Genomic profiling of small bowel adenocarcinoma: a pooled analysis from 3 databases.

BACKGROUND: Small bowel adenocarcinoma is a rare disease. The genomic profiling tumours according to clinical characteristics and its impact on the prognosis remains unclear. METHODS: A pooled analysis of clinical data, genomic profiling and MisMatch Repair (MMR) status from three databases was performed. RESULTS: A total of 188 tumour samples were analysed. A predisposing disease was reported in 22.3%, mainly Lynch syndrome and Crohn's disease. The tumours were localized in 80.2% and metastatic in 18.8%. The most frequent mutations were KRAS (42.0%) among them 7/79 are G12C, TP53 (40.4%), APC (19.1%), PIK3CA (18.6%), SMAD4 (12.8%) and ERBB2 (9.6%). Mutation distribution differed according to predisposing disease for TP53, ERBB2, IDH1, FGFR3, FGFR1 and KDR. KRAS and SMAD4 mutations were more frequent in metastatic tumour, whereas ERBB2 mutations were absent in metastatic tumour. For localized tumour, APC mutation was independently associated with a poor overall survival (OS) (p = 0.0254). 31.8% of localized tumours and 11.3% of metastatic tumours were dMMR (29.8% of the entire cohort). A dMMR status was associated with a better OS (HR = 0.61 [0.39-0.96], p = 0.0316). CONCLUSIONS: There is a different genomic profile according to the stage and predisposing disease. dMMR and APC mutation in localized tumour predict a better prognosis.

FOLFIRI Plus Durvalumab With or Without Tremelimumab in Second-Line Treatment of Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: The PRODIGE 59-FFCD 1707-DURIGAST Randomized Clinical Trial.

Importance: Efficacy of second-line chemotherapy in advanced gastric or gastrooesphageal junction (GEJ) adenocarcinoma remains limited. Ojectives: To determine the efficacy of 1 or 2 immune checkpoint inhibitors combined with FOLFIRI (leucovorin [folinic acid], fluorouracil, and irinotecan) in the treatment of advanced gastric/GEJ adenocarcinoma. Design, Setting, and Participants: The PRODIGE 59-FFCD 1707-DURIGAST trial is a randomized, multicenter, noncomparative, phase 2 trial, conducted from August 27, 2020, and June 4, 2021, at 37 centers in France that included patients with advanced gastric/GEJ adenocarcinoma who had disease progression after platinum-based first-line chemotherapy. Intervention: Patients were randomized to receive FOLFIRI plus durvalumab (anti-programmed cell death 1 [PD-L1]) (FD arm) or FOLFIRI plus durvalumab and tremelimumab (anti-cytotoxic T-lymphocyte associated protein 4 [CTLA-4]) (FDT arm). The efficacy analyses used a clinical cutoff date of January 9, 2023. Main outcome and Measures: The primary end point was progression-free survival (PFS) at 4 months according to RECIST 1.1 criteria evaluated by investigators. Results: Overall, between August 27, 2020, and June 4, 2021, 96 patients were randomized (48 in each arm). The median age was 59.7 years, 28 patients (30.4%) were women and 49 (53.3%) had GEJ tumors. Four month PFS was 44.7% (90% CI, 32.3-57.7) and 55.6% (90% CI, 42.3-68.3) in the FD and FDT arms, respectively. The primary end point was not met. Median PFS was 3.8 and 5.4 months, objective response rates were 34.7% and 37.7%, and median overall survival was 13.2 and 9.5 months in the FD and FDT arms, respectively. Disease control beyond 1 year was 14.9% in the FD arm and 24.4% in the FDT arm. Grade 3 to 4 treatment-related adverse events were observed in 22 (47.8%) patients in each arm. A combined positive score (CPS) PD-L1 of 5 or higher was observed in 18 tumors (34.0%) and a tumor proportion score (TPS) PD-L1 of 1% or higher in 13 tumors (24.5%). Median PFS according to CPS PD-L1 was similar (3.6 months for PD-L1 CPS ≥5 vs 5.4 months for PD-L1 CPS <5) by contrast for TPS PD-L1 (6.0 months for PD-L1 TPS ≥1% vs 3.8 months for PD-L1 TPS <1%). Conclusions and Relevance: Combination of immune checkpoint inhibitors with FOLFIRI in second-line treatment for advanced gastric/GEJ adenocarcinoma showed an acceptable safety profile but antitumor activity only in a subgroup of patients. Trial Registration: ClinicalTrials.gov Identifier: NCT03959293.

A multicenter study evaluating efficacy of immune checkpoint inhibitors in advanced non-colorectal digestive cancers with microsatellite instability.

