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Biomarkers of bone turnover in serum are suggestive of bone dynamics during treatment in multiple myeloma (MM). We evaluated the role of daratumumab on bone remodeling among patients with relapsed/refractory MM in the prospective, open-label, phase 2 study REBUILD. Daratumumab was administered according to the approved indication. A total of 33 out of 57 enrolled patients completed 4 months of treatment. The median percent change from baseline to 4 months in C-terminal cross-linking telopeptide of type 1 collagen (CTX) (primary endpoint) was 3.9%, with 13 (39.4%) and 11 (33.3%) patients showing at least 20% and 30% reduction in CTX levels, respectively. The median percent decrease from baseline to 4 months in tartrate resistant acid phosphatase 5b (TRACP-5b) levels (co-primary endpoint) was 2.6%, with 10 (30.3%) and 6 (18.2%) patients showing at least 20% and 30% reduction in TRACP-5b levels, respectively. However, the changes in these markers of bone catabolism were not statistically significant. Furthermore, the levels of osteocalcin, bone-specific alkaline phosphatase and procollagen type-I N-pro-peptide (bone formation markers) increased from baseline to 4 months (secondary endpoints) by 18.4%, 92.6% and 10.2%, respectively. Furthermore, the median levels of dickkopf-1 and C-C motif ligand-3 showed a significant decrease at 4 months by 17.5% and 16.0%, respectively. In conclusion, daratumumab improved bone turnover by inducing bone formation and reducing osteoblast inhibition.

To evaluate health-related quality of life (HRQoL) and satisfaction with iron chelation therapy (ICT) of patients with transfusion-dependent β-thalassemia (TDT) managed under routine care conditions. This was an observational, multicenter, cross-sectional study conducted in three hospital-based Thalassemia Units of Western Greece. Patients confidentially completed the 36-item short-form (SF-36) and the “satisfaction with ICT” (SICT) instruments to assess HRQoL and ICT satisfaction respectively. One hundred and thirty-one adult TDT patients [74 female, median (IQR) age: 41 (36–47) years] were enrolled. Eighty patients (61.1%) were receiving parenteral ICT, with or without oral chelators (Group I), whereas 51 (38.9%) were only receiving oral ICT (Group II). The median SF-36 physical component summary and mental component summary scores were 76.3 and 75.7 among Group I, and 76.9 and 74.5 among Group II patients, not differing between the two groups. In their majority, Group I (84.6%) and Group II (92.9%) patients reported preferring oral ICT. Moreover, Group I patients reported greater perceived ICT effectiveness (median SICT score: 4.3 versus 4.2; p = 0.039), whereas patients receiving deferasirox-containing ICT reported higher treatment acceptance (median SICT score: 4.0 versus 3.6, p = 0.038) and greater satisfaction with the burden of their ICT (median SICT score: 4.4 versus 3.9, p = 0.033). TDT patients prefer to receive oral ICT and are more satisfied of the burden of deferasirox-containing ICT, even though those receiving parenteral ICT are more satisfied by the effectiveness of their treatment. No differences in HRQoL were not noted between patients receiving parenteral versus oral ICT.

BRCA1/BRCA2 mutation carriers indefinitely comprise a distinct group of patients with breast cancer (BC), with their tumors displaying specific pathologic characteristics. Although these connections are known, they are not fully elucidated. We therefore sought to investigate the clinicopathologic characteristics and overall survival of Greek patients with BC carrying BRCA1/BRCA2 mutations.Greek patients with BC diagnosed between 1999 and 2016, fulfilling the National Comprehensive Cancer Network criteria for genetic testing, were analyzed for BRCA1/BRCA2 mutations by Sanger sequencing or by a 94-gene panel. Medical records and pathology reports were retrospectively reviewed to retrieve patient and tumor baseline characteristics. Potential associations with mutation status were assessed using the Fisher exact, Pearson χOf 2096 selected patients with BC, we identified 297 (14.2%) BRCA1 and 88 (4.2%) BRCA2 carriers. The mean age at BC diagnosis was 40 and 42.6 years, respectively (P = .02). Tumor histologic subtypes in BRCA1 and BRCA2 carriers were predominantly ductal (79%) followed by medullary (10%), and ductal (72%) followed by lobular (15%), respectively. A significantly higher percentage of BRCA2 tumors were human epidermal growth factor receptor 2-positive, compared with BRCA1 tumors (21.7% vs. 5.8%; P .001). Second primary cancer diagnosis was more frequent in BRCA1 compared with BRCA2 mutation carriers (36.2% vs. 10.7%; P .001), whereas there was no difference in 15-year overall survival (hazard ratio, 0.92; 95% confidence interval, 0.48-1.83; P = .804) between the 2 groups.These data confirm established observations in the pathology of BRCA-related tumors and provide further insight on the association of rare histologic entities with mutations in these genes, which can be clinically beneficial.

