BackgroundDespite contributions provided by the recent clinical trials, several issues and challenges still remain unsolved in adjuvant colon cancer (CC). Hence, further studies should be planned to better refine risk assessment as well as to establish the optimal treatment strategy in the adjuvant setting. However, it is necessary to request adequate, contemporary and relevant variables and report them homogeneously in order to bring maximal information when analyzing their prognostic value.Material and methodsThe project was devised to gain a consensus from experts engaged in the planning, accrual and analyses of stage II and III CC clinical trials, to identify mandatory and recommended baseline variables in order to i) harmonize future data collection worldwide in clinical trials dedicated to adjuvant treatment of CC; ii) propose guidance for Case Report Forms to be used for clinical trials in this setting. A total of 72 questions related to variables that should be reported and how to report them in adjuvant clinical trials were approved and then voted to reach a final consensus from panelists.ResultsData items on patient-related factors, histopathological features, molecular profile, circulating biomarkers and blood analyses were analyzed and discussed by the whole expert panel. For each item, we report data supporting the acquired consensus and the relevant issues that were discussed. Nineteen items were deemed to be mandatory for resected stage III patients and 24 for resected stage II disease. In addition, 9 and 4 items were judged as recommended for stage III and II, respectively.ConclusionIn our opinion, these 28 variables should be used and uniformly reported in more comprehensive CRFs as research groups design future clinical trials in the field of adjuvant colon cancer.

Background: The combination of encorafenib with cetuximab has become the standard of care in patients with BRAF V600E-mutated metastatic colorectal cancer (mCRC) after a prior systemic therapy. This study aims to describe the efficacy and safety of encorafenib/cetuximab +/- binimetinib in patients with BRAF V600E-mutated mCRC in a real-world setting. Patients and methods: This retrospective study included patients with BRAF V600E-mutated mCRC who received this combination from January 2020 to June 2022 in 30 centers. Results: A total of 201 patients were included, with 55% of women, a median age of 62 years, and an Eastern Cooperative Oncology Group performance status (ECOG-PS) >1 in 20% of cases. The main tumor characteristics were 60% of right-sided primary tumor, 11% of microsatellite instability/mismatch repair deficient phenotype, and liver and peritoneum being the two main metastatic sites (57% and 51%). Encorafenib/cetuximab +/- binimetinib was prescribed in the first, second, third, and beyond third line in 4%, 56%, 29%, and 11%, respectively, of cases, with the encorafenib/cetuximab/binimetinib combination for 21 patients (10%). With encorafenib/cetuximab treatment, 21% of patients experienced grade >= 3 adverse events (AEs), with each type of grade >= 3 AE observed in <5% of patients. The objective response rate was 32.2% and the disease control rate (DCR) was 71.2%. The median progression-free survival (PFS) was 4.5 months [95% confidence interval (CI) 3.9-5.4 months] and the median overall survival (OS) was 9.2 months (95% CI 7.8-10.8 months). In multivariable analysis, factors associated with a shorter PFS were synchronous metastases [hazard ratio (HR) 1.66, P = 0.04] and ECOG-PS >1 (HR 1.88, P = 0.007), and those associated with a shorter OS were the same factors (HR 1.71, P = 0.03 and HR 2.36, P < 0.001, respectively) in addition to treatment beyond the second line (HR 1.74, P = 0.003) and high carcinoembryonic antigen level (HR 1.72, P = 0.003). Conclusion: This real-world study showed that in patients with BRAF V600E-mutated mCRC treated with encorafenib/cetuximab +/- binimetinib, efficacy and safety data confirm those reported in the BEACON registration trial. The main poor prognostic factors for this treatment are synchronous metastases and ECOG-PS >1.