BACKGROUND: One randomized phase III trial comparing chemotherapy (CT) with immune checkpoint inhibitors (ICI) has demonstrated significant efficacy of ICI in deficient DNA mismatch repair system/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer. However, few studies have compared ICI with CT in other advanced dMMR/MSI-H digestive tumors. METHODS: In this multicenter study, we included patients with advanced dMMR/MSI-H non-colorectal digestive tumors treated with chemotherapy and/or ICIs. Patients were divided retrospectively into two groups, a CT group and an immunotherapy (IO) group. The primary endpoint was progression-free survival (PFS). A propensity score approach using the inverse probability of treatment weighting (IPTW) method was applied to deal with potential differences between the two groups. RESULTS: 133 patients (45.1/27.1/27.8% with gastric/small bowel/other carcinomas) were included. The majority of patients received ICI in 1st (29.1%) or 2nd line (44.4%). The 24-month PFS rates were 7.9% in the CT group and 71.2% in the IO group. Using the IPTW method, IO treatment was associated with better PFS (HR=0.227; 95% CI 0.147-0.351; p < 0.0001). The overall response rate was 26.3% in the CT group versus 60.7% in the IO group (p < 0.001) with prolonged duration of disease control in the IO group (p < 0.001). In multivariable analysis, predictive factors of PFS for patients treated with IO were good performance status, absence of liver metastasis and prior primary tumor resection, whereas no association was found for the site of the primary tumor. CONCLUSIONS: In the absence of randomized trials, our study highlights the superior efficacy of ICI compared with standard-of-care therapy in patients with unresectable or metastatic dMMR/MSI-H non-colorectal digestive cancer, regardless of tumor type, with acceptable toxicity.

Prognostic value of circulating short-length DNA fragments in unresected glioblastoma patients.

BACKGROUND: Liquid biopsy application is still challenging in glioblastoma patients and the usefulness of short-length DNA (slDNA) fragments is not established. The aim was to investigate slDNA concentration as a prognostic marker in unresected glioblastoma patients. METHODS: Patients with unresected glioblastoma and treated by radiochemotherapy (RT/TMZ) were included. Plasmas were prospectively collected at three times: before (pre-) RT, after (post-) RT and at the time of progression. Primary objective was to investigate the impact on survival of slDNA concentration [slDNA] variation during RT/TMZ. Secondary objectives were to explore the association between tumor volume, corticosteroid exposition and [slDNA]; and the impact of slDNA detection at pre-RT on survival. RESULTS: Thirty-six patients were analyzed: 11 patients (30.6 %) experienced [slDNA] decrease during RT/TMZ, 22 patients (61.1 %) experienced increase and 3 patients (8.3 %) had stability. Decrease of [slDNA] during RT/TMZ was associated with better outcome compared to increase or stability: median OS, since end of RT, of 13.2 months [11.4 - NA] vs 10.1 months [7.8 - 12.6] and 6.8 months [4.5 - NA], p = 0.015, respectively. slDNA detection at pre-RT time was associated with improved OS: 11.7 months in the slDNA(+) group versus 8.8 months in the slDNA(-) group, p = 0.004. [slDNA] was not associated with corticosteroids exposition or tumor volume. No influence on survival was observed for both whole cfDNA concentration or slDNA peak size. CONCLUSION: [slDNA] decrease during radiochemotherapy phase is a favorable prognostic marker on OS for unresected glioblastoma patients. Larger and independent cohorts are now required. TRIAL REGISTRATION: ClinicalTrial, NCT02617745. Registered 1 December 2015, https://clinicaltrials.gov/ct2/show/NCT02617745?term=glioplak&draw=2&rank=1.

Clinical relevance of circulating ESR1 mutations during endocrine therapy for advanced hormone-dependent endometrial carcinoma.

OBJECTIVE: Endocrine therapy is frequently administered in patients with hormone dependent (HR+) metastatic endometrial cancer. ESR1 mutations have emerged as a key mechanism of aromatase inhibitor (AI) resistance in HR + metastatic breast cancer and can be monitored using circulating tumor DNA (ctDNA). The aim of this study was to explore the incidence and clinical relevance of circulating ESR1 mutations in patients treated by AI or megestrol acetate (M) for advanced endometrial carcinoma. METHODOLOGY: This single-center retrospective study was performed at the Henri Becquerel Center (Rouen) and looked for circulating ESR1 gene mutations by droplet digital PCR (E380Q, L536R, Y537S, Y537N, Y537C, D538G, S463P) in patients with advanced HR + endometrial carcinoma treated between 2008 and 2020 for at least 30 days by AI or M. Analyses were performed before exposure and at progression/during endocrine therapy. RESULTS: Twenty-two patients were included: 13 were treated with AI, 12 of whom progressed; 9 patients were treated with M, 8 of whom progressed. 68.1% of the patients had low-grade endometrial carcinoma and 54.5% had received chemotherapy in the metastatic setting. The median duration of treatment was 152 days (min 47 - max 629) with AI and 155 days (min 91-max 1297) with M. Under AI, there was no ESR1 mutation at baseline, and one Y537C mutation at progression with a variant allele frequency (VAF) of 0.14%. Under M, one patient had a Y537C (VAF 0.2%) at baseline that disappeared during treatment. Another patient had a Y537S mutation emergence at progression after 91 days of treatment (VAF 1.83%). There was no significant difference between the circulating DNA concentration before and after hormone therapy (p = 0.16). CONCLUSION: ESR1 mutations do not seem to be involved in the mechanisms of resistance to AI or M in HR+ endometrial cancer. The clinical relevance of their detection is not demonstrated.

