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Background: The combination of endocrine therapy with the cyclin-dependent kinases 4/6 inhibitor palbociclib was proven to be effective for the treatment of hormone receptor (HR)-positive/HER2-negative metastatic breast cancer (MBC). Although generally well tolerated, treatment delays and dose reductions are frequently observed with palbociclib, mainly due to severe neutropenia. Predictors of palbociclib-related toxicities are still unknown, as well as the clinical relevance of its relative dose intensity (RDI). Henceforth, this study aimed to identify baseline clinicopathological features associated with a RDI Methods: We reviewed data of 150 consecutive patients with HR-positive/HER2-negative MBC patients treated with palbociclib at two Italian cancer centers from 2017 to 2019. Eligible patients must have received at least 3 cycles of treatment. Those who experienced early suspension due to unacceptable toxicities were still eligible. RDI was calculated as the ratio of actual dose intensity (cumulative administered dose/treatment duration) and planned dose intensity (cumulative planned dose/planned treatment duration). The association of both RDI Results: Overall, 142 patients were deemed eligible. Of these patients, 98 (69.0%) were treated with palbociclib plus fulvestrant, 44 (31.0%) with palbociclib plus aromatase inhibitors, and 73 (51.4%) in the first-line setting. The median number of administered palbociclib cycles was 8 (range: 1-24) and 61 patients (43.0%) required at least a first-level dose reduction (29 within 3 months). Furthermore, the median time to first dose reduction was 3.22 months, with neutropenia being responsible for 85.24% of first-level dose reductions. In the whole cohort, median RDI was 90.5% (95.1% for patients without dose reduction and 80% for those who had received a dose reduction). Notably, 28 patients (19.7%) experienced a RDI Conclusions: In our analysis, baseline weight and WBC were statistically associated with a RDI Citation Format: Giacomo Pelizzari, Elisa Bertoli, Marco Giavarra, Carla Corvaja, Lorenzo Gerratana, Debora Basile, Michele Bartoletti, Camilla Lisanti, Lucia Bortot, Silvia Buriolla, Mattia Garutti, Debora Avoledo, Marta Bonotto, Lucia Da Ros, Silvia Bolzonello, Mauro Mansutti, Paola Di Nardo, Gianpiero Fasola, Simon Spazzapan, Alessandro M Minisini, Fabio Puglisi. Predictors of relative dose intensity and early dose reduction in patients with metastatic breast cancer treated with palbociclib and endocrine therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-14-08.

Historically, metastatic melanoma was considered a highly lethal disease. However, recent advances in drug development have allowed a significative improvement in prognosis. In particular, BRAF/MEK inhibitors and anti-PD1 antibodies have completely revolutionized the management of this disease. Nonetheless, not all patients derive a benefit or a durable benefit from these therapies. To overtake this challenges, new clinically active compounds are being tested in the context of clinical trials. CDK4/6 inhibitors are drugs already available in clinical practice and preliminary evidence showed a promising activity also in melanoma. Herein we review the available literature to depict a comprehensive landscape about CDK4/6 inhibitors in melanoma. We present the molecular and genetic background that might justify the usage of these drugs, the preclinical evidence, the clinical available data, and the most promising ongoing clinical trials.

Simple Summary Immunotherapy has revolutionized the therapeutic landscape of melanoma. However, the absence of clinically validated predictive biomarkers is one of the major causes of unpredictable efficacy of immunotherapy. Indeed, the availability of predictive biomarkers could allow a better stratification of patients, suggesting which type of drugs should be used in a certain clinical context and guiding clinicians in escalating or de-escalating therapy. However, the difficulty in obtaining clinically useful predictive biomarkers reflects the deep complexity of tumor biology. Herein, we review the available literature to depict the most useful or promising biological biomarker able to predict immunotherapy response in melanoma. We also make a meta-analysis regarding PDL1 expression in melanoma and immune checkpoint response. Abstract Immunotherapy has revolutionized the therapeutic landscape of melanoma. In particular, checkpoint inhibition has shown to increase long-term outcome, and, in some cases, it can be virtually curative. However, the absence of clinically validated predictive biomarkers is one of the major causes of unpredictable efficacy of immunotherapy. Indeed, the availability of predictive biomarkers could allow a better stratification of patients, suggesting which type of drugs should be used in a certain clinical context and guiding clinicians in escalating or de-escalating therapy. However, the difficulty in obtaining clinically useful predictive biomarkers reflects the deep complexity of tumor biology. Biomarkers can be classified as tumor-intrinsic biomarkers, microenvironment biomarkers, and systemic biomarkers. Herein we review the available literature to classify and describe predictive biomarkers for checkpoint inhibition in melanoma with the aim of helping clinicians in the decision-making process. We also performed a meta-analysis on the predictive value of PDL-1.