BACKGROUND/AIM: PTEN-loss and PIK3CA mutations have been addressed as markers of PI3K activation in breast cancer. We evaluated these markers in early high-risk breast cancer (EBC) focusing on PTEN immunohistochemistry (IHC) issues, particularly in HER2-positive disease. MATERIALS AND METHODS: We examined PTEN-loss and PIK3CA mutations in 1265 EBC patients treated with adjuvant chemotherapy within two clinical trials. Two different methods for the evaluation of PTEN IHC were used, one upfront binary (loss; no-loss) and the other initially multi-scale allowing for the classification of "grey zone" tumors with low and very low PTEN protein expression. RESULTS: PTEN-loss (33.4% and 22.1%, depending on the IHC method) and PIK3CA mutations (29.6%) were associated with ER/PgR/HER2-negative and ER/PgR-positive disease, respectively. Concordance of the two IHC methods was moderate (Cohen's kappa 0.624). PTEN-loss discrepancy and intra-tumor heterogeneity concerned "grey zone" tumors that were prevalent among HER2-positive cancers. PTEN-loss independently conferred higher risk for relapse and death. Compared to single PIK3CA mutations,single PTEN-loss was independently associated with increased risk for relapse and death. Depending on the evaluation method, in HER2-positive cancer, PTEN-loss was without- or of marginal unfavorable prognostic significance. CONCLUSION: In EBC, PTEN-loss is an independent predictor of poor outcome. When occurring singly, PTEN-loss and PIK3CA mutations have opposite prognostic impact. In HER2-positive disease, assessment of PTEN-loss by IHC appears unreliable and the marker is without clear prognostic significance.

Biomarkers of bone turnover in serum are suggestive of bone dynamics during treatment in multiple myeloma (MM). We evaluated the role of daratumumab on bone remodeling among patients with relapsed/refractory MM in the prospective, open-label, phase 2 study REBUILD. Daratumumab was administered according to the approved indication. A total of 33 out of 57 enrolled patients completed 4 months of treatment. The median percent change from baseline to 4 months in C-terminal cross-linking telopeptide of type 1 collagen (CTX) (primary endpoint) was 3.9%, with 13 (39.4%) and 11 (33.3%) patients showing at least 20% and 30% reduction in CTX levels, respectively. The median percent decrease from baseline to 4 months in tartrate resistant acid phosphatase 5b (TRACP-5b) levels (co-primary endpoint) was 2.6%, with 10 (30.3%) and 6 (18.2%) patients showing at least 20% and 30% reduction in TRACP-5b levels, respectively. However, the changes in these markers of bone catabolism were not statistically significant. Furthermore, the levels of osteocalcin, bone-specific alkaline phosphatase and procollagen type-I N-pro-peptide (bone formation markers) increased from baseline to 4 months (secondary endpoints) by 18.4%, 92.6% and 10.2%, respectively. Furthermore, the median levels of dickkopf-1 and C-C motif ligand-3 showed a significant decrease at 4 months by 17.5% and 16.0%, respectively. In conclusion, daratumumab improved bone turnover by inducing bone formation and reducing osteoblast inhibition.

Background We explored the clinical significance of tumor genotypes and immunophenotypes in non-metastatic colorectal cancer (CRC). Methods In primary tumors (paraffin blocks) from 412 CRC patients treated with adjuvant chemotherapy, we examined pathogenic mutations (panel NGS; 347 informative); mismatch repair (MMR) immunophenotype (360 informative); and CD8+ lymphocyte density (high – low; 412 informative). The primary outcome measure was disease-free survival (DFS). Results We evaluated 1713 pathogenic mutations (median: 3 per tumor; range 0-49); 118/412 (28.6%) tumors exhibited high CD8+ density; and, 40/360 (11.1%) were MMR-deficient. Compared to MMR-proficient, MMR-deficient tumors exhibited higher CD8+ density (chi-square, p

Eleni Res,1 Stella Maria Kyvelou,2 Charalambos Vlachopoulos,2 Kyriaki Manousou,1 Dimitris Tousoulis,3 Christodoulos Stefanadis,2 Dimitris Pektasides3 1Third Department of Medical Oncology, Agioi Anargyroi General Oncology Hospital of Kifissia, 2Cardiology Department, First Cardiology Clinic, Athens Medical School, Hippokration Hospital, 3Second Department of Internal Medicine, School of Medicine, University of Athens, Athens, Greece Background: The aim of the prospective study was to evaluate blood pressure (BP) and the arterial stiffness before and after chemotherapy in three subgroups of patients with metastatic colorectal, renal cell, and gastrointestinal carcinoma and exploit, if possible, the effect of chemotherapy and biological agents in the event of cardiotoxicity.Methods: A total of 171 patients were included in the study: 60 with kidney cancer, 18 with gastrointestinal stromal tumors (GISTs), and 93 with metastatic colorectal cancer. All patients were subjected to full clinical and laboratory evaluation before and after chemotherapy. Arterial-stiffness indices were assessed before the initiation and after the completion of chemotherapy by means of pulse wave velocity (PWV; Complior) and augmentation index (AIx; SphygmoCor).Results: Patients in all three cancer cohorts exhibited significantly (P