Biweekly vs Triweekly Cabazitaxel in Older Patients With Metastatic Castration-Resistant Prostate Cancer: The CABASTY Phase 3 Randomized Clinical Trial.

Importance: Many patients 65 years or older with metastatic castration-resistant prostate cancer (mCRPC) are denied taxane chemotherapy because this treatment is considered unsuitable. Objective: To determine whether biweekly cabazitaxel (CBZ), 16 mg/m2 (biweekly CBZ16), plus prophylactic granulocyte colony-stimulating factor (G-CSF) at each cycle reduces the risk of grade 3 or higher neutropenia and/or neutropenic complications (eg, febrile neutropenia, neutropenic infection, or sepsis) compared with triweekly CBZ, 25 mg/m2 (triweekly CBZ25), plus G-CSF (standard regimen). Design, Setting, and Participants: A total of 196 patients 65 years or older with progressive mCRPC were enrolled in this prospective phase 3 randomized clinical trial conducted in France (18 centers) and Germany (7 centers) between May 5, 2017, and January 7, 2021. All patients had received docetaxel and at least 1 novel androgen receptor-targeted agent. Interventions: Patients were randomly assigned 1:1 to receive biweekly CBZ16 plus G-CSF and daily prednisolone (experimental group) or triweekly CBZ25 plus G-CSF and daily prednisolone (control group). Main Outcome and Measures: The primary end point was the occurrence of grade 3 or higher neutropenia measured at nadir and/or neutropenic complications. Results: Among 196 patients (97 in the triweekly CBZ25 group and 99 in the biweekly CBZ16 group), the median (IQR) age was 74.6 (70.4-79.3) years, and 181 (92.3%) had an Eastern Cooperative Oncology Group performance status of 0 or 1. The median (IQR) follow-up duration was 31.3 (22.5-37.5) months. Relative dose intensities were comparable between groups (median [IQR], 92.7% [83.7%-98.9%] in the triweekly CBZ25 group vs 92.8% [87.0%-98.9%] in the biweekly CBZ16 group). The rate of grade 3 or higher neutropenia and/or neutropenic complications was significantly higher with triweekly CBZ25 vs biweekly CBZ16 (60 of 96 [62.5%] vs 5 of 98 [5.1%]; odds ratio, 0.03; 95% CI, 0.01-0.08; P < .001). Grade 3 or higher adverse events were more common with triweekly CBZ25 (70 of 96 [72.9%]) vs biweekly CBZ16 (55 of 98 [56.1%]). One patient (triweekly CBZ25 group) died of a neutropenic complication. Conclusions and Relevance: In this randomized clinical trial, compared with the standard regimen, biweekly CBZ16 plus G-CSF significantly reduced by 12-fold the occurrence of grade 3 or higher neutropenia and/or neutropenic complications, with comparable clinical outcomes. The findings suggest that biweekly CBZ16 regimen should be offered to patients 65 years or older with mCRPC for whom the standard regimen is unsuitable. Trial Registration: ClinicalTrials.gov Identifier: NCT02961257.

Avelumab vs Standard Second-Line Chemotherapy in Patients With Metastatic Colorectal Cancer and Microsatellite Instability: A Randomized Clinical Trial.

