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PURPOSE In patients with resectable gastric/gastroesophageal junction (GEJ) adenocarcinoma, surgery plus perioperative platinum-based chemotherapy is the standard of care. Perioperative chemotherapy remains debatable for gastric/GEJ adenocarcinoma with deficient mismatch repair (dMMR)/microsatellite instability–high (MSI-H). PATIENTS AND METHODS NEONIPIGA (ClinicalTrials.gov identifier: NCT04006262 ) phase II study evaluated neoadjuvant nivolumab 240 mg once every two weeks ×6 and ipilimumab 1 mg/kg once every six weeks ×2, followed by surgery and adjuvant nivolumab 480 mg once every four weeks (nine injections) in patients with locally advanced resectable dMMR/MSI-H, clinical (c) tumor (T)2-T4 node (N)x metastasis (M)0 gastric/GEJ adenocarcinoma. The primary end point was a pathological complete response (pCR) rate. RESULTS Between October 2019 and June 2021, 32 patients with dMMR/MSI-H gastric/GEJ adenocarcinoma were enrolled. The median age was 65.5 years (range, 40-80). Clinical stages were cT2-T3N0 (n = 9), cT2-T3N1 (n = 22), and cT3N1M1 (n = 1, wrongly included). With a median follow-up of 14.9 months (95% CI, 10.6 to 17.6), 32 patients received neoadjuvant immunotherapy (27 patients completed all cycles). Neoadjuvant therapy-related grade 3/4 adverse events occurred in six patients (19%). Twenty-nine patients underwent surgery; three did not have surgery and had complete endoscopic response with tumor-free biopsies and a normal computed tomography scan (two refused surgery and one had metastasis at inclusion). The rate of surgical morbidity (Clavien-Dindo classification) was 55% (one postoperative death occurred). All 29 patients had an R0 resection, and 17 (58.6%; 90% CI, 41.8 to 74.1) had pCR (pathological T0N0). Becker tumor regression grades 1a, 1b, 2, and 3 were observed in 17 patients, three (including two pathological T0N1), two, and seven patients, respectively. Of the 29 patients with surgery, 23 received adjuvant nivolumab. At database lock, no patient had relapse and one died without relapse. CONCLUSION Nivolumab and ipilimumab-based neoadjuvant therapy is feasible and associated with no unexpected toxicity and a high pCR rate in patients with dMMR/MSI-H resectable gastric/GEJ adenocarcinoma.

International audience; IntroductionThe SARS-CoV-2 pandemic has impacted the care of cancer patients. This study sought to assess the pandemic’s impact on the clinical presentations and outcomes of newly referred patients with lung cancer from the Greater Paris area.MethodsWe retrospectively retrieved the electronic health records and administrative data of 11.4 million patients pertaining to Greater Paris University Hospital (AP-HP). We compared indicators for the 2018-2019 period to those of 2020 in regard to newly referred lung cancer cases. We assessed initial tumor stage, delay between first multidisciplinary tumor board (MTB) and anticancer treatment initiation, and 6-month overall survival (OS) rates depending on the anticancer treatment including surgery, palliative systemic treatment, and best supportive care (BSC).ResultAmong 6,240 patients with lung cancer, 2,179 (35%) underwent tumor resection, 2,069 (33%) systemic anticancer therapy, 775 (12%) BSC, whereas 1,217 (20%) did not receive any treatment. During the first lockdown, the rate of new diagnoses decreased by 32% compared with that recorded in 2018-2019. Initial tumor stage, repartition of patients among treatment categories, and MTB-related delays remained unchanged. The 6-month OS rates of patients diagnosed in 2018-2019 who underwent tumor resection were 98% vs. 97% (HR=1.2; 95% CI: 0.7-2.0) for those diagnosed in 2020; the respective rates for patients who underwent systemic anticancer therapy were 78% vs. 79% (HR=1.0; 95% CI: 0.8-1.2); these rates were 20% vs. 13% (HR=1.3; 95% CI: 1.1-1.6) for those who received BSC. COVID-19 was associated with poorer OS rates (HR=2.1; 95% CI: 1.6-3.0) for patients who received systemic anticancer therapy.ConclusionsThe SARS-CoV-2 pandemic has not exerted any deleterious impact on 6-month OS of new lung cancer patients that underwent active anticancer therapy in Greater Paris University hospitals.