Background Endocrine therapy (ET) plus cyclin-dependent-kinases 4/6 inhibitors (CDK4/6i) represents the standard treatment for luminal-metastatic breast cancer (MBC). However, prospective head-to-head comparisons are still lacking for 1st line (L) options, and it is still crucial to define the best strategy between 1st and 2nd L. Materials and methods 717 consecutive luminal-MBC pts treated between 2008 and 2020 were analyzed at the Oncology Department of Aviano and Udine, Italy. Differences about survival outcomes (OS, PFS and PPS) were tested by log-rank test. The attrition rate (AR) between 1st and 2ndL was calculated. Results At 1stL, pts were treated with ET (49%), chemotherapy (CT) (31%) and ET-CDKi (20%) while, at 2ndL, 33% received ET, 33% CT and 8% ET-CDKi. Overall AR was 10%, 7% for CT, 8% for ET and 17% for ET-CDKi. By multivariate analysis, 1stL ET-CDK4/6i showed a better mPFS1 and OS. Moreover, 2ndL ET-CDK4/6i demonstrated better mPFS2 compared to ET and CT. Notably, 1stL ET-CDKi resulted in higher mPFS than 2ndL ET-CDKi. Intriguingly, 1stL ET-CDK4/6i was associated with worse mPPS compared to CT and ET. Secondarily, 1stL ET-CDK4/6i followed by CT had worse OS compared to 1stL ET-CDK4/6i followed by ET. Notably, none of baseline characteristics at 2ndL influenced 2ndL treatment choice (ET vs. CT) after ET-CDKi. Conclusion Our real-world data demonstrated that ET-CDKi represents the best option for 1stL luminal-MBC compared to ET and CT. Also, the present study pointed out that 2ndL ET, potentially combined with other molecules, could be a feasible option after CDK4/6i failure, postponing CT on later lines., Highlights • To define the best treatment strategy for 1st and 2nd L is crucial for luminal mBC. • 1st L CDK4/6i-based therapies represent the standard treatment in luminal mBC. • This study confirmed the key role of 1st L CDK4/6i on a real-world cohort. • This study suggested a preeminent role for ET after first-line CDK4/6i. • The 2nd line ET with other molecules could allow to further postpone CT.