Importance: Only 1 randomized clinical trial has shown the superiority of immune checkpoint inhibitors in patients with deficient mismatch repair and/or microsatellite instability (dMMR/MSI) metastatic colorectal cancer (mCRC) in the first-line setting. Objectives: To determine whether avelumab (an anti-programmed cell death ligand 1 antibody) improves progression-free survival (PFS) compared with standard second-line chemotherapy in patients with dMMR/MSI mCRC. Design, Setting, and Participants: The SAMCO-PRODIGE 54 trial is a national open-label phase 2 randomized clinical trial that was conducted from April 24, 2018, to April 29, 2021, at 49 French sites. Patients with dMMR/MSI mCRC who experienced progression while receiving standard first-line therapy were included in the analysis. Interventions: Patients were randomized to receive standard second-line therapy or avelumab every 2 weeks until progression, unacceptable toxic effects, or patient refusal. Main Outcome and Measures: The primary end point was PFS according to RECIST (Response Evaluation Criteria in Solid Tumours), version 1.1, evaluated by investigators in patients with mCRC and confirmed dMMR and MSI status who received at least 1 dose of treatment (modified intention-to-treat [mITT] population). Results: A total of 122 patients were enrolled in the mITT population. Median age was 66 (IQR, 56-76) years, 65 patients (53.3%) were women, 100 (82.0%) had a right-sided tumor, and 52 (42.6%) had BRAF V600E-mutated tumors. There was no difference in patients and tumor characteristics between treatment groups. No new safety concerns in either group were detected, with fewer treatment-related adverse events of at least grade 3 in the avelumab group than in the chemotherapy group (20 [31.7%] vs 34 [53.1%]; P = .02). After a median follow-up of 33.3 (95% CI, 28.3-34.8) months, avelumab was superior to chemotherapy with or without targeted agents with respect to PFS (15 [24.6%] vs 5 [8.2%] among patients without progression; P = .03). Rates of PFS rates at 12 months were 31.2% (95% CI, 20.1%-42.9%) and 19.4% (95% CI, 10.6%-30.2%) in the avelumab and control groups, respectively, and 27.4% (95% CI, 16.8%-39.0%) and 9.1% (95% CI, 3.2%-18.8%) at 18 months. Objective response rates were similar in both groups (18 [29.5%] vs 16 [26.2%]; P = .45). Among patients with disease control, 18 (75.7%) in the avelumab group compared with 9 (19.1%) in the control group had ongoing disease control at 18 months. Conclusions: The SAMCO-PRODIGE 54 phase 2 randomized clinical trial showed, in patients with dMMR/MSI mCRC, better PFS and disease control duration with avelumab over standard second-line treatment, with a favorable safety profile. Trial Registration: ClinicalTrials.gov Identifier: NCT03186326.

Beyond atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma: overall efficacy and safety of tyrosine kinase inhibitors in a real-world setting.

Background: In patients with advanced hepatocellular carcinoma (HCC) progressing after atezolizumab and bevacizumab, the optimal therapeutic sequence is still unclear and no second-line agent has proven its efficacy. Objectives: The aim of this retrospective multicenter real-world cohort study was to provide an evaluation of the efficacy and safety of the use of second-line tyrosine kinase inhibitors (TKIs) in this population. Methods: All patients with advanced HCC, treated in first-line setting by atezolizumab-bevacizumab, and who received at least one dose of treatment with TKI were included in this study. All the data were retrospectively collected from medical records. The primary outcome was progression-free survival (PFS). Secondary outcomes were overall survival (OS), overall global survival (OGS), and safety. A total of 82 patients were included in this study. Results: Patients were assigned to the regorafenib group (n = 29, 35.4%) or other TKI (sorafenib n = 41, lenvatinib n = 8, or cabozantinib n = 4) group (n = 53). PFS was not significantly different between the two groups [2.6 versus 2.8 months, HR 1.07 (95% CI: 0.61-1.86), p = 0.818]. Median PFS rates were 2.6, 4.4, and 2.8 months in sorafenib-, lenvatinib-, and cabozantinib group, respectively. OS was statistically different between the regorafenib group and other TKI group [15.8 versus 7.0 months, HR 0.40 (95% CI: 0.20-0.79), p = 0.023]. When adjusting on confounding factors, there was still a difference in OS favoring the regorafenib group (adjusted hazard ratio 0.35, p = 0.019). OGS of patients who received regorafenib was improved compared to other TKI [18.6 versus 15.0 months, HR 0.42 (95% CI: 0.22-0.84), p = 0.036]. Twenty percent of patients had grade 3 and none had grade 4 or 5 adverse events. In patients who experienced disease progression and fit for a third-line treatment, 80% and 50% received cabozantinib in regorafenib group and other TKI group, respectively. Conclusion: Efficacy of any TKI in the second-line setting was not affected by atezolizumab-bevacizumab treatment as first-line therapy. The safety profile in the second-line setting was consistent with the results shown in pivotal studies. PFS rates of patients were similar, regardless of TKI type. Regorafenib was associated with better OS and OGS rates compared to other TKI. These data need to be confirmed in prospective comparative studies.

Associated Factors with Breast Nurses Unplanned Interventions in Patients Treated for an Early Breast Cancer.

