Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy Abstract: NUT midline carcinoma (NMC) is a rare and aggressive subtype of squamous carcinoma that typically arises from midline supradiaphragmatic structures, frequently from the head and neck area. NMC is genetically driven by a chromosomal rearrangement involving the NUT gene, which forms oncoproteins considered major pathogenic drivers of cellular transformation. Diagnosis of NMC has been made remarkably easier with the availability of a commercial antibody against NUT, and can be established through positive nuclear immunohistochemical staining. Although NMC remains an underrecognized malignancy, in recent years there has appeared to be increasing awareness of disease and frequency of diagnosis in adults. To date, a standard treatment for head and neck NMC has not been established and a multimodal approach with systemic chemotherapy, surgery and radiation therapy is currently adopted in clinical practice. Recently, BET inhibitors and histone deacetylase inhibitors have emerged as two promising classes of targeted agents, currently investigated in clinical trials for adults with head and neck NMC. At the same time, combination approaches and novel targeted agents, such as next-generation BET inhibitors and CDK9 inhibitors, have shown preclinical activity. The present review explores the clinical pathological characteristics of NMC of the head and neck and presents the current state of the art on diagnosis, prognosis, and treatment of this rare but lethal disease.

In the last decade, several clinical trials have investigated novel endocrine combinations for the first-line treatment of hormone receptor-positive metastatic breast cancer. Nevertheless, the use of combinations for the first-line treatment of bone-only disease is widely discussed as a result of its indolent natural history. We performed a comprehensive search of phase 3 randomized clinical trials published in the literature through September 2018. Our aim was to explore the role of the new endocrine approaches in bone-only metastatic breast cancer, suggesting a possible strategy for their selection. In particular, we evaluated the comparative risk of adverse event occurrence during these treatments. A total of 6 studies were deemed suitable for meta-analysis: the Monaleesa-2, Monaleesa-7, Monarch-3, Paloma-2, SWOG, and Alliance trials. Overall, the novel strategies were shown to improve progression-free survival in bone-only disease (hazard ratio = 0.65; 95% confidence interval, 0.49-0.86; P = .003). Combinations with cyclin-dependent kinase inhibitors improved progression-free survival (hazard ratio = 0.54; 95% confidence interval, 0.39-0.75; P < .001) with an acceptable toxicity profile. Abemaciclib was associated with increased anemia and gastrointestinal toxicity (especially diarrhea), whereas palbociclib was associated with increased leukopenia (but not neutropenia) compared to the other compounds. Increased aspartate aminotransferase levels were reported for both ribociclib and abemaciclib. The combination of cyclin-dependent kinase 4/6 inhibitors and endocrine therapy represents an effective and well-tolerated approach for first-line treatment in bone-only disease settings. Because no direct comparison between the 3 cyclin-dependent kinase 4/6 inhibitors is available, the selection of the most appropriate treatment should be based on toxicity profile as well as patient preference and copathologies.

Abstract: NUT midline carcinoma (NMC) is a rare and aggressive subtype of squamous carcinoma that typically arises from midline supradiaphragmatic structures, frequently from the head and neck area. NMC is genetically driven by a chromosomal rearrangement involving the NUT gene, which forms oncoproteins considered major pathogenic drivers of cellular transformation. Diagnosis of NMC has been made remarkably easier with the availability of a commercial antibody against NUT, and can be established through positive nuclear immunohistochemical staining. Although NMC remains an underrecognized malignancy, in recent years there has appeared to be increasing awareness of disease and frequency of diagnosis in adults. To date, a standard treatment for head and neck NMC has not been established and a multimodal approach with systemic chemotherapy, surgery and radiation therapy is currently adopted in clinical practice. Recently, BET inhibitors and histone deacetylase inhibitors have emerged as two promising classes of targeted agents, currently investigated in clinical trials for adults with head and neck NMC. At the same time, combination approaches and novel targeted agents, such as next-generation BET inhibitors and CDK9 inhibitors, have shown preclinical activity. The present review explores the clinical pathological characteristics of NMC of the head and neck and presents the current state of the art on diagnosis, prognosis, and treatment of this rare but lethal disease.