Introduction: In systemic light chain (AL) amyloidosis free light chains produced by clonal plasma cells form amyloid fibrils that are deposited in tissues and organs resulting in organ dysfunction. Cardiac involvement by AL amyloidosis is frequent and the most critical prognostic factor. Prognostic evaluation in AL is based on cardiac biomarkers and patients with very high levels of both NTproBNP (≥8500 pg/ml) and cardiac Troponins (Mayo stage 3B) are at high-risk of early death and have a median survival of just 3-6 months in most series. The outcome of stage 3B patients has not improved despite the introduction of bortezomib-based therapies and there is an urgent need for new non-toxic treatments which can also lead to rapid and deep hematologic responses. Daratumumab, an IgGκ monoclonal antibody targeting CD38, has proved highly effective either alone or in combination with bortezomib, cyclophosphamide and dexamethasone and with good tolerability in AL amyloidosis patients. Methods: EMN22 is a phase 2, open-label, multicenter study planning to enroll 40 newly diagnosed patients with stage 3B AL amyloidosis from 5 sites in Greece, the Netherlands, Italy and France. Eligible patients should have high-sensitivity troponin T (hsTnT) >54 pg/mL and NT-proBNP ≥8500 pg/mL. Primary treatment consists of daratumumab monotherapy, initially administered intravenously at 16 mg/mL, and since February 2020 administered subcutaneously at a fixed dose of 1800 mg; weekly during Cycles 1-2, every 2 weeks for Cycles 3-6 and every 4 weeks thereafter. Patients who do not achieve a hematologic VGPR or better by Cycle 4 may also receive at investigator's discretion weekly bortezomib and low dose dexamethasone. Treatment continues until disease progression according to major organ deterioration progression-free survival criteria, start of new therapy, or for a maximum of 2 years. The current analysis includes patients who started treatment at least 3 months prior to the cut-off date (16 June 2021). Results: Among 17 patients included in this analysis, 9 (53%) are still on treatment and 8 (47%) have discontinued, either due to an adverse event (n=5, 29%), or due to disease progression (n=3, 18%). Most patients were males (n=12, 71%) and median age was 65 years (range 45-84). Eastern Cooperative Oncology Group performance status was 1 for 5 (29%), 2 for 11 patients (65%), and 3 for one patient (6%). Eight (47%) patients had New York Heart Association (NYHA) class II symptoms, and 9 (53%) NYHA class IIIA. At screening, median NT-proBNP was 13,994 pg/mL (range 8,816-40,428), median hsTnT 119.1 pg/mL (range 59.8-692) and median difference of involved to uninvolved free light chains (dFLC) was 553 mg/L (range 49-2823). Apart from the heart, the median number of other organs involved was 1 (range 0-5), with nervous system (n=8, 47%) and kidneys (n=7, 41%) most commonly affected. The median number of daratumumab infusions was 13 and the median duration of therapy with daratumumab therapy was 3.7 months. Overall, 5 patients (29%) started additional treatment with bortezomib after completion of 3 cycles of daratumumab monotherapy. All 17 patients had at least one treatment-emergent adverse event. Eleven patients (65%) had a serious adverse event (SAE); 9 (53%) had at least one cardiac-related serious adverse event, and one SAE (fatigue) was related to bortezomib. Six patients (35%) suffered a fatal SAE: sepsis (n=1), sudden death (n=3), and cardiac failure (n=2). Most common grade 3 or 4 non-serious AEs were peripheral edema (n=4, 24%), dyspnea (n=3, 18%), and atrial fibrillation (n=2, 12%), and only one non-serious neutropenia grade 3 was related to daratumumab. The overall response rate was 71%, with 3 patients (18%) achieving CR, 6 (35%) VGPR, and 3 (18%) a PR, with a combined CR+VGPR rate of 53% (9/17). One-, two-, and three-month overall response rates were 65% (n=11), 71% (n=12), and 71% (n=12), and the median time to first response was 7 days while the median time to at least VGPR was 14 days. The 6-month and 12-month OS rate were 70% and 53% respectively (median OS has not been reached). Conclusions: In this prospective phase 2 study, in patients with high-risk AL amyloidosis (stage 3B), daratumumab monotherapy shows a favorable safety profile and induced very rapid and deep hematologic responses with a median time to first response of 7 days, with 53% of the patients achieving VGPR or better and a 6-month OS of 70%. Figure 1 Figure 1. Disclosures Kastritis: Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria. Minnema: Jansen-Cilag: Consultancy; Kite/Gilead: Consultancy; Alnylam: Consultancy; Celgene: Other: Hospitality; BMS: Honoraria. Dimopoulos: Amgen: Honoraria; Beigene: Honoraria; BMS: Honoraria; Takeda: Honoraria; Janssen: Honoraria. Huart: Janssen: Honoraria. Leonidakis: Health Data Specialists: Current Employment. Manousou: Health Data Specialists: Current Employment. Sonneveld: Amgen: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; SkylineDx: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Palladini: Pfizer: Honoraria; Siemens: Honoraria; Janssen Global Services: Honoraria, Other: advisory board fees.