Background: The presence of a breast nurse is recommended to advise and guide early breast cancer patients before and during chemotherapy/radiation therapy, and at the end of planned treatments. Nevertheless, some patients will need extra guidance. Little is known about the predisposing factors for additional requests. Aim and Objective: Determine time, reasons, and risk factors for breast nurse unplanned solicitations. Design and Methods: This monocentric retrospective study included all early breast cancer patients treated with chemotherapy during 1 year. Unplanned solicitations (in person, by phone, or by e-mail) were recorded in the medical file. They were extracted and stratified in four categories: treatment adverse events, medical condition, psychological support, and counselling. Results: 368 unplanned solicitations were observed for 265 patients, 140 patients (52.8%) asked for at least one unplanned solicitation and 57 (21.5%) asked for at least three. There was no significant difference between the four categories. Most of unplanned solicitations occurred significantly during chemotherapy, essentially after first docetaxel infusion (57% of calls). In univariate and multivariate analyses, anxiolytic treatment was significantly associated with more unplanned solicitations (OR = 2, p = 0.02), while a personal breast cancer history was associated with fewer unplanned solicitations (OR = 0.49, p = 0.05). Conclusion: Breast nurse unplanned solicitations during adjuvant or neoadjuvant chemotherapy in early breast cancers are frequent. Even if patients with anxiolytic treatment have a slightly higher risk of solicitation, no typical profile of a patient who will need extra support exists. Because of its known toxicity, the first cycle of docetaxel is associated with a clear increase in solicitations. Despite physicians' consultations, breast nurses guidance, and leaflets on supportive care and treatments side effects, optimal patient management during early breast cancer remains challenging. Further randomized studies testing more customized tools are required to improve patient support.

Bevacizumab plus FOLFIRI after failure of platinum-etoposide first-line chemotherapy in patients with advanced neuroendocrine carcinoma (PRODIGE 41-BEVANEC): a randomised, multicentre, non-comparative, open-label, phase 2 trial.

BACKGROUND: There is no standard second-line treatment after platinum-etoposide chemotherapy for gastroenteropancreatic neuroendocrine carcinoma. We aimed to evaluate the efficacy of FOLFIRI plus bevacizumab, and FOLFIRI alone, in this setting. METHODS: We did a randomised, non-comparative, open-label, phase 2 trial (PRODIGE 41-BEVANEC) at 26 hospitals in France. We included patients aged 18 years or older with locally advanced or metastatic gastroenteropancreatic neuroendocrine carcinoma or neuroendocrine carcinoma of unknown primary origin, documented progressive disease during or after first-line platinum-etoposide chemotherapy, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomly assigned (1:1; block size of three), without stratification, to receive FOLFIRI (irinotecan 180 mg/m2, calcium folinate 400 mg/m2 or levofolinate 200 mg/m2, and fluorouracil 400 mg/m2 bolus then 2400 mg/m2 over 46 h) plus bevacizumab 5 mg/kg or FOLFIRI alone, intravenously, every 2 weeks until disease progression or unacceptable toxicity. Neither patients nor investigators were masked to group assignment. The primary outcome was overall survival at 6 months after randomisation, evaluated in the modified intention-to-treat population (all enrolled and randomly assigned patients who received at least one cycle of FOLFIRI). This study is now complete and is registered with ClinicalTrials.gov, NCT02820857. FINDINGS: Between Sept 5, 2017, and Feb 8, 2022, 150 patients were assessed for eligibility and 133 were enrolled and randomly assigned: 65 to the FOLFIRI plus bevacizumab group and 68 to the FOLFIRI group. 126 patients (59 in the FOLFIRI plus bevacizumab group and 67 in the FOLFIRI group) received at least one cycle of FOLFIRI and were included in the modified intention-to-treat population, 83 (66%) of whom were male and 43 (34%) were female, and the median age of the patients was 67 years (IQR 58-73). The primary tumour location was colorectal in 38 (30%) of 126 patients, pancreatic in 34 (27%), gastro-oesophageal in 22 (17%), and unknown in 23 (18%). After a median follow-up of 25·7 months (95% CI 22·0-38·2), 6-month overall survival was 53% (80% CI 43-61) in the FOLFIRI plus bevacizumab group and 60% (51-68) in the FOLFIRI group. Grade 3-4 adverse events that occurred in at least 5% of patients were neutropenia (eight [14%] patients), diarrhoea (six [10%]), and asthenia (five [8%]) in the FOLFIRI plus bevacizumab group, and neutropenia (seven [10%]) in the FOLFIRI group. One treatment-related death (ischaemic stroke) occurred in the FOLFIRI plus bevacizumab group. INTERPRETATION: The addition of bevacizumab did not seem to increase the benefit of FOLFIRI with regard to overall survival. FOLFIRI could be considered as a standard second-line treatment in patients with gastroenteropancreatic neuroendocrine carcinoma. FUNDING: French Ministry of Health and Roche SAS.

Evaluation of sarcopenia biomarkers in older patients undergoing major surgery for digestive cancer. SAXO prospective cohort study.