Abstract The standard first-line for endocrine sensitive metastatic breast cancer (BC) is represented by endocrine therapy. Several phase III clinical trials searched for more effective endocrine strategies. Nevertheless, the use of combinations for the first-line treatment of bone-only disease (BoD) is widely discussed, due to its indolent course. Our meta-analysis aims to explore the role of new endocrine strategies in BoD. A systematic review of electronic databases was conducted to identify the phase III clinical trials comparing the standard AI to novel experimental strategies. The hazard ratios (HR) for PFS were pooled in a meta-analysis. The heterogeneity of the data was evaluated by Chi-square Q test and I2 statistic. 8 studies were included in the analyses. 4 trials explored the role of CDK4/6 inhibitors (Monaleesa2 and 7, Monarch3 and Paloma2), 2 trials analyzed Fulvestrant + AI (SWOG and FACT), one trial studied Fulvestrant monotherapy (FALCON), while one trial evaluated the association between Bevacizumab and Letrozole (ALLIANCE). 6 trials reported data regarding the BoD, while 2 trials included the BoD in the non-visceral disease. Overall, the meta-analyses showed a PFS advantage for the experimental arms [HR 0.70 p 0.012], with a significant moderate/high heterogeneity [I2 66.48% p 0.004]. Only the FALCON and Paloma2 showed a significant improvement in PFS, respectively for Fulvestrant and Palbociclib + Letrozole. Considering only trials reporting data for BoD, the experimental arms significantly improved the PFS [HR 0.66 p 0.005], with a low/moderate non-significant heterogeneity [I2 44.95% p 0.106]. The novel strategies showed to be able to improve the PFS of BoD. Nonetheless, only Palbociclib + Letrozole provided statistically significant data of advantage in this setting. In clinical trials, BoD is often included in the non-visceral disease subgroup. Future clinical trials should take into account the differences in natural history and better prognosis of BoD, in order to define the best approach to these patients. Citation Format: Toss A, Venturelli M, Sperduti I, Isca C, Molinaro E, Barbieri E, Piacentini F, Omarini C, Cortesi L, Cascinu S, Moscetti L. First-line treatment for endocrine sensitive bone-only metastatic breast cancer: Is more always better? [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-18-06.

Introduction: Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and the second leading cause of cancer-related mortality worldwide. Its incidence and prevalence are increasing, especially in some parts of the world. When diagnosed at an advanced stage, the prognosis is poor and approved treatment options are limited. Sorafenib, an oral multi-tyrosine kinase inhibitor (VEGFR-1/2/3, PDGFR, Flt3, c-Kit, Raf kinases), has been established as the standard of care for patients with advanced HCC since 2007, on the basis of two landmark trials (SHARP and Asia-Pacific). Although its efficacy is not a matter of doubt, this drug is effective only in a proportion of patients and may cause adverse effects that negatively impact on patient quality of life. Ten years have already passed since sorafenib was introduced in healthcare practice and, despite a lot of research in the field, no validated prognostic markers are available for patients treated with this therapeutic agent. Moreover, much of what we know comes from sub-analyses and pooled analyses of randomized controlled trials, rather than from real life. Therefore, we conducted a field-practice study aimed at identifying which baseline factors are associated with overall survival (OS) of patients affected by HCC and treated with sorafenib. Methods: Three hundred and ninety-eight patients with HCC consecutively treated with sorafenib twice daily between March 2008 and December 2018 were included in the study. For every patient we collected 37 biological/clinical parameters the day before the start of the treatment. OS was estimated by the Kaplan-Meier method and curves were compared by the log-rank test. Unadjusted and adjusted hazard ratios (HRs) by baseline characteristics were calculated using the Cox proportional hazards model. Results: Based on univariate analysis, AFP(> 400 vs < 400; HR 1.51; P =.0066), albumin(< 35 vs > 35; HR 1.47; P = .03), AST(> 40 vs < 40; HR 1.92; P = .001), bilirubin(> 1.2 vs 0 vs 0; HR 1.71; P < .0001), SII(>360 vs < 360; HR 1.36; P = .04), ALBI grade (1 vs 2; HR 2.47; P = .0008) and portal vein thrombosis (yes vs no; HR 1.45; P = .0065) were significantly associated with a shorter OS. Following adjustment for clinical covariates positive in univariate analysis, the multivariate analysis including AFP (cut-off 400), age (> or < 70 years), aetiology (HBV, HCV and others), albumin (> or < NV), AST (> or < NV), bilirubin (> or < NV), Child Pugh (A vs B), LDH as a continuous variable, PLR (> or < 16), ECOG (0 vs > 0), ALBI grade (1 vs 2), portal vein thrombosis (yes vs. no), SII (< 360 vs > 360), BCLC stage (B vs C), identified increase of LDH, age > 70 years, other aetiologies, ECOG > 0, albumin 40, were identified as prognostic factors for poorer OS based on the 5% significance level. Conclusion: Our study highlights that hepatic function (ALBI grade, AST, albumin, LDH), patient-centered variables (ECOG, age) and aetiology, rather than immune inflammation indicators, AFP or tumor stage, have prognostic value. Our study provides insights into the impact of baseline characteristics on the OS of sorafenib-treated HCC patients in real-life usual care. This information might have implications in terms of therapeutic decision-making and patient counseling.