Background: The combination of lenalidomide with dexamethasone (Rd) represents a preferred treatment backbone for newly diagnosed, transplant-ineligible patients (pts) with multiple myeloma (MM), while the addition of a third drug (i.e., daratumumab, bortezomib, carfilzomib or ixazomib) leads to higher response rates and deeper responses. Belantamab mafodotin (belamaf; GSK2857916) is a multi-modal antibody-drug conjugate that has demonstrated a clinically meaningful anti-myeloma activity with a manageable safety profile in heavily pre-treated pts with relapsed or refractory MM. Preclinical evidence suggest a potential synergy between belamaf and lenalidomide; at the same time, these drugs do not have overlapping toxicities. Thus, there is strong rationale for investigating the clinical activity of upfront belamaf in combination with Rd in transplant-ineligible MM pts. Aims: The present analysis evaluates the safety profile of belamaf in 3 different dosing schemes in combination with Rd in treatment-naïve, transplant-ineligible MM pts. Methods: BelaRd (study short title) is an open-label, single-center, phase 1/2 study conducted in Greece, aiming to enroll 66 newly diagnosed, transplant-ineligible MM pts. The study comprises 2 parts. Part 1 will evaluate 3 doses of belamaf (2.5, 1.9, and 1.4 mg/kg) in combination with Rd, each given in an individual cohort of pts, and will determine the recommended phase 2 dose (RP2D). In this part, belamaf will be administered q8w and, depending on toxicity, dosing may be rescheduled to q4w or q12w. In Part 2, a single cohort of pts will be treated with belamaf in the RP2D in combination with Rd to further evaluate the safety and clinical activity of this regimen. Part 2 will also evaluate 2 different sets of guidelines for ocular adverse events (AEs) in 2 separate groups of pts to identify the optimal method for the management of belamaf-related keratopathy. This is the initial safety analysis of Part 1 and includes pts who received ≥1 belamaf dose and were followed up for ≥8 weeks. Results: Overall, as of 16 July 2021 (cut-off date), 18 pts completed the dose-limiting toxicity (DLT) observation period, defined as specific ≥ grade 3 AEs occurring during the first cycle of study treatment, and were included in the safety analysis. The median age was 72 years (range: 65-82), and the majority of pts were male (55.6%). Lytic bone lesions were present in 12 (66.7%) pts; no pts had extramedullary disease. Most pts (9, 50.0%) had Eastern Cooperative Oncology Group performance status 0 followed by those at 1 (8, 44.4%) and 2 (1, 5.6%). Regarding the revised International Staging System, most pts (13, 72.2%) were at stage II, followed by those at stages III (2, 11.1%) and I (3, 16.7%); 3 (16.7%) pts had high-risk cytogenetics, defined as del17p13, t(4;14) or t(14;16). By the cut-off date, pts had received a median of 4 treatment cycles, with 17 (94.4%) pts still being on treatment; 1 (5.6%) pt died due to pneumonia, unrelated to the study treatment. 16 (88.9%) pts experienced ≥1 treatment emergent adverse event (TEAE). In total, 11 (61.1%) pts had ≥1 TEAE grade 3/4, of which 1 was related to belamaf; 1 (5.6%) pt experienced a serious adverse event (SAE). There were 2 cases of dose reduction and 1 case of dose delay. The most common grade 3/4 TEAEs were fatigue (5 pts, 27.8%) and rash (4 pts, 22.7%), all related to lenalidomide. One SAE was reported: pneumonia grade 5 in the 2.5 mg/kg cohort. DLTs were noted in 3 (16.7%) pts: 1 pt with grade 3 fatigue in the 1.4 mg/kg cohort and 1 pt with grade 3 rash in each of the 1.9 and 1.4 mg/kg cohorts, all related to lenalidomide. Regarding belamaf-related ocular AEs, there were 2 cases of superficial punctuate keratopathy (grade 1 and 2 each, both in the 2.5 mg/kg cohort), 10 cases of decreased visual acuity (grade 1 [8 pts, 44.4%]: 4 in the 1.9 mg/kg cohort and 4 in the 1.4 mg/kg cohort; grade 2 [2 pts, 11.1%] in the 2.5 mg/kg cohort), and 1 case of grade 1 blurred vision in 2.5 mg/kg cohort. Conclusions: In the first safety analysis of the BelaRd study no new safety signals for the belamaf-Rd combination were observed. The frequency of ocular AEs was within the anticipated range. This early analysis shows that the triplet combination can be safely administered in treatment-naïve, transplant-ineligible MM pts. The enrollment in the study is ongoing, and more safety and efficacy data will become available with the inclusion of additional pts in an updated analysis. Disclosures Terpos: Novartis: Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Honoraria. Gavriatopoulou: Janssen: Honoraria; Takeda: Honoraria; Karyopharm: Honoraria; GSK: Honoraria; Genesis: Honoraria; Sanofi: Honoraria; Amgen: Honoraria. Gkolfinopoulos: Health Data Specialists: Current Employment. Manousou: Health Data Specialists: Current Employment. Dimopoulos: Janssen: Honoraria; Beigene: Honoraria; Takeda: Honoraria; BMS: Honoraria; Amgen: Honoraria.