Background: Over the last few years, the introduction of newer systemic therapies (e.g. CDKi) significantly changed the treatment paradigm of patients (pts) with MBC. The purpose of this work is to evaluate the impact of CDKi introduction in clinical practice in terms of medical oncology workload. Methods: We examined a consecutive series of 492 pts who received therapy for MBC in Academic Hospital of Udine during two historical cohorts A (2016-2017) and B (2018-2019), respectively before and after the first CDKi approval in Italy. Data about 2020 were not collected due to confounding effect of SARS-CoV-2 pandemic. Pts with no luminal MBC or enrolled in clinical trial were excluded. We performed descriptive analyses to examine any differences in terms of number and type of outpatient visits to the oncology department (i.e. planned visits, unplanned presentations and i.v. treatment sessions) between the two cohorts. Results: We analyzed a total number of 2,645 oncology activities deriving from 42 pts (cohort A) and 57 pts (cohort B) who started first line treatment for luminal MBC. Median age was 66 and 70 years respectively. In the first group, pts receiving chemotherapy were 23.8% and those treated with CDKi were 7,14%. In the second group, chemotherapy was administered in 22.8% of pts and CDKi in 49.12%. In cohort A, number of planned visits, unplanned presentations and i.v. treatment sessions were respectively 643, 82 and 418. In cohort B, number of planned visits, unplanned presentations and treatment sessions were 892, 114 and 496. During the period of observation (two years), for each pts mean number of planned visits were 15,30 (cohort A) vs 15,64 (cohort B), mean number of unplanned presentations were 1,95 (cohort A) vs 2 (cohort B), treatment i.v. sessions were 9,9 (cohort A) vs 8,7 (cohort B). Conclusions: With the limits of a retrospective analysis, no differences were found between two cohorts of pts. Notably, there was a slight decrease of i.v. treatment sessions after CDKi introduction. Other analysis are ongoing to evaluate the workload in terms of instrumental and blood chemistry tests. This data further support the handy use of this drugs into clinical practice. Legal entity responsible for the study: Azienda Sanitaria Universitaria Friuli Centrale (ASUFC) Funding: Has not received any funding. Disclosure: M. Mansutti: Financial Interests, Institutional, Advisory Board: AstraZeneca;Financial Interests, Institutional, Advisory Board, invited speaker: Novartis;Financial Interests, Institutional, Advisory Board, invited speaker: Eli Lilly;Financial Interests, Institutional, Advisory Board, invited speaker: Pfizer;Financial Interests, Institutional, Advisory Board: MSD Italia;Financial Interests, Institutional, Advisory Board, invited speaker: EISAI;Financial Interests, Institutional, Advisory Board: Pierre Fabre;Financial Interests, Institutional, Advisory Board: Roche;Financial Interests, Institutional, Advisory Board: Celgene. All other authors have declared no conflicts of interest.

Summary Background Body composition, has been established as a risk factor for colorectal cancer diagnosis and disease progression. Aim of this study was to investigate the prognostic role of adiposity, especially visceral fat (VAT), in patients (pts) with metastatic colorectal cancer (MCRC). Material and methods A retrospective cohort of 71 MCRC pts treated between 2013 and 2017 was evaluated. VAT was measured as cross-sectional (cm2) area at the L3 level divided by the square of the height (m2). A ROC analysis was performed to define a prognostic threshold according to VAT. Results Before first-line therapy start, 40 pts (56%) had a body mass index (BMI) > 25 kg/m2. The obtained cut-off value for VAT was 44. Median OS was 30.97 months. At univariate analysis, primary tumor resection (HR 0.40, p = 0.029), VAT>44 (HR 2.85, p = 0.011) and metastasectomy (HR 0.22, p = 0.005) were significantly associated with OS. By multivariate analysis, VAT>44 (HR 2.6; p = 0.020) and metastasectomy were still significantly associated with OS. Conclusion This exploratory study suggests a prognostic role for VAT in MCRC pts, with higher VAT values predicting worse outcome.

Introduction/Background Women aged ≥65 represent nearly 50% of ovarian cancer (OC) patients (pts). However, elderly OC pts are less likely to receive optimal treatment. Furthermore, they are significantly under-represented in clinical trials and multidimensional geriatric assessment is still underused. The present study aims to provide an overview of real-life treatment strategies for elderly advanced-OC pts and to investigate clinico-pathological features that could potentially drive choice of first-line treatment. Methodology A retrospective analysis was conducted on a consecutive series of 45 OC pts aged ≥69 treated with first-line chemotherapy (1L_CT) from 2011 to 2018 at CRO Aviano National Cancer Institute (Italy). Factors associated with treatment choice and rate of adverse events were investigated through Fisher-exact test; differences in progression free survival (PFS) and overall survival (OS) were tested by log-rank test. Results 67% of pts received 1L_CT with a standard carboplatin-paclitaxel combination (CPC). Conversely, 33% received a monotherapy (MT) (31% with carboplatin, 2% with paclitaxel). ECOG PS ≥1 was the only factor significantly associated with choice of MT (P=0.021). No differences were observed between CPC and CPC with dose reductions (CPCdr), neither in terms of PFS (HR=1.29 P=0.59) nor OS (HR=1.40 P=0.56). On the other hand, MT was associated with shorter PFS (HR=4.35 P=0.001) and OS (HR=4.48 P=0.005). No differences in treatment discontinuation rate, neutropenia, thrombocytopenia, neuropathy, constipation, diarrhoea and asthenia in CPC, CPCdr and MT were detected (P>0.05). Conclusion The present study confirms CPC as the standard first-line chemotherapy also in advanced OC elderly pts and suggests that CPCdr is preferable to MT regimens. Notwithstanding the limitations due to the small sample size, the evaluated regimens showed a comparable toxicity profile. Notably, clinical decision-making was mainly driven by PS ECOG highlighting the pivotal role of multidimensional geriatric assessment for pts stratification. Further prospective studies are needed to investigate improved tailored strategies. Disclosure Nothing to disclose.