Background ABC portend a dismal prognosis despite standard chemotherapy treatment. A proper risk-stratification is key to optimize the benefit-to-risk ratio of palliative treatment. The PNI is an immune-inflammatory and nutritional indicator showing to be prognostic across a number of malignancies. We aimed at investigating the impact on survival of the PNI in ABC patients (pts) treated with 1L. Methods Electronic medical records of pts diagnosed with ABC and treated with 1L between 2002 and 2018 at the Modena Cancer Centre were retrospectively reviewed. Clinical, pathological and biochemical variables of potential interest were collected. The PNI was calculated as follows: 10 × serum albumin concentration (g/dL) + 0.005 × peripheral lymphocyte count (number/mm2) and dichotomized using the ROC analysis with 36.7 as the cut-off value. Univariate and multivariate analysis were performed to assess the impact of covariates on overall survival (OS). Kaplan-Meier survival curves were generated and log-rank testing was used to make comparisons. Results Overall, 114 pts fulfilled the inclusion criteria and were included in the analysis. 51% (n = 58) were female and 49% (n = 56) had an ECOG PS of 0. 35% (n = 40) of pts received a platinum/gemcitabine doublet, while 65% (n = 74) were treated with other regimens. The median OS in the cohort was 8.1 months. At the univariate analysis the following covariates were associated with OS: PNI (P 36.7 and Conclusions We demonstrated an independent prognostic role for the PNI in a cohort of ABC treated with 1L. Since it is based on easy-to-collect and inexpensive parameters it should be implemented in the clinical practice to improve the accuracy of current available tools. Legal entity responsible for the study Francesco Caputo. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Background: Because of the high costs associated with genetic analyses, BRCA1/2-testing has traditionally been restricted to breast cancer patients having an 'a priori high risk' of being a carrier. Particularly, according to The National Institute for Health and Care Excellence (NICE) in the UK, BRCA testing should be offered to breast cancer patients with a probability of having a mutation ≥ 10%. Regardless of family history, International Guidelines include among the BRCA testing Criteria, a personal history of triple negative breast cancer diagnosed ≤ 60 years. According to previous research, 15-30% of unselected TNBC had confirmed BRCA mutations. Whereas, among patients without breast/ovarian cancer family history mutation prevalence decrease to 6-15 %. Methods: In the archives of the Modena Family Cancer Clinic, we identified 126 patients diagnosed with TNBC without family history of breast/ovarian cancer, which underwent BRCA-genetic testing. Mutation prevalence and clinical-pathological characteristics were evaluated. Results: Among 126 triple-negative breast cancer patients without a family history of breast and/or ovarian cancer, a total of 20 patients (15.8%) were BRCA mutation carriers: 18 BRCA1 (14.2%), 2 BRCA2 (1.5%), 2 BRCA2 VUS (1.5%). The mutation prevalence was 7/20 (35%) in the age group 30-39 years, 9/55 (16.3%) in 40-49, 4/48 (8.3%) in 50-59, 0/1 (0%) in 60-69 and 0/2 (0%) in 70-79. BRCA1 patients were younger at diagnosis (44 yrs) than non-carriers (48 yrs). Histotype, tumor grade, ki-67 and the presence of second primary BC were equally distributed between carriers and non-carriers. Conclusions: Our results are aligned with the recent results of the German Consortium for Hereditary Breast and Ovarian Cancer, and justify BRCA mutation screening among women with TNBC diagnosed before the age of 60 years and no family history. Legal entity responsible for the study: Laura Cortesi. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

The prognostic role of pregnancy occurring before or after a breast cancer diagnosis is still unclear. Data of young women with breast cancer and pregnancy treated from 2002 and 2014 in our institution were retrospectively analyzed and compared with data of patients with breast cancer not associated with pregnancy. The aim of the study was to evaluate the role of pregnancy on the prognosis of these patients. The main analysis was performed using Kaplan Meyer curves for DFS and OS and Log-rank test to evaluate differences between the two groups. They were matched for the following prognostic markers: age, histology, grade, hormone receptor status, human epidermal growth factor 2 status, BRCA1or BRCA 2 mutations, type of chemotherapy and use of trastuzumab, radiotherapy and hormonal therapy. The first group consisted of 40 patients with breast cancer and pregnancy of whom 6 patients with breast cancer during pregnancy, 7 patients with cancer during breast feeding and 27 patients with breast cancer after pregnancy (< 5 years). The non pregnant group consists in 83 women. Median age was 44 years for the pregnant and 37 years for the non pregnant patients. Median follow up was 37.5 mos. Median DFS of pregnancy group was not reached, 54,7% of the patients is disease free at 154 months, median DFS of non pregnancy group was 97 months, CI 95% (82-111), p = 0,27. There were not statistical differences in DFS for estrogen receptor positive, Her 2 positive and triple negative subgroups between the two cohorts. No deaths were observed within the two groups. In conclusion, although our analysis shows some limitations such as a small sample size and a short follow up, we found similar outcome for patients with primary breast cancer diagnosed during pregnancy when compared with non pregnant patients with breast cancer. In line with previous reports we found no evidence that a pregnancy during or after breast cancer has a negative role for prognosis.