogranin A, synaptophysin, or CD56) at immunohistochemistry and high tumor grade (defined as necrosis and high Ki67 ≥ 50% or high mitotic rate, ≥ 10 mitoses per 2 mm2). Clinical features, pathological features, and blood test values (including neuron-specific enolase [NSE], carcinoembryonic antigen [CEA], cytokeratin 19 fragment [cyfra 21-1]) were correlated with progression-free survival to first-line chemotherapy (PFS) and overall survival from the diagnosis of extensive disease (OS). Results: Eighty-one LCNEC patients (median age 69 years, range 63-76) were identified. Twenty-seven (33.3%) had limited-stage disease and 52 patients (67.5%) had Eastern cooperative oncology group performance status (ECOG PS) ≥ 1 at diagnosis. When extensive disease was found (ED-LCNEC, N = 67), 23 patients (34.3%) had liver metastases, 10 (14.9%) had brain metastases and 24 (35.8%) had bone metastases. Treatment in ED-LCNEC was platinum plus etoposide in 45 patients (81.9%) and platinum plus paclitaxel in 10 patients (18.1%). Among 55 patients treated with platinum-based chemotherapy, 5 patients (9.1%) received cisplatin, while 50 (90.9%) received carboplatin. Overall, OS was 9.17 months (95% confidence interval [95%CI]7.17-13.87), PFS was 4.87 months (95%CI 4.21-6.02) and ORR was 38.2% (95%CI 25.4-42.3, N = 21/56). At univariate analysis, ECOG PS ≥ 1 (P = 0.049), presence of liver (P = 0.004) and bone metastases (P = 0.009), ≥ 2 non-nodal metastatic sites (P < 0.001), elevated NSE (P = 0.009) and CEA level at diagnosis (P = 0.011) were associated with increased risk of death. At multivariate analysis, ECOG PS ≥ 1 (P = 0.020), ≥ 2 metastatic sites (P = 0.002), and elevated NSE level at diagnosis (P = 0.009) were independently associated with the risk of death. At univariate analysis brain metastases (P = 0.017), ≥2 metastatic sites (P = 0.006) and elevated value of CEA at baseline (P = 0.026) were associated with increased risk of progression. At multivariate analysis, only the presence of brain metastases (P = 0.043) retained its association with the risk of progression. Conclusions: In ED-LCNEC of the lung, ECOG PS, number of non-nodal sites of metastases and NSE at baseline are associated with worse survival, while the presence of brain metastases is associated with shorter PFS.

e16203 Background: Goblet cell carcinoma (GCC) is a rare mixed endocrine-neuroendocrine tumor arising almost exclusively in the appendix. The optimal management of these patients is still unclear, given GCC rarity and the difficulty in proper pathology diagnosis. We sought to explore the efficacy of adjuvant chemotherapy (ACT) in GCC extracted from the Surveillance, Epidemiology and End Result (SEER) US registry. Methods: Patients with pathology diagnosis of GCC were identified in the SEER registry by the 8243 ICD-09 code. Data about sex, age, tumor stage at diagnosis, number of analyzed and positive lymph-nodes, chemotherapy and survival were collected. Lymph node ratio (LNR) was calculated as the ratio between the number of metastatic lymph-nodes and removed lymph nodes. The best cutoff to predict survival state at 5-year from diagnosis was calculated. The primary endpoint was overall survival (OS). Results: Overall, 1055 GCC patients (51.7% male, median age 57 years) were identified. The median tumor diameter was 20 mm. According to the American Joint Committee on Cancer staging manual 7th edition, 128 patients (12.1%) had nodal involvement (N+): 95 were N1 and 33 were N2, while 66 (6.3%) had distant metastasis (M+). Prognostic LNR cutoff was 0.16. Using this cutoff, LNR was ≤0.16 in 674 patients (63.9%), and > 0.16 in 125 patients (11.8%). The median OS was 232 months (95% confidence interval [95%CI]: 153.4-310.5). Overall, 5-year survival rate (OS-5) was 73.4% (N = 453). At univariate analysis age, tumor diameter, M+, N+, number of lymph nodes removed, number of metastatic lymph nodes and LNR were significantly associated with the risk of death. At multivariate analysis, age, M+, N+, number of removed lymph nodes, and number of metastatic lymph nodes retained their association. After excluding M+ and N+ patients, 897 localized GCC patients (52.8% male) were analyzed. Fifty-five patients (6.1%) received ACT and OS-5 was 83.8% (N = 425). CT was administered more often in tumors with higher histological grade, higher T stage and greater tumor diameter. At the multivariate analysis, only age and number of removed lymph nodes were independently associated with the risk of death. Notably, ACT was not associated with increased survival. Ninety-two patients (57.6% male) had nodal involvement without distant metastases: 73 were N1 and 19 were N2. In 56 patients (60.9%) LNR was ≤0.16, while it was > 0.16 in 35 (38.0%). Thirty-five patients (38%) received ACT, without significant imbalances. OS-5 was 45.2% (N = 28). At univariate analysis, age, N2, number of metastatic lymph nodes and LNR were significantly associated with the risk of death. At multivariate analysis, only the number of metastatic lymph nodes retained its association. Of note, ACT was not associated with increased survival. Conclusions: In GCC, ACT was not associated with increased survival in our population-based analysis, irrespective of nodal involvement.

Thymic tumors are a group of rare mediastinal malignancies that include three different histological subtypes with completely different clinical behavior: the thymic carcinomas, the thymomas, and the rarest thymic neuroendocrine tumors. Nowadays, few therapeutic options are available for relapsed and refractory thymic tumors after a first-line platinum-based chemotherapy. In the last years, the deepening of knowledge on thymus’ biological characterization has opened possibilities for new treatment options. Several clinical trials have been conducted, the majority with disappointing results mainly due to inaccurate patient selection, but recently some encouraging results have been presented. In this review, we summarize the molecular alterations observed in thymic tumors, underlying the great biological differences among the different histology, and the promising targeted therapies for the future.

Thymic epithelial tumors (TETs) are a group of rare thoracic malignancies, including thymic carcinomas (TC) and thymomas (Tm). Autoimmune paraneoplastic diseases are often observed in TETs, especially Tms. To date, chemotherapy is still the standard treatment for advanced disease. Unfortunately, few therapeutic options are available for relapsed/refractory TETs. In the last few years, the deepening of knowledge on thymus’ immunobiology and involved altered genetic pathways have laid the foundation for new treatment options in these rare neoplasms. Recently, the immunotherapy revolution has landed in TETs, showing both a dark and light side. Indeed, despite the survival benefit, the occurrence of severe autoimmune treatment-related adverse events has risen crescent uncertainty about the feasibility of immunotherapy in these patients, prone to autoimmunity for their cancer biology. In this review, after summarizing immunobiology and immunopathology of TETs, we discuss available data on immune-checkpoint inhibitors and future perspectives of this therapeutic strategy.