e13008 Background: Liquid biopsy-based biomarkers, including circulating tumor DNA (ctDNA), are increasingly important for the characterization of metastatic breast cancer (MBC). Currently, CA15.3 is the most commonly used serum marker for monitoring disease burden. To date, no liquid biopsy-based biomarkers have been proposed for this scope in clinical practice. Methods: The CRO-2018-56 multicenter study prospectively enrolled 83 patients (pts) with luminal-like MBC treated with first line endocrine therapy (ET) and CDK4/6 inhibitors. All pts were characterized for ctDNA through droplet digital PCR (ddPCR) in from 2018 to 2021. Clinicopathological and laboratory characteristics at baseline were tested for associations with tumor markers, ACTB fragments lengths, methylation status of ESR1 main promoters (expressed as promA and promB ratio, i.e., met_ratio) and ESR1/PIK3CA mutational status through Kruskal-Wallis test and Chi-square test. Prognosis was tested in terms of Progression Free Survival (PFS) and Overall Survival (OS) through log-rank test. Results: At baseline, in 26 (31%) pts disease was diagnosed as de novo metastatic, 66 (80%) pts had < 3 of metastatic sites, and 41 (49%) pts had < 5 of metastatic lesions. Bone metastases were detected in 53 (64%) pts, liver metastases in 21 (25%) pts, and lung lesions in 30 (36%) pts. A ctDNA-detected ESR1 mutation and a PIK3CA mutation were found in 15% of pts and in 34% pts, respectively. Met_ratio was > 1.5 in 35 (42%) of pts. Median CA15.3 was 48.2 U/mL and median CEA was 3.8 U/mL. Number of liver metastases and number of metastatic sites were significantly higher in pts with ESR1 mutation (respectively, P = 0.0055 and P = 0.0208). CA15.3 and ctDNA yield were significantly higher in pts with number of metastatic sites ≥ 3, (respectively, P = 0.0164, and P = 0.0239), while number of metastatic sites ≥ 3 and number of metastatic lesions ≥ 5 were significantly associated with CEA > 3.8 U/mL (respectively, P = 0.039, and P = 0.029). Presence of bone metastases was significantly associated with PIK3CA mutation (P = 0.040), while number of metastatic sites ≥ 3 was significantly associated with ESR1 mutation (P = 0.022). No association with tumor burden was observed for different ACTB DNA fragments lengths. Met_ratio > 1.5 was significantly associated with lower number of metastatic lesions (P = 0.031). Number of metastatic sites ≥ 3, high ctDNA yield and CEA were associated with worse OS (respectively P = 0.0465, P = 0.0250 and P = 0.0474), while only CEA impacted on PFS (P = 0.0097). Conclusions: In pts with luminal-like MBC, some liquid biopsy-based biomarkers (i.e., ctDNA-detected ESR1 and PIK3CA mutations, ctDNA yield) were significantly associated with the burden of disease. The potential clinical validity and utility of these results deserve to be tested in an expansion cohort.