Introduction: Extramedullary disease (EMD) in patients (pts) with multiple myeloma (MM) is a poor prognostic feature which is not curable with currently approved treatments. Consequently, there is a significant unmet need for effective therapies with good safety profiles. Daratumumab with cyclophosphamide, bortezomib and dexamethasone (daraVCD) is a novel treatment combination with a good efficacy profile in pts with EMD based on preclinical synergistic data. Methods: EMN19 is a phase 2, open-label, multicenter study which aims to enroll 40 MM pts presenting with EMD either at diagnosis or following one line of treatment but not refractory to bortezomib-based regimens, from 8 sites in Turkey, Greece and Italy. Pts with bortezomib or daratumumab hypersensitivity, who received previous autologous stem cell transplant (ASCT) ≤12 weeks before Day 1 of treatment Cycle 1, or with previous allogenic stem cell transplant were excluded. Daratumumab was initially administered intravenously at 16 mg/mL, and since July 2020 has been administered subcutaneously at a fixed dose of 1800 mg, weekly during Cycles 1-2, every 2 weeks for Cycles 3-6, and every 4 weeks thereafter. Intravenous bortezomib 1.5 mg/m 2 and oral/intravenous cyclophosphamide 300 mg/m 2 is administered weekly, and oral/intravenous dexamethasone 20 mg is administered on Days 1, 2, 8, 9, 15, 16, 22 and 23. DaraVCD will be administered until progression or unacceptable toxicity unless refractory disease is detected by the end of Cycle 3 (progressive disease [PD] or failure to achieve a confirmed partial response [PR] or better). The present analysis includes pts who initiated study treatment ≥3 months prior to the cut-off date (01 June 2021). Results: In total, 34 patients were screened, 27 patients were enrolled, 2 relapsing patients died during the screening phase due to severe COVID-19 infection, 22 pts were analyzed (59% female; median age 56 years, range 44-77); 14 pts (64%) were still on treatment and 8 (36%) discontinued; due to inadequate response after 3 cycles of treatment (n=3, 38%), PD (n=4, 50%), death (n=1, 13%). Fourteen pts (64%) were newly diagnosed and 8 (36%) first relapsed. International Staging System stage at baseline was I, II and III for 8 (36%), 9 (41%) and 5 (23%) pts, respectively. Eastern Cooperative Oncology Group performance status was 0, 1 and 2 for 14 (64%), 7 (32%), and 1 patient (5%), respectively. On average, 3.0 (range 1-20) extramedullary plasmacytomas were observed per patient; most commonly reported sites were thorax (6 pts, 27%), brain, head and lower extremities (4 pts, 18% each). Twenty (91%) pts had ≥1 serious or non-serious treatment-emergent adverse event (TEAE); 8 pts (36.4%) experienced ≥1 sTEAEs; COVID-19 infection (n=3, 14%) urinary tract infection (n=2, 9%), infectious myocarditis, hip arthroplasty, pneumonia, cytomegaloviral pneumonia and thrombocytopenia (n=1 each, 4.5%). Thirteen (59%) pts ≥1 Grade 3/4 TEAE; neutropenia observed in 8 pts (36%), followed by thrombocytopenia (n=4, 18%) and COVID-19 infection (n=3, 14%). Overall, 16 (73%) pts missed ≥1 dose of any of the study drugs; 2 (9%) pts missed ≥1 dose due to COVID-19 infection (7 doses), 8 (36%) due to COVID-19 vaccination (37 doses), 2 (9%) due to other COVID-19-related issues (65 doses), 10 (46%) due to other safety events (104 doses) and 9 (41%) due to other reasons (25 doses). Overall, 20 cycle delays were observed in 13 (59%) pts, with median (range) delay of 12.0 (4-133) days. Two pts (9%) had a cycle delay due to COVID-19 infection (2 cycles), 1 (5%) due to COVID-19 vaccination (1 cycle), 5 (23%) due to adverse events (8 cycles), 2 (9%) due to ASCT (2 cycles) and 7 (32%) due to other reasons (7 cycles). Total number of missed doses (missed doses due to COVID-19-related issues) were 17 (3) for daratumumab, 53 (11) for bortezomib, 45 (9) for cyclophosphamide and 123 (86) for dexamethasone; 238 doses missed in total. No fatalities occurred due to any infection. Conclusions: DaraVCD was associated with a good safety profile in this high risk MM with EMD patient population. The COVID-19 impact on missed doses was greater for dexamethasone (>60% of missed doses) than other components (~20%), however overall, the pandemic did not significantly affect the patients' safety and data integrity of the study. The enrollment in the study is ongoing, and more safety and efficacy data will become available with the inclusion of additional pts in an updated analysis. Disclosures Beksac: Amgen,Celgene,Janssen,Takeda,Oncopeptides,Sanofi: Consultancy, Speakers Bureau. Tuglular: GSK: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding; Genesis Pharma: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding. Cavo: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive Biotechnologies: Consultancy, Honoraria. Gay: GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Membership on an entity's Board of Directors or advisory committees. Katodritou: GSK, Amgen, Karyopharm, Abbvie, Janssen-Cilag, Genesis Pharma, Sanofi: Honoraria, Research Funding. Merante: EMN Italy Medical Monitor: Research Funding. Manousou: Health Data Specialists: Current Employment. Sonneveld: Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; SkylineDx: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Terpos: GSK: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding.