BACKGROUND:The optimal strategy for second-line (IIL) treatment in KRAS wt metastatic colorectal cancer (mCRC) is not determined yet. METHODS:A random-effect NMA of phase II/III RCTs was conducted to evaluate IIL treatment for all-RAS wt mCRC, comparing anti-EGFR or anti-VEGF, and chemotherapy (CT). RESULTS:Overall, 11 RCTs (3613 patients) were included. In KRAS wt patients, PFS was improved with anti-VEGF (HR 0.43) and anti-EGFR (HR 0.63) vs CT. However, anti-VEGF based therapy had the highest likelihood of being ranked as the best treatment in terms of PFS (SUCRA 99.3%) and OS (SUCRA 99.4%). Bevacizumab-based treatment is most likely to be the best treatment in terms of PFS (SUCRA 89.1%) and OS (SUCRA 86.7%). CONCLUSIONS:Second line treatment with anti-VEGF and anti-EGFR improved PFS in mCRC patients, however, anti-VEGF based therapy, particularly CT plus bevacizumab, is the best treatment according to SUCRA in terms of PFS and OS.

Background: Histological characteristics at the invasive front may reflect tumor aggressiveness; specifically, tumor budding (Bd) is an emerging prognostic biomarker in colon cancer (CC). We explored further the significance of Bd for risk stratification by evaluating survival of stage III CC patients included in the IDEA-France phase III trial. Patients and methods: This post-hoc study was conducted on tissue slides from 1048 stage III CC patients. Bd was scored by central review by the Bd criteria of the 2016 International Tumor Budding Consensus Conference (ITBCC 2016) and classified as Bd1 (0-4 buds/0.785 mm(2)), Bd2 (5-9 buds), and Bd3 (>= 10 buds) categories. Disease-free survival (DFS) and overall survival (OS) were analyzed by the log-rank test. Clinicopathological features and Immunoscore (R) were correlated with Bd. Results: Overall, Bd1, Bd2, and Bd3 were observed in 39%, 28%, and 33% of CC, respectively. Bd2 and Bd3 were associated with vascular (P = 0.002) and perineural invasions (P = 0.0009). The 3-year DFS and the 5-year OS rates for Bd (1 versus 2-3) were 79.4% versus 67.2% (P = 0.001) and 89.2% versus 80.8% (P = 0.001), respectively. This was confirmed after adjustment for relevant clinicopathological features for DFS [hazard ratio (HR) 1.41, 95% confidence interval (CI) 1.12-1.77, P = 0.003] and OS (HR 1.65, 95% CI 1.22-2.22, P = 0.001). When combined with pTN stage and Immunoscore (R) subgroups, Bd significantly improved disease prognostication. Conclusions: Bd demonstrated its independent prognostic value for DFS and OS. Given these findings, Bd as per the ITBCC 2016 should be mandatory in every pathology report in stage III CC patients. Bd and Immunoscore (R) could play a complementary role in personalized health care in this setting.

Background: The advent of antibody-drug conjugates such as trastuzumab deruxtecan (T-Dxd), has significantly increased the awareness towards drug-induced Interstitial Lung Disease (ILD), a pulmonary disorder caused by several conditions including drugs, which may cause a wide range of pathological processes, from inflammation to interstitial fibrosis.However, the differential magnitude of risk among the available treatments is still unknown.This network meta-analysis (NMA) aims to provide first preliminary data on the risk of ILD across antiHER2 regimens.