e16102 Background: Lactate dehydrogenase (LDH) is recognized as indirect marker of tumor hypoxia and angiogenesis for several solid tumors. Ramucirumab is the first antiangiogenic agent approved for second-line therapy in advanced gastric cancer (GC), alone or in association with chemotherapy. To date, no reliable biomarkers can predict the potential benefit from anti-VEGFR2 treatment. This retrospective multicenter study aimed to assess the prognostic role of baseline LDH levels in patients (pts) undergoing second-line treatment for advanced GC. Methods: The study analyzed a retrospective cohort of consecutive advanced GC pts treated with second line therapy at IRCCS, CRO of Aviano and at Mauriziano Hospital of Torino, Italy, from 2010 to 2020. LDH levels prior to second-line treatment were classified as low-normal or high and standardized according to the upper limit of the reference range. To better determine the optimal LDH cut-off value, ROC analysis was performed (using PFS < 3 months as binary outcome). Normalized LDH values were subsequently sorted according to the ROC curve cut-off in order to test the association with overall survival (OS) through the Kaplan-Meier method and compared using the Log-Rank test. A multivariate Cox regression analysis assessed the prognostic impact of normalized LDH levels for OS calculated from the start of second line treatment. Results: Overall, 125 pts were enrolled. Of these, 81 pts (64.80%) received ramucirumab alone or plus paclitaxel as second line treatment, while 44 (35.20%) had taxanes or fluoropyrimidines combined with irinotecan. Median age was 68 years, 93% had an ECOG PS ≤ 1, 64.80% was first diagnosed with metastatic disease and 40.80% underwent primary tumor resection. Median second line PFS and OS were 4.2 and 7.9 months, respectively. Baseline LDH values were available for 99 pts. ROC analysis identified a normalized LDH value of 0.83 as the optimized cut-off point to define pts with poor prognosis. At univariate analyses, surgery of the primary tumor (HR 0.51, 95% CI 0.31-0.82, p = 0.005) was associated with better OS, while low-normal BMI ( < 25 kg/m2) at second line start (HR 1.99, 95% CI 1.21-3.28, p = 0.007), normalized LDH values ≥ 0.83 (HR 1.86, 95% CI 1.13-3.07, p = 0.015) and PS > 1 (HR 5.65, 95% CI 2.29-13.92, p < 0.001) were associated with poorer outcome. At multivariable model, only PS > 1 was independently associated with poor prognosis (HR 9.93, 95% CI 3.27-30.08, p < 0.001). Subgroup analyses showed no significant heterogeneity in OS outcome according to normalized LDH levels between patients treated with or without ramucirumab. Conclusions: Elevated LDH levels are indicators of worse outcome in advanced gastric cancer pts. Notably, the LDH cut-off value identified a poor prognosis subgroup among pts with normal baseline levels, suggesting that current laboratory ranges could be suboptimal for patient stratification.

1027 Background: The combination of ET and CDK4/6i is the current standard of care for hormone receptor (HR)-positive/HER2-negative MBC (luminal MBC), with neutropenia being the main dose limiting toxicity. We previously observed the potential association between leucocyte count (WBC) and different fractions of cell free circulating DNA (cfDNA) (Bortot et al 2020). The present study aimed to evaluate the feasibility of a cfDNA-based workflow as a new tool to assess the risk of treatment induced neutropenia. Methods: The study analyzed a prospective cohort 83 luminal MBC patients (pts) treated with first line ET and CDK4/6i in the CRO-2018-56 multicenter study from 2018 to 2021. cfDNA was characterized through droplet digital PCR (ddPCR) based on different ACTB DNA fragments lengths: short (s), medium (m) and long (l). Blood samples were collected before treatment start (BL) and at the first clinical evaluation after 3 months (E1). Associations between clinical characteristics, neutropenia and cfDNA were explored through Kruskal Wallis, time to G3 neutropenia (NG3) (TTN) was analyzed through log-rank and Cox regression. Results: Neutropenia was G3 in 44 out of 83 pts (53%) and G4 in 2 pts (2%). Median TTN was 1.8 months, 60% of NG3 occurred within 3.7 months. Overall, 74 pts (89%) resolved toxicity within 7 days, 10 pts (12%) reduced CDK4/6i dose after NG3. BL neutrophils count (Neu) and WBC were significantly lower in pts that developed NG3 (P = 0.0013 and P = 0.0020 respectively). De novo metastatic pts had numerically higher Neu (median 4825 vs 3895), but only a numerically lower risk of NG3 was observed (HR 0.53 P = 0.064). Although bone involvement was not associated with risk of developing NG3, the total number of metastatic lesions was associated with higher NG3 (P = 0.0016). In particular, > 5 metastatic lesions were associated with higher NG3 risk (p = 0.013). E1 ACTB_m was significantly lower with respect to BL in pts that experienced NG3 (median 100% vs 16%, P = 0.0136 in NG3 no vs yes) with a consistent impact on the risk of NG3 (HR: 2.81, P = 0.025). No associations were observed for the other ACTB fragment length fractions. BL Neu and ACTB_m dichotomized at the median were then combined to describe 4 distinct TTN risk groups (P = 0.0006). Interestingly, pts with low BL Neu and low E1 ACTB_m had a median TTN of 0.9 months, while pts with high BL Neu and high E1 ACTB_m have not experienced NG3 after a median follow-up of 16.1 months. Conclusions: The present study proofed the concept of using cfDNA to provide clinically meaningful data not only about tumor biology, but also for a comprehensive patient assessment. Based on these results, a prospective study focused on a multiparametric neutropenia risk assessment will be started.