Patients with hepatocellular carcinoma (HCC) displaying overexpression of immune gene signatures are likely to be more sensitive to immunotherapy, however, the use of such signatures in clinical settings remains challenging. We thus aimed, using artificial intelligence (AI) on whole-slide digital histological images, to develop models able to predict the activation of 6 immune gene signatures.AI models were trained and validated in 2 different series of patients with HCC treated by surgical resection. Gene expression was investigated using RNA sequencing or NanoString technology. Three deep learning approaches were investigated: patch-based, classic MIL and CLAM. Pathological reviewing of the most predictive tissue areas was performed for all gene signatures.The CLAM model showed the best overall performance in the discovery series. Its best-fold areas under the receiver operating characteristic curves (AUCs) for the prediction of tumors with upregulation of the immune gene signatures ranged from 0.78 to 0.91. The different models generalized well in the validation dataset with AUCs ranging from 0.81 to 0.92. Pathological analysis of highly predictive tissue areas showed enrichment in lymphocytes, plasma cells, and neutrophils.We have developed and validated AI-based pathology models able to predict the activation of several immune and inflammatory gene signatures. Our approach also provides insights into the morphological features that impact the model predictions. This proof-of-concept study shows that AI-based pathology could represent a novel type of biomarker that will ease the translation of our biological knowledge of HCC into clinical practice.Immune and inflammatory gene signatures may be associated with increased sensitivity to immunotherapy in patients with advanced hepatocellular carcinoma. In the present study, the use of artificial intelligence-based pathology enabled us to predict the activation of these signatures directly from histology.

This prospective pharmacokinetic (PK) ancillary study of the TEXCAN phase II GERCOR trial of patients with chemorefractory metastatic colorectal cancer and treated with regorafenib (REGO) investigated correlations between overall survival (OS) and concentrations (C) of REGO and its active metabolites, M-2 and M-5.55 patients received REGO 160 mg/day for 21 days of a 28-day cycle (NCT02699073). REGO, M-2, M-5 were measured by liquid chromatography-mass spectrometry assay on day 15 of cycle 1 (C1) and 2 (C2). We studied the association between OS and Cmin of REGO, M-2 and M-5 at C1 and their accumulations between C1 and C2.Medians of C2/C1 M-2 and M-5 ratios were 0.82 (interquartile range 0.50-1.78) and 0.75 (interquartile range 0.41-1.93), respectively. Patients with C2/C1 M-2 ratio ≥ median had improved survival compared to those median (12.6 versus 4.0 months, P = 0.023), corresponding to a 66% mortality risk reduction in multivariate analysis. The C2/C1 M-2 ratio correlated with C1 REGO+M-2+M-5 (Csum; P = 0.006). Restricted cubic spline analysis showed an increased OS benefit as the C2/C1 M-2 ratio raises and when C1 Csum ranged between 2.5 and 5.5 mg/L. Patients within the Csum range had a reduced incidence of serious adverse events and improved OS.We identified PK parameters associated with a survival benefit in patients with metastatic colorectal cancer treated by REGO. OS and safety were favourable when C1 REGO+M-2+M-5 Csum ranged between 2.5 and 5.5 mg/L. These results pave the way for individual REGO dose modification strategies based on PK monitoring.NCT02699073.