Introduction Despite the availability of novel agents in treating multiple myeloma (MM), renal impairment (RI) remains a poor prognostic factor, and the median survival of patients (pts) with MM and RI is approximately half of that for MM pts with normal renal function. RI can affect up to 50% of pts with MM at presentation, highlighting the need for effective treatment options for this patient population. Daratumumab, an IgG1 κ human monoclonal antibody that targets CD38, has shown efficacy and a favorable safety profile in pts with relapsed or refractory MM (RRMM). The DARE study assessed the safety and efficacy of daratumumab with dexamethasone in pts with RRMM and severe RI or requiring hemodialysis. Methods DARE is a prospective, open-label, phase 2 study, conducted in eight sites in Greece and Italy. Eligible pts were adults with documented RRMM and severe RI (estimated glomerular filtration rate [eGFR] Results The study has completed accrual and 38 pts were enrolled. The pts' median (range) age was 72 (40-89) years, and most pts were male (29, 76.3%). At baseline, 37 (97.4%) pts had ECOG PS ≤1 and 34 (89.5%) were at International Staging System (ISS) stage III. By revised ISS, 20 (52.6%) and 16 (42.1%) pts were at stages II and III, respectively. Pts had a median (range) of 3 (2-6) prior systemic therapies; thirteen (34.2%) pts had undergone prior autologous stem cell transplantation. The median eGFR at baseline was 13.0 mL/min/1.73m 2 and seventeen (44.7%) pts were on dialysis at the time of enrollment. The median (range) number of cycles given was 8.0 (1.0-38.0), and the median (range) follow-up was 11.3 ( Overall, 19 (50.0%) pts had ≥1 grade 3/4 adverse event (AE), and 10 (26.3%) had ≥1 serious AE (SAE). The most common grade 3/4 AEs were anemia (6 pts, 15.8%), hyperglycemia (5 pts, 13.2%), and hypercalcemia (3 pts, 7.9%). The most common SAE was septic shock (3 pts, 7.9%). Conclusions The administration of daratumumab with dexamethasone in pts with RRMM and severe RI or requiring hemodialysis is safe and effective therapy associated with a median PFS of approximately 12 months; hematologic responses were rapid and observed within one month from treatment initiation and approximately one-fifth of pts achieved a major renal response. Almost half of the pts were on dialysis and the combination was active and safe also for those on dialysis. No new safety signals were observed with daratumumab in pts with RRMM and severe RI or in need of dialysis. Figure 1 Figure 1. Disclosures Kastritis: Janssen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Terpos: Sanofi: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Janssen-Cilag: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Symeonidis: Demo: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; WinMedica: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GenesisPharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Consultancy, Research Funding; Sanofi/Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Delimpasi: Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau. Cavo: Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive Biotechnologies: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; Novartis: Honoraria. Zamagni: Janssen: Honoraria; Bristol-Myers-Squibb: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Katodritou: GSK, Amgen, Karyopharm, Abbvie, Janssen-Cilag, Genesis Pharma, Sanofi: Honoraria, Research Funding. Kyrtsonis: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/Genesis Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria; Sanofi: Membership on an entity's Board of Directors or advisory committees. Hatjiharissi: Gilead: Honoraria; Genesis: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Leonidakis: Health Data Specialists: Current Employment. Manousou: Health Data Specialists: Current Employment. Gavriatopoulou: Sanofi: Honoraria; Genesis: Honoraria; Amgen: Honoraria; Janssen: Honoraria; GSK: Honoraria; Karyopharm: Honoraria; Takeda: Honoraria. Dimopoulos: Amgen: Honoraria; Beigene: Honoraria; Janssen: Honoraria; BMS: Honoraria; Takeda: Honoraria.

Genomic patterns of nasopharyngeal carcinomas (NPC) have as yet been studied in Southeast Asian (SEA) patients. Here, we investigated genomic patterns of locally advanced NPC Southeast European (SEE) patients treated with chemo-radiotherapy. We examined 126 tumors (89% EBV positive) from Greek and Romanian NPC patients with massively parallel sequencing. Paired tumor-cell-rich (TC) and infiltrating-lymphocyte-rich (TILs) samples were available in 19, and paired tumor – germline samples in 68 cases. Top mutated genes were BRCA1 (54% of all tumors); BRCA2 (29%); TP53 (22%); KRAS (18%). Based on the presence and number of mutations and mutated genes, NPC were classified as stable (no mutations, n=27); unstable (>7 genes with multiple mutations, all BRCA1 positive, n=21); and of intermediate stability (1-7 singly mutated genes, n=78). BRCA1 p.Q563* was present in 59 tumors (48%), more frequently from Romanian patients (p

Tumor-infiltrating lymphocytes (TILs) and their subsets contribute to breast cancer prognosis. We investigated the prognostic impact of CD3+, CD8+ and FOXP3+ TILs in patients with early intermediate/high-risk breast cancer treated with adjuvant anthracycline-based chemotherapy within two randomized trials conducted by our Group. We examined 1011 patients (median follow-up 130.9 months) and their tumors for total, stromal (s) and intratumoral (i) CD3, CD8 and FOXP3 lymphocyte density (counts/mm2) on tissue-microarray cores by immunohistochemistry. Morphological sTIL density on whole H&E-stained sections was also evaluated. The majority of TILs were CD3+. Total CD3 and CD8, sCD3 and sCD8, iCD3 and iCD8, sFOXP3 and iFOXP3 were strongly correlated (Spearman’s rho values > 0.6). High individual lymphocytic subsets and sTIL density were strongly associated with high tumor grade, higher proliferation and HER2-positive and triple-negative tumors (all p values

Background The clinical relevance of mismatch repair (MMR) status in patients with nonmetastatic cancer across tumour types remains unclear. Our goal was to investigate the prognostic role of MMR deficiency in patients with stage I-III colorectal and endometrial cancer.Methods Patients with nonmetastatic colorectal and endometrial cancer with tumour tissue available for analysis were identified through the Hellenic Cooperative Oncology Group (HeCOG)’s tumour repository. Patients had been referred to Departments of Medical Oncology affiliated with HeCOG. MMR protein expression was evaluated by immunohistochemistry. The primary outcome measure was overall survival (OS).Results From May 1990 to September 2012, 1158 patients with nonmetastatic colorectal (N = 991) and endometrial cancer (N = 167) were identified (median age: 64 years, men: 544). All patients with colorectal and 109 (65%) with endometrial cancer had received adjuvant treatment. MMR deficiency was observed in 114 (11.5%) of colorectal and 80 (47.9%) of endometrial tumours. More commonly deficient proteins were PMS2 (69 patients, 7%) and MLH1 (63 patients, 6.5%) in colorectal cancer and MSH2 (58 patients, 34.7%) in endometrial cancer. Colorectal MMR-deficient (dMMR) tumours were more likely to be right sided (65 % dMMR vs 27 % proficient MMR, pMMR; p < 0.001), high grade (31% vs 15%, χ2, p < 0.001) and with a mucinous component (64% vs 42%, p < 0.001). Endometrial dMMR tumours were more often of endometrioid histology (51.4 % endometrioid vs 20 % serous/clear cell, p = 0.020). Compared with MMR proficiency, MMR deficiency was associated with improved OS in patients with endometrial cancer (HR = 0.38, 95% CI 0.20 to 0.76, p = 0.006), but not in patients with colorectal cancer (HR = 0.73, 95% CI 0.49 to 1.09, p = 0.130). After adjusting for age, stage and grade, MMR deficiency maintained its favourable prognostic significance in patients with endometrial cancer (HR = 0.42, 95% CI 0.20 to 0.88, p = 0.021).Conclusions DMMR was associated with improved outcomes in patients with nonmetastatic endometrial cancer, but not in patients with nonmetastatic colorectal cancer who received adjuvant chemotherapy.