Background Patients (pts) with melanoma brain metastases (BM) have a historically poor prognosis, with a reported median overall survival (mOS) of 4-6 months. Aim of this study is to evaluate predictive factors of survival in pts with melanoma BM. Secondly, a multivariate model was used to define groups with distinct prognosis. Methods Consecutive pts with melanoma BM treated in two Italian cancer centers were included in this 10-year retrospective cohort study (2008-2018). Baseline clinicopathological factors, systemic and loco-regional treatments were registered. The Kaplan-Meier method and the Cox model were used to analyze the association of prognostic factors and OS. Results 150 pts with melanoma BM were enrolled in this study: 42% with a single BM, 51.3% with ≥ 3 extracranial metastatic sites and 38% with an ECOG performance status (PS) of 0. About 50.7% of pts had a BRAF mutation. Notably, 56% of pts were asymptomatic at BM diagnosis, and 40% presented high LDH levels at baseline. Overall, mOS after BM diagnosis was 5.78 months (95% CI 4.80-6.67), and median intracranial progression-free survival was 4.63 months (95% CI 3.81-5.12). According to treatment modality, stereotactic radiosurgery/neurosurgery plus systemic therapy showed the best outcome (mOS 12.32 months, 95% CI 7.92-25.30). A multivariate model was used to identify baseline prognostic factors independently associated with OS (Table). Conversely, sex and symptomatic BM did not significantly impact on OS. Predicted survival functions defined 3 distinct prognostic groups (P Table . 1363P Covariates HR 95% CI P Points BRAF wild type 1.95 1.22-3.12 1 BM > 1 2.20 1.35-3.59 1 LDH ≥ 2 x upper normal limit 1.83 1.07-3.11 0.026 1 ECOG PS > 0 2.68 1.62-4.43 0.0001 1 Extracranial metastatic sites ≥ 3 1.91 1.17-3.1 1 Age ≥ 65 1.86 1.15-3.02 0.012 1 Conclusions This score can be useful for stratifying prognosis in pts with melanoma BM. Prospective studies are needed to validate this score and to explore how it may guide treatment strategy. Legal entity responsible for the study Dipartimento di Oncologia, Azienda Sanitaria Universitaria Integrata di Udine. Funding Has not received any funding. Disclosure F. Puglisi: Honoraria (self), Advisory / Consultancy: Amgen; Advisory / Consultancy: Celgene; Advisory / Consultancy: Eisai; Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Research grant / Funding (self): Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Research grant / Funding (self): Roche; Honoraria (self): Pierre Fabre; Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: Takeda; Research grant / Funding (self): Astrazeneca. All other authors have declared no conflicts of interest.