Background Severe chemotherapy-related toxicities are frequent among older patients. The Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) and the Cancer and Aging Research Group Study (CARG) score were both developed to predict these events. Patients and Methods The objective of this study was to evaluate the scores’ predictive performance in a prospective cohort, which included patients aged 70 years and older referred for a geriatric assessment prior to chemotherapy for a solid tumor. The main endpoints were grades 3/4/5 toxicities for the CARG score and grades 4/5 hematologic toxicities and grades 3/4/5 non-hematologic toxicities for the CRASH score. Results A total of 248 patients were included, of which 150 (61%) and 126 (51%) experienced at least one severe adverse event as defined respectively in CARG and CRASH studies. The incidence of adverse events was not significantly greater in the intermediate and high-risk CARG groups than in the low-risk group (odds ratio (OR) [95% CI] = 0.3 [0.1-1.4] (P = .1) and 0.4 [0.1-1.7], respectively). The area under curve (AUC) was 0.55. Similarly, the incidence of severe toxicities was no greater in the intermediate-low, intermediate-high, and high-risk CRASH groups than in the low-risk CRASH group (OR [95%CI] = 1 [0.3-3.6], 1 [0.3-3.4], and 1.5 [0.3-8.1], respectively). The AUC was 0.52. The type of cancer, performance status, comorbidities, body mass index, and MAX2 index were independently associated with grades 3/4/5 toxicities. Conclusion In an external cohort of older patients referred for a pretherapeutic GA, the CARG and CRASH scores were poor predictors of the risk of chemotherapy severe toxicities.

Supplementary Figure from PD-1 Blockade in Solid Tumors with Defects in Polymerase Epsilon

Supplementary Data from PD-1 Blockade in Solid Tumors with Defects in Polymerase Epsilon

Missense mutations in the polymerase epsilon (POLE) gene have been reported to generate proofreading defects resulting in an ultramutated genome and to sensitize tumors to checkpoint blockade immunotherapy. However, many POLE-mutated tumors do not respond to such treatment. To better understand the link between POLE mutation variants and response to immunotherapy, we prospectively assessed the efficacy of nivolumab in a multicenter clinical trial in patients bearing advanced mismatch repair–proficient POLE-mutated solid tumors. We found that only tumors harboring selective POLE pathogenic mutations in the DNA binding or catalytic site of the exonuclease domain presented high mutational burden with a specific single-base substitution signature, high T-cell infiltrates, and a high response rate to anti–PD-1 monotherapy. This study illustrates how specific DNA repair defects sensitize to immunotherapy. POLE proofreading deficiency represents a novel agnostic biomarker for response to PD-1 checkpoint blockade therapy.Significance:POLE proofreading deficiency leads to high tumor mutational burden with high tumor-infiltrating lymphocytes and predicts anti–PD-1 efficacy in mismatch repair–proficient tumors. Conversely, tumors harboring POLE mutations not affecting proofreading derived no benefit from PD-1 blockade. POLE proofreading deficiency is a new tissue-agnostic biomarker for cancer immunotherapy.See related video: https://vimeo.com/720727355This article is highlighted in the In This Issue feature, p. 1397

Supplemental figures 1-10

Supplementary Table 5: Difference in gene expression between Immune High (IH) and Immune Low (IL) subgroups from the validation dataset (n=20, Coulouarn et al, Carcinogenesis, 2012) (33).

Influence of bevacizumab (Beva), erlotinib (Erlo) and their combination (Beva + Erlo) on the tumor growth of CRC xenografts.

Purpose: There is extensive cross-talk between VEGF- and EGFR-pathway signaling in colorectal cancer. However, combinations of VEGF- and EGFR-targeted monoclonal antibodies (mAb) show disappointing activity, in particular for patients with mutant RAS. Previous results show that tyrosine kinase inhibitors (TKI) can be active in colorectal cancer models resistant to mAbs. This prompted us to examine whether the activity of bevacizumab can be increased by combination with erlotinib.Experimental Design: The antitumor activity of bevacizumab, erlotinib, and their combination was determined in colorectal cancer models with different RAS status and bevacizumab sensitivity. EGFR/VEGF pathway activation was characterized by immunohistochemistry, Western blot, and ELISA assays. The influence of cetuximab and erlotinib on EGF-mediated migration and the EGFR–EGF ligand feedback loop was established in colorectal cancer cell lines with different RAS status.Results: The addition of erlotinib increased bevacizumab activity in all models independent of RAS status. Bevacizumab exposure was accompanied by marked EGFR activation in tumor cells as well as in tumor-associated endothelial cells (TECs) and resulted in strong accumulation of intracellular EGFR, which could be attenuated by erlotinib. In cellular models, erlotinib was able to attenuate EGF-mediated functions in all cell lines independent of RAS status while cetuximab only showed activity in RAS wild-type cells.Conclusions: These results should provide a molecular framework to better understand the increased activity of the bevacizumab–erlotinib combination, compared with bevacizumab alone, in the GERCOR DREAM phase III clinical trial. Differential activity of mAbs and TKIs targeting the same signaling pathway is likely applicable for other tumor types. Clin Cancer Res; 24(11); 2548–58. ©2018 AACR.