BACKGROUND: The aim of the study was to prospectively evaluate different biomarkers to identify the most reliable for anticipating complications after major abdominal surgery for digestive cancer in older patients and compare their performance to the existing definition and screening algorithm of sarcopenia from EWGSOP. METHODS: Ninety-five consecutive patients aged over 65 years who underwent elective surgery for digestive cancer were prospectively included in the SAXO study. Sarcopenia was defined according to EWGSOP criteria (four level from no sarcopenia to severe sarcopenia). Strength and physical performance were evaluated with the handgrip test (HGT) and gait speed test (GST), respectively. CT scan analysis was used to calculate the skeletal muscle index (SMI), intermuscular adipose tissue (IMAT), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT). Measures were adjusted to body mass index (BMI). Complication grading was performed using the Clavien‒Dindo classification. A doubly robust estimator with multivariable regression was used to limit bias. RESULTS: Sixteen patients presented with sarcopenia. Adjusted to BMI, sarcopenic patients had an increased IMATBMI (0.35 vs. 0.22; p = 0.003) and increased VATBMI (7.85 vs. 6.13; p = 0.048). In multivariable analysis, IMAT was an independent risk factor for minor and severe complications (OR = 1.298; 95% CI [1.031: 1.635] p = 0.027), while an increased SAT area was a protective factor (OR = 0.982; 95% CI [0.969: 0.995] p = 0.007). Twenty-two patients were obese (BMI ≥30 kg/m2). While no association was observed between obesity and sarcopenia (according to EWGSOP definition), obese patients had increased IMATBMI (0.31 vs. 0.23; p = 0.010) and VATBMI (8.40 vs. 6.49; p = 0.019). The combination of SAT, VAT and IMAT performed well to anticipate severe complication (AUC = 0.759) while AUC of EWGSOP 2010 and 2019 algorithm were 0.660 and 0.519, respectively. DISCUSSION: Non-invasive and imaging related measures of IMAT, SAT and VAT seems to be valuable tools to refine risk-assessment of older patients in surgery and specially to detect myosteatosis in obese ones.

Postoperative circulating tumor DNA detection is associated with the risk of recurrence in patients resected for a stage II colorectal cancer.

Circulating tumor DNA (ctDNA) is reported to be promising in localized colorectal cancer (CRC). The present study aimed to retrospectively evaluate the impact of ctDNA in patients with a resected stage II CRC from the PROGIGE 13 trial with available paired tumor and blood samples. A group of recurrent patients were matched one-to-one with nonrecurrent patients according to sex, tumor location, treatment sequence, and blood collection timing. CtDNA was analyzed by digital PCR according to NGS of tumors. Disease-free survival (DFS) and overall survival (OS) were analyzed based on ctDNA, and the risks of recurrence and death were determined. A total of 134 patients were included, with 67 patients in each group. At least one alteration was identified in 115/134 tumors. Postoperative ctDNA was detected in 10/111 (9.0%) informative samples and was detected more frequently in the recurrent group (16.7% versus 1.8%; p = 0.02). The median DFS of ctDNA+ versus ctDNA- patients was 16.8 versus 54 months (p = 0.002), respectively, and the median OS was 51.3 versus 69.5 months (p = 0.03), respectively. CtDNA was associated with recurrence (ORa = 11.13, p = 0.03) and death (HRa = 3.15, p = 0.01). In conclusion, the presence of postoperative ctDNA is associated with both recurrence and survival in stage II CRC.

Lanreotide as maintenance therapy after first-line treatment in patients with non-resectable duodeno-pancreatic neuroendocrine tumours: An international double-blind, placebo-controlled randomised phase II trial - Prodige 31 REMINET: An FFCD study.

BACKGROUND: Following European guidelines, patients with aggressive metastatic or locally advanced, non-resectable, duodeno-pancreatic (DP) neuroendocrine tumours (NETs) should receive systemic combination chemotherapy until progression. Aggressive disease is defined as progressive and/or symptomatic metastases with or without significant hepatic invasion (>30-50%), and/or bone metastases. METHODS: This academic randomised, double-blind, placebo-controlled phase II study aims to evaluate lanreotide autogel 120 mg (LAN) as maintenance treatment after at least 2 months of first-line treatment (L1) in aggressive G1-G2 DP-NET. Patients were randomly assigned in a 1:1 ratio to receive LAN or placebo (PBO), every 28 days, until progression or toxicity. The primary end-point was progression-free survival (PFS) at 6 months. RESULTS: Among the 118 planned patients, 53 were included. Of these, 81.1% had a G2 tumour, and 90.6% had metastatic disease. L1 therapy consisted of chemotherapy (96.8%). Median duration of L1 was 4.6 months (range: 2.0-7.7). At the time of randomisation, 81.1% of patients had stable disease. Median follow-up was 27.0 months (95% CI: 19.5; 31.2). PFS at 6 months was 73.1% (90% CI: 55.3; 86.6) in LAN versus 54.2% (90% CI: 35.8; 71.8) in PBO. Median PFS was 19.4 months (95% CI: 7.6; 32.6) and 7.6 months (95% CI: 3.0; 9.0), respectively. Median overall survival was 41.9 months in PBO and was not reached in LAN. The toxicity profile was mainly grade 1-2 expected toxicities. CONCLUSIONS: The encouraging results of lanreotide autogel 120 mg as a maintenance treatment after L1 in aggressive G1/2 DP-NET should be confirmed. TRIAL REGISTRATION: NCT02288377 (clinicaltrials.gov).