About 50% of BC presented with HER2-low expression. There is a paucity of markers apt to characterize this novel subtype, defined by HER2 immunohistochemistry score of 1+ or 2+ with negative in situ hybridization assay. The aim of this study was to explore the role of liquid biopsy–based biomarkers for the characterization of HER2-low metastatic breast cancer (mBC). A cohort of 81 patients (pts) with HR+ HER2-negative mBC was prospectively enrolled in the CRO-2018-56 study and characterized for ctDNA through droplet digital PCR (ddPCR) and next generation sequencing (NGS) before treatment start (BL). ESR1 epigenetic status was defined by assessing the methylation of its main promoters (promA and promB). Associations were tested through Mann–WhitneyU test and Fisher exact test, matched pairs variations through Wilcoxon signed rank test; survival was analyzed by log-rank test. In the total population HER2 0 mBC patients (pts) were 40 (49%) and HER2-low were 41 (51%). No significant association with the number of metastatic sites and metastatic lesions was detected for HER2-low (P=0.87 and P=0.78 respectively). Pts with low expression of HER2 showed a comparable outcome in terms of PFS at first-line (at 12 months 81% vs 70% P=0.38) and OS (at 12 months 91% vs 97% P=0.37). At BL, ctDNA-detected ESR1 and PIK3CA mutations (muts) were respectively found in 11% and 21% of pts in the HER2 0 cohort and in 8% and 31% of pts in the HER2-low cohort. No differences in distribution were observed (P=1 for ESR1;P=0.8 for PIK3CA). ACTB short fragments weren't significantly different in pts with HER2-low disease (P=0.95).Moreover, in HER2-low mBC the median methylation for promA was 56% vs 52.3% and for promB resulted 42.9% vs 55% with no significant differences (P=0.78 and P=0.40). This study characterized a prospective cohort of HER2-low and HER2 score 0 MBC, showing no significant differences for endocrine resistance biomarkers on a mutational and epigenetic standpoint. Since novel antibody drug conjugates are gaining momentum as a viable treatment strategy in luminal-like mBC, highlighting biomarkes linked to intrinsic endocrine resistance will be of pivotal importance for tailoring therapeutic sequences.

The pattern of metastatic spreading in luminal-like mBC is a current field of research, but few data are available on the evolution of distant involvement after first-line (1L). We aimed to describe the trend in metastatic sites after progression to a 1L. The study retrospectively analysed 717 consecutive luminal-like mBC patients (pts) treated at the Oncology Departments of Aviano and Udine, in Italy, between 2008 and 2020, with endocrine therapy (ET) (alone or in combination with cyclin-dependent-kinases 4/6 inhibitors [CDK4/6i]) or chemotherapy (CT) (alone or with ET maintenance). Data were collected at baseline of 1L (BL1) and at progression (PD1). McNemar and Fisher tests were used to explore pairwise differences and associations between newly identified metastatic sites and 1L treatments. Overall, bone involvement was 71.2% at BL1 and 76.4% at PD1, lung metastasis (mts) was detected in 21.7% of pts at BL1 and in 32.3% at PD1, liver mts in 21.4% at BL1 and in 31.6% at PD1. Central nervous system (CNS) mts were detected in 2.4% of pts at BL1 and in 3.5% at PD1. In the overall population, at paired nominal data test, metastatic sites were consistently increased at PD1 (liver P < 0.0001, bone P = 0.0001, CNS P = 0.0039, bone-only P < 0.0001, lung P < 0.0001, nodes P < 0.0001), as expected. Notably, a similar trend was observed across all 1L treatments, apart for CNS mts in the ET cohort, bone and CNS in both the ET+CDK4/6i and CT subgroups, bone-only disease and CNS mts in CT-ET maintenance group where no significant pairwise changes were highlighted. Analysing newly identified metastatic sites at PD1, pts treated with ET+CDK4/6i had a higher risk of developing new CNS mts (P = 0.018, expected frequency [EF] 1.1 pts vs observed frequency [OF] 3 pts), while pts treated with CT-ET maintenance had a higher risk of developing new lymph node mts (P = 0.014, EF 32.5 pts vs OF 45 pts). The present study suggested the potential impact of first-line treatment strategies on the evolution of metastatic spreading in luminal-like mBC. Based on these results, future studies will be designed to develop new personalized monitoring strategies.