577 Background: It is matter of current debate which would be the best chemotherapy backbone of neoadjuvant HER2-targeted therapy for HER2+ BC. The TRAIN 2 trial showed no significant difference in terms of pathological complete response (pCR) when anthracyclines–based (CTA) or anthracyclines–free regimens (CT) were combined with dual HER2 blockade. However, it remains unclear how anthracyclines may influence the relative benefit across different anti-HER2 treatments. Methods: A systematic review was conducted which included all phase II/III randomized clinical trials (RCTs) comparing different neoadjuvant regimens for HER2+ BC. pCR (yT0/isN0) was the outcome of interest. Indirect comparisons of all combination of anti-HER2 agents with CTA or CT were estimated with a random-effects frequentist NMA. Estimated pCR rates were inferred adopting a Bayesian NMA. Results: 17 RCTs (3933 patients) were included. Overall, 8 arms were identified, comprising all possible combinations of CTA and CT with trastuzumab (H), lapatinib (L) and dual HER2 blockade (D) but also CTA and D only. Odds ratios (OR) for pCR and 95% confidence interval (CI) of selected NMA comparisons are shown in the table. Estimated rates of pCR for each treatment and 95% credible interval (CrI) are reported in the table. Conclusions: Through indirect comparisons, no significant pCR gain was found for CTA vs CT when combined to D, H and L. In particular, considering double vs single-agent anti-HER2 regimens, D-CT remains superior to H-CTA, supporting a possible omission of anthracyclines when dual anti-HER2 block is used. On the contrary, our pooled estimate suggests a more relevant role for anthracyclines when comparing H-CT/A vs CTA. Moreover, we estimated a 4% pCR gain for D-CTA vs D-CT, and an 8% higher pCR rate for H-CTA vs H-CT. [Table: see text]

e16118 Background: Changes in peripheral blood cells composition may reflect immune microenvironment and its role in cancer growth. High monocyte-to-lymphocyte ratio (MLR) could be a marker of tumor’s recruitment of suppressive cells, showing a prognostic role. This study aimed to assess the prognostic impact of macrophage infiltration and MLR in stage III colon cancer (CC) patients (pts). Methods: This multicentric study retrospectively analyzed a consecutive cohort of 423 CC pts treated between 2008-2019 at the Cancer Centre of Aviano (Italy) (n = 300) and at the European Georges Pompidou Hospital of Paris (France) (n = 123). The association of MLR with disease-free survival (DFS) and overall survival (OS) was evaluated with Cox regression analyses. Random Forrest was implemented on python using h2oai. Performance was assessed in terms of accuracy (ACC) and Matthews Coefficient (MCC). Analyses was adjusted on classical prognostic factors of stage III CC such as pT, pN, grade, location, ECOG PS. Results: Overall, 77% had pT1-3, 30% pN2 and 73% G1-2 tumors. Interestingly, 25% had a lymphatic and vascular invasion, 42/230 (18%) had MSI status, 69/152(45%) and 19/114 (13%) were KRAS and BRAF mutant. 56% had CEA > 5. Pts were treated with fluoropyrimidine and oxaliplatin as adjuvant therapy. Notably, 130 cases were analyzed according to lymphocytic and macrophage infiltration (CD163, CD68, CD3, CD8). Of them, 78% had a CD163/CD8 ratio ≤3 and 74% a CD8/CD3 ratio ≤1.5. At median follow-up of 57 months, median DFS and OS were not reached, 31% of pts relapsed and 23% dead. By multivariate analysis, including statistically significant prognostic variables, CD163/CD8 ratio (HR 1.15, p = 0.039, 95%C.I. 1.1-1.32) and MLR > 0.45 (HR 2.98, p = 0.008, 95%C.I. 1.33-6.67) were associated with worse DFS. By multivariate analysis for OS, including statistically significant confounding variables, MLR > 0.45 (HR4.32, P = 0.012, 95%C.I. 1.37-9) and BRAF mutation predicted worse OS. According random survival forest for OS, CD68/CD3 were the first variable of importance (0.06), followed by MLR (0.009) and CD8 (0.007). Interestingly, high MLR followed by CEA, MSI, KRAS were the features linked with organotropism on liver (ACC 0.6 ±0.3), while high MLR, KRAS, pN, pT were mainly linked with lung colonization (ACC 0.6 ±0.2). Conclusions: High pre-treatment levels of MLR and CD163/CD8 ratio in stage III CC are independently associated with worse prognosis. The present study paves the way to a prospective validation of these promising cost-effective biomarkers.