Colorectal cancer chemoprevention: is aspirin still in the game?

Screening strategies have demonstrated their potential for decreasing the incidence and mortality of cancers, particularly that of colorectal cancer (CRC). Another strategy that has been developed to reduce CRC occurrence is the use of chemoprevention agents. Among them, aspirin is the most promising. Aspirin acts in colorectal tumourigenesis through several mechanisms, either directly in tumor cells or in their microenvironment, such as through its anti-inflammatory activity or its effect on the modulation of platelet function. Many retrospective studies, as well as follow-up of large cohorts from trials with primary cardiovascular end points, have shown that long-term treatment with daily low-dose aspirin decreases the incidence of adenomas and colorectal cancers. Therefore, aspirin is currently recommended by the United States Preventive Services Task Force (USPSTF) for primary prevention of CRC in all patients aged 50 to 59 with a 10-y risk of cardiovascular events greater than 10%. Furthermore, several studies have also reported that long-term aspirin treatment taking after CRC resection decreases recurrence risk and increases overall survival, especially in patients with PIK3CA-mutated tumors. This review summarizes current knowledge on the pathophysiological mechanisms of aspirin chemoprevention, discusses the primary clinical results on CRC prevention and highlights the potential biomarkers identified to predict aspirin efficacy.

Are patients living far from hospital at higher risk of late adjuvant chemotherapy for colon cancer?

AIMS: Late adjuvant chemotherapy (aCT) administration after colectomy (>56 d) is known to be associated with impaired prognosis. We aim to identify risk factors associated with late aCT, especially the travel time between patients' home and hospital. METHODS: We performed a retrospective monocentre cohort study. Patients included had a colectomy for a stage III or high risk stage II colon cancer between 2009 and 2015 performed at a French university hospital. Risk factors for late aCT were identified using a fractional polynomial logistic regression. RESULTS: Ninety-four patients were included. The risk of late aCT was associated with travel time length, emergent colectomy, the need for scheduled care before aCT, and length of time between colectomy and postoperative multidisciplinary meeting advising aCT. CONCLUSION: Our study suggests that, in patients with colon cancer, factors unrelated to disease severity and complexity could be associated with a higher risk of late aCT.

Impact of the COVID-19 pandemic on disease stage and treatment for patients with pancreatic adenocarcinoma: A French comprehensive multicentre ambispective observational cohort study (CAPANCOVID).

BACKGROUND: The COVID-19 pandemic caused major oncology care pathway disruption. The CAPANCOVID study aimed to evaluate the impact on pancreatic adenocarcinoma (PA) - from diagnosis to treatment - of the reorganisation of the health care system during the first lockdown. METHODS: This multicentre ambispective observational study included 833 patients diagnosed with PA between September 1, 2019 and October 31, 2020 from 13 French centres. Data were compared over three periods defined as before the outbreak of COVID-19, during the first lockdown (March 1 to May 11, 2020) and after lockdown. RESULTS: During the lockdown, mean weekly number of new cases decreased compared with that of pre-pandemic levels (13.2 vs. 10.8, -18.2%; p = 0.63) without rebound in the post-lockdown period (13.2 vs. 12.9, -1.7%; p = 0.97). The number of borderline tumours increased (13.6%-21.7%), whereas the rate of metastatic diseases rate dropped (47.1%-40.3%) (p = 0.046). Time-to-diagnosis and -treatment were not different over periods. Waiting neoadjuvant chemotherapy in resectable tumours was significantly favoured (24.7%-32.6%) compared with upfront surgery (13%-7.8%) (p = 0.013). The use of mFOLFIRINOX preoperative chemotherapy regimen decreased (84.9%-69%; p = 0.044). After lockdown, the number of borderline tumours decreased (21.7%-9.6%) and advanced diseases increased (59.7%-69.8%) (p = 0.046). SARS-CoV-2 infected 39 patients (4.7%) causing 5 deaths (12.8%). CONCLUSION: This cohort study suggests the existence of missing diagnoses and of a shift in disease stage at diagnosis from resectable to advanced diseases with related therapeutic modifications whose prognostic consequences will be known after the planned follow-up. TRIAL REGISTRATION: Clinicaltrials.gov NCT04406571.

Circulating DNA changes are predictive of disease progression after transarterial chemoembolization.