Background: Emerging data suggest that gender-related immune system composition affects both immune response and efficacy of immunotherapy in cancer patients (pts). This study aimed to investigate the sex-related prognostic role of MLR in metastatic colorectal cancer (mCRC) pts. Methods: We analyzed a retrospective consecutive cohort of 490 mCRC patients treated from 2009 to 2018 at the Oncology Departments of Aviano and Pordenone (training set) and Udine (validation set), Italy. The prognostic impact of MLR on overall survival (OS) was evaluated with uni- and multivariable Cox regression models. The best cut-off value to predict survival was defined through ROC analyses. Results: Overall, we identified 288 males (59%) and 202 females (41%); 161 patients (33%) had a right-sided, 202 (42%) a left-sided primary, and 122 (25%) a rectal tumor. Interestingly, gender was associated with MLR (p = 0.004) and sidedness (p = 0.006). The obtained cut-off value for MLR in females and males was 0.27 and 0.49, respectively. According to univariate analysis of the training set, MLR (HR 9.07, p ≤ 0.001), MLR > 0.27 in females (HR 1.95, p = 0.003), and MLR > 0.49 in males (HR 2.65, p = 0.010) were associated with poorer OS, which was also confirmed in the validation set. In multivariate analysis, MLR > 0.27 in females (HR 2.77, p = 0.002), MLR > 0.49 in males (HR 5.39, p ≤ 0.001), BRAF mutation (HR 3.38, p ≤ 0.001), and peritoneal metastases (HR 2.50, p = 0.003) were still independently associated with worse OS. Conclusions: Males and females have a different immune response. Our study showed that high MLR, both in males and females, is an unfavorable Independent prognostic factor. Further prospective studies are needed to confirm these data.

Recently, laboratory parameters have been explored as potential prognostic biomarkers in several tumour types. Here we present our findings in the population enrolled in the interim analysis of the DISTINCTIVE trial (NCT04252456), a prospectively stratified, biologically enriched phase II study of second-line FOLFIRI-aflibercept in RAS wild type (wt) metastatic colorectal cancer (mCRC) patients (pts) progressing after first-line anti-epidermal growth factor receptor (EGFR) drugs.

Stage II colon cancer (CC) is probably one of the best prognosis gastrointestinal tumors seen in our consultations, but often takes a lot of time for physicians to determine appropriate treatment because of the limited benefit of adjuvant chemotherapy (CT) in these patients, together with the limited evidence in this situation. How to choose the best treatment for each individual patient is thus dependent on molecular (microsatellite instability/microsatellite stability status) and clinico-pathological features relevant enough to classify these tumors into low-, intermediateand high-risk stage II disease and to choose an appropriate attitude for each of these subgroups. In practice, the first step in treatment decision making must be to assess the patient's status and comorbidities to see if the patient is eligible for an adjuvant treatment. Then, as fluoropyrimidines (FPs) are the corner stone of CC adjuvant treatment, screening for dihydropyrimidine dehydrogenase deficiency is mandatory in western countries. Finally, depending on the patient's characteristics and tumor risk stage, the strategy may be surveillance, adjuvant FP alone or oxaliplatin-based adjuvant CT. In the near future, new tools such as Immunoscore (R) (HalioDx; Luminy Biotech Enterprises, Marseille Cedex, France) and circulating tumor DNA may help to identify more precisely patients with minimal residual disease for more personalized adjuvant treatment approaches.

Histological growth characteristics at the invasive front may reflect tumor aggressiveness. Specifically, tumor budding (TB), defined as single cancer cells or cluster comprising less than five cells and representing the dynamic process of epithelial-mesenchymal transition, is listed among prognostic markers in colon cancer (CC). However, its use for a better disease stratification needs to be further explored. Its prognostic role was thus evaluated in a phase III trial investigating 3 vs 6 months of oxaliplatin-based adjuvant treatment in stage III CC patients.