Background/aim Early-stage colorectal cancer (CRC) carries a wide range of survival probabilities. Novel biomarkers in this setting are eagerly awaited. Cancer stem cells (CSCs) are considered one of the reasons for treatment failure. This study sought to determine whether activation of pathways governing the function of CSC's could correlate with treatment outcomes. Materials and methods Tumor specimens from 325 patients were analyzed with immunohistochemistry (IHC) for Hedgehog and Notch pathway activation and results were correlated with prognosis. Results Positive Notch3 protein expression was an unfavorable prognostic factor for disease-free survival (DFS) and overall survival (OS) (HR=2.43, p=0.024 and HR=2.56, p=0.028, respectively). Activation of the Shh pathway showed univariately longer DFS (HR=0.49, p=0.032). Possible crosstalk between the two pathways was indicated. No further associations between pathway activation and outcome were evident. Conclusion Apart from Notch 3, activation of the pathways, as indicated by IHC expression of their components, did not result in differences in terms of DFS or OS.

Background/Aim: PTEN-loss and PIK3CA mutations have been addressed as markers of PI3K activation in breast cancer. We evaluated these markers in early high-risk breast cancer (EBC) focusing on PTEN immunohistochemistry (IHC) issues, particularly in HER2-positive disease. Materials and Methods: We examined PTEN-loss and PIK3CA mutations in 1265 EBC patients treated with adjuvant chemotherapy within two clinical trials. Two different methods for the evaluation of PTEN IHC were used, one upfront binary (loss; no-loss) and the other initially multi-scale allowing for the classification of “grey zone” tumors with low and very low PTEN protein expression. Results: PTEN-loss (33.4% and 22.1%, depending on the IHC method) and PIK3CA mutations (29.6%) were associated with ER/PgR/HER2-negative and ER/PgR-positive disease, respectively. Concordance of the two IHC methods was moderate (Cohen’s kappa 0.624). PTEN-loss discrepancy and intra-tumor heterogeneity concerned “grey zone” tumors that were prevalent among HER2-positive cancers. PTEN-loss independently conferred higher risk for relapse and death. Compared to single PIK3CA mutations, single PTEN-loss was independently associated with increased risk for relapse and death. Depending on the evaluation method, in HER2-positive cancer, PTEN-loss was without- or of marginal unfavorable prognostic significance. Conclusion: In EBC, PTEN-loss is an independent predictor of poor outcome. When occurring singly, PTEN-loss and PIK3CA mutations have opposite prognostic impact. In HER2-positive disease, assessment of PTEN-loss by IHC appears unreliable and the marker is without clear prognostic significance.

Several studies support an important role of angiogenesis in breast cancer growth and metastasis. The main objectives of the study were to investigate the immunohistochemical expression of vascular endothelial growth factor (VEGF) family ligands (VEGF-A and VEGF-C) and receptors (VEGFR1, VEGFR2 and VEGFR3) in breast cancer and their associations with clinicopathological parameters, cancer subtypes/subgroups and patient outcome. Formalin-fixed paraffin-embedded tumor tissue samples were collected from early-stage breast cancer patients treated with anthracycline-based chemotherapy within a randomized trial. Immunohistochemistry was performed on serial 2.5 μm thick tissue sections from tissue microarray blocks. High VEGF-A, VEGF-C, VEGFR1, VEGFR2 and VEGFR3 protein expression was observed in 11.8% (N = 87), 80.8% (N = 585), 28.1% (N = 202), 64.6% (N = 359) and 71.8% (N = 517) of the cases, respectively. Significant associations were observed among all proteins (all p-values

Genomic patterns of nasopharyngeal carcinomas (NPCs) have as yet been studied in Southeast Asian (SEA) patients. Here, we investigated genomic patterns of locally advanced NPC Southeast European (SEE) patients treated with chemoradiotherapy. We examined 126 tumors (89% EBV positive) from Greek and Romanian NPC patients with massively parallel sequencing. Paired tumor-cell-rich (TC) and infiltrating-lymphocyte-rich (TILs) samples were available in 19 and paired tumor-germline samples in 68 cases. Top mutated genes were BRCA1 (54% of all tumors); BRCA2 (29%); TP53 (22%); KRAS (18%). Based on the presence and number of mutations and mutated genes, NPC were classified as stable (no mutations, n = 27); unstable (7 genes with multiple mutations, all BRCA1 positive, n = 21); and of intermediate stability (1-7 singly mutated genes, n = 78). BRCA1 p.Q563* was present in 59 tumors (48%), more frequently from Romanian patients (p 0.001). No pathogenic germline mutations were identified. NPC exhibited APOBEC3A/B and nucleotide-excision-repair-related mutational signatures. As compared to TC, TILs demonstrated few shared and a higher number of low frequency private mutations (p 0.001). In multivariate analysis models for progression-free survival, EBV positivity was a favorable prognosticator in stable tumors; BRCA1 mutations were unfavorable only in tumors of intermediate stability. In conclusion, other than described for SEA NPC, somatic BRCA1 mutations were common in SEE NPC; these were shared between TC and TILs, and appeared to affect patient outcome according to tumor genomic stability status. Along with the identified mutational signatures, these novel data may be helpful for designing new treatments for locally advanced NPC.