Transarterial chemoembolization (TACE) is used to treat patients with unresectable hepatocellular carcinoma (HCC). We evaluated the clinical impact of a-fetoprotein (AFP) and circulating cell-free and tumor DNA (cfDNA and ctDNA) changes around the TACE procedure. Our prospective monocentric study enrolled consecutive patients treated with TACE, with samples collected at baseline (D - 1), Day 2 (D + 2) and 1 month (M + 1) after TACE. cfDNA was quantified by the fluorometric method, and ctDNA was quantified by digital polymerase chain reaction designed for two hotspot TERT mutations. Computerized tomography scans or magnetic resonance imaging were performed at M + 1 every 3 months following TACE and independently reviewed. The objective was to identify thresholds of cfDNA, ctDNA and AFP changes associated with progressive disease (PD) using receiver operating characteristic curves. Thirty-eight patients were included from March 2018 to March 2019. All markers significantly increased from D - 1 to D + 2 (P < .005), and cfDNA and ctDNA significantly decreased from D + 2 to M + 1 (P < .0001). The analysis of changes from D - 1 to M + 1 identified thresholds at +31.4% for cfDNA and 0% for ctDNA that were significantly associated with PD at M + 1 (44.4% [>+31.4%] vs 3.8% [≤+31.4%] and 50.0% [>0%] vs 5.0% [≤0%], respectively). No significant threshold was identified for AFP. Using a score combining cfDNA and ctDNA, the patients were classified into high- or low-risk PD groups at M + 1, with PD rates of 80.0% vs 4.3% (P = .001) and median progression-free survival times of 1.3 vs 10.3 months (P = .002). Our study suggests that cfDNA and ctDNA increases around the TACE procedure and are associated with therapeutic failure.

Circulating PIK3CA mutation detection at diagnosis in non-metastatic inflammatory breast cancer patients.

Inflammatory breast cancer (IBC) is an aggressive BC subtype with poor outcomes. A targetable somatic PIK3CA mutation is reported in 30% of IBC, allowing for treatment by PI3Kα-specific inhibitors, such as alpelisib. The aim of this study was to evaluate the detection rate of circulating PIK3CA mutation in locally-advanced IBC (LAIBC) patients harbouring a PIK3CA mutation on initial biopsy. This monocentric retrospective study was based on available stored plasma samples and tumour biopsies at diagnosis from all LAIBC patients treated with neo-adjuvant chemotherapy (NCT) between 2008 and 2018 at the Centre Henri Becquerel. PIK3CA mutations (E542K, E545K, H1047R/L) were assessed by droplet digital PCR (ddPCR) in plasma samples and tumoral tissue at diagnosis. A total of 55 patients were included. Overall, 14/55 patients (25%) had a PIK3CA mutation identified on baseline biopsy (H1047R = 8; H1047L = 3; E545K = 2; E542K = 1). Among them, 11 (79%) patients had enough DNA for circulating DNA analyses, and corresponding circulating PIK3CA mutations were found in 6/11 (55%). Among the 41 patients without PIK3CA mutations on biopsy, 32 (78%) had enough DNA for circulating DNA analysis, and no circulating PIK3CA mutation was identified. Our results revealed no prognostic or predictive value of PIK3CA mutations at the diagnosis of non-metastatic IBC but highlighted the prognostic value of the cfDNA rate at diagnosis. Our study showed that a corresponding circulating PIK3CA mutation was identified in 55% of LAIBC patients with PIK3CA-mutated tumours, while no circulating mutation was found among patients with PI3KCA wild-type tumours.

Place des biopsies liquides dans le diagnostic et la caractérisation moléculaire des cancers du sein: Role of liquid biopsies in the diagnosis and molecular characterization of breast cancer.

The tumor biopsy remains essential for breast cancer diagnosis and characterization. Indeed, the treatment is decided according to histological subtype, and according to the presence of targetable molecular alterations. Notably, the presence of hormone receptors, ERBB2 hyperexpression or the existence of PIK3CA or ESR1 mutations are among the alterations commonly investigated. But these biological characteristics are determined only partially by tumor biopsy, due to tumor heterogeneity or tumor plasticity that happens spontaneously or under treatment. Liquid biopsy, and in particular circulating tumor DNA and circulating tumor cells, is a non-invasive method to identify and characterize the presence of cancer in the blood. The aim of this review is to determine the value of liquid biopsy to enhance or replace the data provided by a tumor biopsy.

Deprived social status is associated with decreased use of oral chemotherapy in patients with metastatic colorectal cancer: A retrospective cohort study on administrative databases in a French University Hospital.

Factors associated with the choice of oral versus intravenous CT are not clearly established. Our purpose was to evaluate the influence of social status and home distance to hospital on the use of oral CT in patients with metastatic colorectal cancer (mCRC). This retrospective single-center study included mCRC patients between 2011 and 2017. Patient social status was assessed by European Deprivation Index (EDI) and home distance to the hospital was calculated. Univariable and multivariable logistic regression analyses were performed. One hundred and seventy-five mCRC patients were included, with 71 receiving oral CT. Most deprived patients received less oral CT (OR 0.5 [0.26, 0.96], p = .039). No association was found for road distance. Previous use of adjuvant oral CT was associated with oral CT in mCRC (OR 2.65 [1.06, 6.66], p = .038). Our results suggest that deprived social status is a factor associated with decreased use of oral CT in patients with mCRC. Clinical trial registration: no registration.