Background: Cyclin-dependent kinases (CDK) 4/6 inhibitors have recently reshaped the therapeutic scenario for hormone receptor (HR)-positive/HER2-negative metastatic breast cancer (MBC). Elevated serum lactate dehydrogenase (LDH) levels correlate with poor prognosis in various malignancies, including MBC. However, no data are available on LDH prognostic value in patients treated with CDK4/6 inhibitors. Henceforth, we explored whether plasmatic LDH could represent a prognostic biomarker in patients treated with endocrine therapy (ET) and the CDK4/6 inhibitor palbociclib.

The impact of regular follow-up on the clinical outcome after recurrent breast cancer (rBC) is still debated. Aim of this study is to describe the modalities of detection of inoperable rBC that could serve to design prospective studies that evaluate the prognostic impact of surveillance. We retrospectively analyzed a consecutive series of 169 pts with rBC detected between 2012-2016 at the Department of Oncology of Udine, Italy. Pts with de novo advanced BC were not eligible. Baseline features at the diagnosis of early BC (eBC) and modalities of detection of rBC were analyzed. The main disease characteristics at the diagnosis of eBC were: pT1 (46%), N+ (57%), Ki67≥14% (60%), luminal HER2-neg subgroup (63%), triple negative (TN) subgroup (17%), HER2-pos subgroup (15%). Of note, 25% received a radical resection for loco-regional recurrence. The median time to recurrence (TTR) was 66.6 months. At the diagnosis of rBC, 53% of pts had ECOG PS 0, 54% had visceral metastases, 2% with visceral crisis, and 76% had less than 3 metastatic sites involved. Among symptomatic pts (46%), 40% reported pain, 21% thoracic symptoms, 12% neurological symptoms, 8% constitutional symptoms and 19% had locoregional symptoms/signs of relapse. The majority of rBC in asymptomatic pts was detected by radiological exams (47%), followed by serum markers (34%) and other changes in blood tests (7%). Of note, 43%, 14% and 33% of rBC were intercepted by oncologist, general practitioner and other specialists, respectively. rBC diagnosis was made during a scheduled oncological follow-up visit in 30% of cases. Clinical symptoms were detected mainly in Ki67≥14% pts (OR 2.75, 95%CI 1.01-7.51, p=0.04), while biochemical alterations were mainly evident in ER-pos (OR 4.61, 95%CI 1.01-21.22, p=0.05). These finding were not confirmed in the multivariate logistic regression model. None of analyzed factors were associated with detection through radiological exams. These findings provide information about the modality of detection of rBC. Albeit purely descriptive, they could be helpful in drawing prospective randomized studies to explore the prognostic impact of surveillance programmes.