Supplementary Table 3: Difference in gene expression between IH1 and IH2 subtypes IH: Immune - High

Supplementary Table 1: Difference in gene expression between IL and IH subtypes

Supplementary Table 6: Difference in gene expression between Immune High 1 (IH1) and Immune High 2 (IH2) subgroups in the validation dataset (n=20, Coulouarn et al, Carcinogenesis, 2012) (33).

The influence of 72 hrs exposure to vehicle, erlotinib (Erlo, 10 µM) or cetuximab (Cetux, 1 µg/mL) on the viability of the indicated CRC cell lines as measured by the TUNEL assay.

The expression of total VEGFR1 and VEGFR2 was determined by ELISA analysis of tumor extracts (3 tumors per treatment).

Supplementary Table 8: Molecular alterations identified in cHCC-CCA

Supplementary Table 7: Difference in gene expression between Immune Low 1 (IL1) and Immune Low 2 (IL2) subgroups in the validation dataset (n=20, Coulouarn et al. Carcinogenesis. 2012) (33).

Supplementary Table 4: Difference in gene expression between IL1 and IL2 subtypes IL: Immune - Low

Legend to supplementary data

Purpose:Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare malignancy associated with an overall poor prognosis. We aimed to investigate the immune profile of cHCC-CCA and determine its impact on disease outcome.Experimental Design:We performed a multicenter study of 96 patients with cHCC-CCA. Gene expression profile was analyzed using nCounter PanCancer IO 360 Panel. Densities of main immune cells subsets were quantified from digital slides of IHC stainings. Genetic alterations were investigated using targeted next-generation sequencing.Results:Two main immune subtypes of cHCC-CCA were identified by clustering analysis: an “immune-high” (IH) subtype (57% of the cases) and an “immune-low” (IL) subtype (43% of the cases). Tumors classified as IH showed overexpression of genes related to immune cells recruitment, adaptive and innate immunity, antigen presentation, cytotoxicity, immune suppression, and inflammation (P < 0.0001). IH cHCC-CCAs also displayed activation of gene signatures recently shown to be associated with response to immunotherapy in patients with HCC. Quantification of immunostainings confirmed that IH tumors were also characterized by higher densities of immune cells. Immune subtypes were not associated with any genetic alterations. Finally, multivariate analysis showed that the IH subtype was an independent predictor of improved overall survival.Conclusions:We have identified a subgroup of cHCC-CCA that displays features of an ongoing intratumor immune response, along with an activation of gene signatures predictive of response to immunotherapy in HCC. This tumor subclass is associated with an improved clinical outcome. These findings suggest that a subset of patients with cHCC-CCA may benefit from immunomodulating therapeutic approaches.

International audience; Background: The coronavirus disease 2019 (COVID-19) pandemic has had a dramatic impact on cancer diagnosis and treatment. Most patients newly diagnosed with digestive system cancer are aged 65 and over. Methods: We performed a retrospective, observational, multicentre cohort study based on prospectively collected electronic health records. All adults aged 65 or over and having been newly treated for a digestive system cancer between January 2018 until August 2020 were enroled. Results: Data on 7882 patients were analysed. The first COVID-19 lockdown period led to a 42.4% decrease in newly treated digestive system cancers, and the post-lockdown period was associated with a 17% decrease. The decrease in newly treated digestive system cancer did not differ as a function of age, sex, comorbidities, primary tumour site, and disease stage. The proportion of patients admitted to an emergency department increased during the lockdown period. We do not observe a higher 3-month mortality rate in 2020, relative to the corresponding calendar periods in 2018 and 2019. Conclusion: To avoid a decrease in newly treated cancers during future lockdown periods, access to healthcare will have to be modified. Although 3-month mortality did not increase in any of the patient subgroups, the 2020 cohort must be followed up for long-term mortality.