Background: Epidermal growth factor receptor (EGFR) aberrations have been implicated in the pathogenesis of triple-negative breast cancer (TNBC) but their impact on prognosis and, therefore, druggability, remain controversial. Herein, we studied EGFR aberrations at different molecular levels and assessed their prognostic impact in patients with operable TNBC treated with adjuvant anthracycline-based chemotherapy. Materials and Methods: We evaluated the prognostic impact of EGFR gene status by fluorescent in situ hybridization (FISH), EGFR coding mutations by Sanger and next-generation sequencing, relative EGFR messenger RNA (mRNA) levels by qPCR (upper quartile) and EGFR and p53 protein expression by immunohistochemistry (IHC), in 352 centrally-assessed tumors from an equal number of TNBC patients. Results: Approximately 53.5% of the tumors expressed EGFR, 59.3% p53 and 35.9% both EGFR and p53 proteins; 4.1% showed EGFR gene amplification and 4.4% carried EGFR mutations. The latter were located outside the druggable kinase domain region and presented at low frequencies. Amplification and mutations overlapped only in one case of glycogen-rich carcinoma. EGFR and CEN7 copies were higher in tumors from older patients (p=0.002 and p=0.003, respectively). Patients with amplified tumors (n=11) had excellent prognosis (0 relapses and deaths). Upon multivariate analysis, high EGFR copies conferred significantly favorable disease-free survival (HR=0.57, 95% CI 0.36-0.90, Wald’s p=0.017) and high CEN7 copies favorable overall survival (HR=0.49, 95% CI=0.29-0.83, Wald’s p=0.008). Patients with EGFR–/p53+ and EGFR+/p53– tumors had significantly higher risk for relapse than those with EGFR–/p53– and EGFR+/p53+ tumors (HR=1.73, 95% CI=1.12-2.67, Wald’s p=0.013). Conclusion: EGFR gene amplification and mutations are rare in TNBC, the latter of no apparent clinical relevance. Surrogate markers of EGFR-related chromosomal aberrations and combined EGFR/p53 IHC phenotypes appear to be associated with favorable prognosis in patients with operable TNBC receiving conventional adjuvant chemotherapy.

e24286Background: CXCL13 mRNA expression has been associated with subtype specific outcome in breast cancer and its prognostic markers. Methods: Early breast cancer patients with T1-4, N1-2, M0 wer...

e15606Background: Right- and left-sided colorectal cancers (CRC) demonstrate a distinct clinical behavior. Whether this heterogeneity is associated with specific molecular profiles has yet to be de...

Background The Notch pathway has been implicated in triple-negative breast cancer (TNBC). Herein, we studied the subcellular localization of the less investigated Notch2 and Notch3 and that of the Jagged1 (Jag1) ligand in patients with operable TNBC. Patients and methods We applied immunohistochemistry for Notch2, Notch3 and Jag1 in 333 tumors from TNBC patients treated with adjuvant anthracycline-based chemotherapy. We evaluated cytoplasmic (c), membranous (m) and nuclear (n) protein localization. Results c-Notch2 (35% positive tumors), c-Notch3 (63%), c-Jag1 (43%), m-Notch3 (23%) and n-Jag1 (17%) were analyzed individually and by using hierarchical clustering for prognostic evaluation. Upon multivariate analysis, compared to high m-Notch3 in the absence of n-Jag1 (cluster 4), all other marker combinations (clusters 1, 2, 3) conferred significantly higher risk for relapse (p Conclusion Specific Notch3 and Jag1 subcellular localization patterns may provide clues for the behavior of the tumors and potentially for Jag1 targeting in TNBC patients.

BACKGROUND: Infectious diseases are among the major causes of death worldwide. We evaluated the trends of mortality due to septicemia in Greece and compared it with mortality due to other infections. METHODS: Data on mortality stratified by cause of death during 2003-2010 was obtained from the Hellenic Statistical Authority. Deaths caused by infectious diseases were grouped by site of infection and analyzed using SPSS 17.0 software. RESULTS: 45,451 deaths due to infections were recorded in Greece during the 8-year period of time, among which 12.2% were due to septicemia, 69.7% pneumonia, 1.5% pulmonary tuberculosis, 0.2% influenza, 0.5% other infections of the respiratory tract, 7.9% intra-abdominal infections (IAIs), 2.5% urinary tract infections (UTIs), 2.2% endocarditis or pericarditis or myocarditis, 1.6% hepatitis, 1% infections of the central nervous system, and 0.7% other infections. A percentage of 99.4% of deaths due to septicemia were caused by bacteria that were not reported on the death certificate (noted as indeterminate septicemia). More deaths due to indeterminate septicemia were observed during 2007-2010 compared to 2003-2006 (3,558 versus 1,966; p