Standard treatment for metastatic gastric cancer (GC) is chemotherapy (CT). Most commonly, first-line chemotherapy is based on a combination of fluoropyrimidines, platinum derivates, and, in case of a HER2 overexpression, trastuzumab. First choice for second-line chemotherapy is paclitaxel associated with ramucirumab. However, there is a dearth of data about the optimal second-line treatment in patients (pts) who progress on first-line treatment including taxanes. For these pts, second-line paclitaxel and ramucirumab could incur in lack of efficacy due to taxanes cross-resistance. This exploratory analysis aims to address effectiveness and safety of second-line treatment with paclitaxel and ramucirumab after a first-line treatment including docetaxel; moreover, it investigates clinicopathological features that could be associated with a better response and, thus, potentially drive clinical decision-making. A retrospective analysis was conducted on a consecutive series of 22 GC pts previously treated with first-line docetaxel, oxaliplatin and capecitabine (1 pt with fluorouracil) at National Cancer Institute, IRCCS CRO Aviano (Italy). In the univariate survival analysis, overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan-Meier method. In our analysis, 20/22 pts were males; median age was 58y (41-73). 7/22 pts had HER2-positive cancer. 7/22 pts had locally advanced tumors at diagnosis (T3 and N+/-); 15/22 pts had stage IV disease at diagnosis; 1/22 had more than 3 metastatic sites at diagnosis; 4/22 had more than 3 metastatic before paclitaxel. Median number of docetaxel cycles received before starting paclitaxel was 6 (1-12); median number of months since completion of docetaxel was 7 months (1-31). Paclitaxel and ramucirumab was usually given as second-line; 3/22 pts had it as third-line; median number of cycles administered was 3. 8/22 pts had a baseline performance status (PS) = 0; 12/22 a PS =1; 2/22 a PS =2. 15/22 pts underwent maintenance treatment after completion of first-line treatment. Only 2/22 pts had a partial response to paclitaxel and ramucirumab; 3/22 had stable disease; the disease control rate was 22.7%. 2/22 pts had G3/4 haematological toxicity; no patient had non-haematologic G3/4 adverse events; 5/22 patients had G2 neuropathy. 11/22 patients required a dose reduction while on paclitaxel, mostly due to neurotoxicity or PS deterioration. Median OS was 6 months, median PFS was 3 months. At the time of this analysis, 3 patients were still alive. Our analysis showed that patients who undergo treatment with paclitaxel and ramucirumab after a first-line therapy including docetaxel have a median PFS of 3 months and an OS of 6 months, both shorter than the historical control of the randomised phase 3 RAINBOW trial. PS was the only feature significantly associated with OS. The main limits of our study are its retrospective design and the small number of patients included in the analysis. Interestingly, we noticed an imbalance in the number of male patients and of HER2-positive patients. As such, further studies are needed to determine whether paclitaxel is a viable option for GC patients who received docetaxel.

Circulating monocytes are recruited in the tumor site where they differentiate into tumor-associated macrophages, acquiring pro-tumor functions and suppressing adaptive immune response. This study aims to investigate a prognostic tool based on lymphocytes ratio (LR) in patients (pts) with stage III colon cancer (CC). This is a multicentric study conducted on 653 consecutive CC pts treated between 2008-2019 at the Centres of Aviano, Pordenone, Udine and Paris (HEGP). A Cox regression model was used to determine the prognostic impact in terms of overall survival (OS) and disease-free survival (DFS). The performance of the prognostic model was evaluated using the Harrell’s C statistic (HCS). Random Forest (RF) to predict pattern of metastasis was implemented on python using H2oai. Overall, 70% of pts had stage IIIB, 75% G1-2 tumors and 57% CEA>5. Notably, 50%, 41% and 14% had a lymphatic (LI), vascular (VI) and perinervouse infiltration (PI), respectively. About molecular profile, 45/263 had MSI status, 94/212 and 28/199 were KRAS and BRAF muted. At median follow-up of 59 mo, median DFS and OS were not reached, 32% of pts relapsed and 24% died. At 3-year follow-up, 24% had a DFS event. By multivariate analysis, including potential confounders, significantly shorter DFS (HR 1.84, 95%CI 1.13-3.00, p=0.014) and OS (HR 2.32, 95%CI 1.27-4.25) were observed among pts with high monocyte-to-LR (MLR >0.45) compared to those with low MLR. Notably, MLR was significantly associated with 3y-DFS (p=0.02). The addition of MLR improved the performance of the prognostic model (from 0.69 to 0.87 HCS). RF showed that BRAF, LR, sidedness, KRAS, CEA, and LDH were the main features linked with hepatic (ACC 0.67) and nodal (0.68) organotropism. LDH, PI, LR, KRAS, pT, pN with lung (0.77), while LR, sidedness, KRAS, BRAF, MMR and VI with bone involvement (ACC 0.55). Factors linked with peritoneal involvement were LR, CEA, BRAF, pT, pN (ACC 0.57). A prognostic model including MLR results more accurate in predicting survival and pattern of metastatic spread in patients with stage III CC, allowing a more tailored monitoring. These findings paved the way at constructing a potential nomogram based on MLR and macrophages immune-score to more accurately define stage III CC.