IMPORTANCE: Patients with solid cancer are more susceptible to develop SARS-CoV-2 infection and severe complications; the immunogenicity in patients treated with anticancer agents remains unknown. OBJECTIVE: To assess the immune humoral response to 2 or 3 doses of the BNT162b2 (BioNTech; Pfizer) vaccine in patients treated with anticancer agents. DESIGN, SETTING, AND PARTICIPANTS: A prospective observational cohort study was conducted between February 1 and May 31, 2021. Adults treated with anticancer agents who received 2 or 3 doses of vaccine were included; of these, individuals with a weak humoral response 1 month after the second dose received a third injection. INTERVENTIONS: Quantitative serologic testing of antibodies specific for SARS-CoV-2 was conducted before vaccination and during follow-up. MAIN OUTCOMES AND MEASURES: Humoral response was evaluated with a threshold of anti–SARS-CoV-2 spike protein antibody levels at 1000 arbitrary units (AU)/mL to neutralize less-sensitive COVID-19 variants. RESULTS: Among 163 patients (median [range] age, 66 [27-89] years, 86 men [53%]) with solid tumors who received 2 or 3 doses of vaccine, 122 individuals (75%) were treated with chemotherapy, 15 with immunotherapy (9%), and 26 with targeted therapies (16%). The proportions of patients with an anti-S immunoglobulin G titer greater than 1000 AU/mL were 15% (22 of 145) at the time of the second vaccination and 65% (92 of 142) 28 days after the second vaccination. Humoral response decreased 3 months after the second dose. Treatment type was associated with humoral response; in particular, time between vaccine and chemotherapy did not interfere with the humoral response. Among 36 patients receiving a third dose of vaccine, a serologic response greater than 1000 AU/mL occurred in 27 individuals (75%). CONCLUSIONS AND RELEVANCE: The results of this cohort study appear to support the use of a third vaccine dose among patients with active cancer treatment for solid tumors.

International audience; (EDS) regroupent de nombreuses informations disponibles sur les patients traités au sein d'un établissement hospitalier. Ces données ont été largement utilisées pendant la pandémie de Covid-19 pour informer rapidement des conséquences de la crise Covid-19 sur l'état de santé des patients, notamment en cancérologie. Néanmoins, ces analyses nécessitent une grande prudence car différents types de biais peuvent survenir lors de l'exploitation de ces données. Nous présentons un bilan réflexif du travail réalisé sur l'EDS de l'Assistance Publique-Hôpitaux de Paris (AP-HP) pour analyser l'impact de la Covid19 sur la prise en charge des patients atteints de cancer. Nous analysons différents biais constatés sur les données structurées et non-structurées, et leur impact sur l'étude. Une fois ces points pris en compte, les EDS présentent un potentiel indéniable. Pour l'illustrer, nous présentons brièvement les résultats obtenus sur l'impact du Covid19 sur la prise en charge en cancérologie à l'AP-HP.

Missense mutations in the polymerase epsilon (POLE) gene have been reported to generate proofreading defects resulting in an ultramutated genome and to sensitize tumors to checkpoint blockade immunotherapy. However, many POLE-mutated tumors do not respond to such treatment. To better understand the link between POLE mutation variants and response to immunotherapy, we prospectively assessed the efficacy of nivolumab in a multicenter clinical trial in patients bearing advanced mismatch repair–proficient POLE-mutated solid tumors. We found that only tumors harboring selective POLE pathogenic mutations in the DNA binding or catalytic site of the exonuclease domain presented high mutational burden with a specific single-base substitution signature, high T-cell infiltrates, and a high response rate to anti–PD-1 monotherapy. This study illustrates how specific DNA repair defects sensitize to immunotherapy. POLE proofreading deficiency represents a novel agnostic biomarker for response to PD-1 checkpoint blockade therapy. Significance: POLE proofreading deficiency leads to high tumor mutational burden with high tumor-infiltrating lymphocytes and predicts anti–PD-1 efficacy in mismatch repair–proficient tumors. Conversely, tumors harboring POLE mutations not affecting proofreading derived no benefit from PD-1 blockade. POLE proofreading deficiency is a new tissue-agnostic biomarker for cancer immunotherapy. See related video: https://vimeo.com/720727355 This article is highlighted in the In This Issue feature, p. 1397