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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

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

This article presents the protective measures put in place at the “Institut de Cancérologie des Hospices de Lyon” (IC-HCL) during the first wave of the COVID-19 pandemic in France (spring 2020) and how they impacted IC-HCL clinical activity. Spring 2020 activities were compared to winter 2019–2020. Results showed a decrease of activity of 9% for treatment dispensations, 17% for multidisciplinary team meetings, 20% for head and neck and thoracic surgeries, and 58% for new patient enrolment in clinical trials. Characteristics of patients treated for solid cancer and hospitalized for COVID-19 during spring 2020 were collected in a retrospective study. Mortality was attributed to COVID-19 for half of the cases, 82% being patients above 70 and 73% being stage IV. This is in concordance with current findings concluding that the risk of developing severe or critical symptoms of COVID-19 is correlated with factors co-occurring in cancer patients and not to the cancer condition per se. While a number of routines and treatment regimens were changed, there was no major decline in numbers of treatments conducted at the IC-HCL during the first wave of the COVID-19 pandemic that hit France between March and May 2020, except for clinical trials and some surgery activities.

Simple Summary This article presents the protective measures put in place at the “Institut de Cancérologie des Hospices de Lyon” (IC-HCL) during the first wave of the COVID-19 pandemic in France (spring 2020) and how they impacted IC-HCL clinical activity. Spring 2020 activities were compared to winter 2019–2020. Abstract This article presents the protective measures put in place at the “Institut de Cancérologie des Hospices de Lyon” (IC-HCL) during the first wave of the COVID-19 pandemic in France (spring 2020) and how they impacted IC-HCL clinical activity. Spring 2020 activities were compared to winter 2019–2020. Results showed a decrease of activity of 9% for treatment dispensations, 17% for multidisciplinary team meetings, 20% for head and neck and thoracic surgeries, and 58% for new patient enrolment in clinical trials. Characteristics of patients treated for solid cancer and hospitalized for COVID-19 during spring 2020 were collected in a retrospective study. Mortality was attributed to COVID-19 for half of the cases, 82% being patients above 70 and 73% being stage IV. This is in concordance with current findings concluding that the risk of developing severe or critical symptoms of COVID-19 is correlated with factors co-occurring in cancer patients and not to the cancer condition per se. While a number of routines and treatment regimens were changed, there was no major decline in numbers of treatments conducted at the IC-HCL during the first wave of the COVID-19 pandemic that hit France between March and May 2020, except for clinical trials and some surgery activities.

Food-related sensory alterations are prevalent among cancer patients and negatively impact their relationship with food, quality of life, and overall health outcome. In addition to taste and smell, food perception is also influenced by somatosensation comprising tactile, thermal, and chemesthetic sensations; yet studies on oral somatosensory perception of cancer patients are lacking to provide patients with tailored nutritional solutions. The present review aimed to summarise findings on the oral somatosensory perception of head and neck cancer (HNC) patients and the potential aetiologies of somatosensory alterations among this population. Subjective assessments demonstrated alterations in oral somatosensory perception such as sensitivity to certain textures, spices, and temperatures. Physiological changes in oral somatosensation have been observed through objective assessments of sensory function, showing reduced localised tactile function and thermal sensitivity. Changes in whole-mouth tactile sensation assessed using texture discrimination and stereognosis ability seem to be less evident. Available evidence indicated oral somatosensory alterations among HNC patients, which may affect their eating behaviour, but more studies with larger sample sizes and standardised assessment methods are needed. Unlike other types of cancers, sensory alterations in HNC patients are not only caused by the treatments, but also by the cancer itself, although the exact mechanism is not fully understood. Prevalent oral complications, such as xerostomia, dysphagia, mucositis, and chemosensory alterations, further modify their oral condition and food perception. Oral somatosensory perception of cancer patients is an under-investigated topic, which constitutes an important avenue for future research due to its potential significance on eating behaviour and quality of life.

Context: Polymerase epsilon (POLE) gene missense hotspot mutations can generate pathogenic (p) proofreading defects resulting in hypermutated genomic profiles. Aim: Determine the prevalence, genomic consequences and immunotherapy sensitivity of advanced POLE mutated tumors according to mutation site, primary tumor and tumor mutational burden (TMB). Results: Pan-Cancer TCGA & MSKCC databases genomic analyses found a prevalence of non-pathogenic POLE mutations (POLEnp) of 3.4% with median TMB of 11 mutations/Megabase (mt/Mb, IQR 3-34). Pathogenic POLE mutations (POLEp) prevalence was 0.4% with median TMB of 215 mt/Mb (IQR 107-324), predominantly in colorectal and endometrial cancers. Prevalence dropped to 0.1% in metastatic cancers. We assessed prospectively the efficacy of PD-1 blockade in mismatch repair proficient advanced solid tumors harboring POLE missense mutations (phase II ASCe Nivolumab trial; NCT03012581). Variants were categorized prospectively by a molecular board as POLEp, POLEnp or Variants with Unknown significance (VUS). The primary endpoint was the Overall Response Rate (ORR) at 12 weeks according to RECIST 1.1, and secondary endpoints included survival analyses according to POLE variants pathogenicity. Among 61 screened patients, 21 were eligible and 20 received Nivolumab and 19 were assessable for response (table 1). The 12-week ORR was 37% for patients harboring POLEp and VUS and resulted in major survival improvement compared to POLEnp patients (HR=0.1 ; CI95% 0.02-0.7); see results in Table 1. Among patients POLEp tumors, while higher TMB was not predictive of response, higher proportion of POLE-related mutational signature correlated with improved benefit. In silico exonucleasic POLE domain analyses confirmed that all POLEp and 2 VUS clustered in the DNA binding or the Catalytic site. Recategorizing the VUS according to the location within the exonucleasic domain improved the prediction of survival outcomes. Impact: This study gives new insights on how DNA repair defects, mutational burden and signatures sensitize to PD-1 blockade and may offer emerging tumor agnostic biomarkers for benefit to checkpoint blockade. POLE variant pathogenicity All(N=21) POLEnp(N=5) VUS(N=4) POLEp(N=12) Age, years ± SD 57 ± 16 64 ± 10 56 ± 16 54 ± 17 Sex, Male (%) 12 (57) 5 (100) 2 (50) 5 (42) PS (ECOG)=1 (%) 16 (75) 4 (80) 2 (50) 10 (83) Primary tumor Colorectal 9 (43) 2 (40) 2 (50) 5 (42) Endometrial 6 (29) 0 (0) 0 (0) 6 (50) Gastric 2 (9) 2 (40) 0 (0) 0 (0) Glial 1 (5) 0 (0) 0 (0) 1 (8) Biliary tract 1 (5) 0 (0) 1 (25) 0 (0) Pancreas 2 (9) 1 (20) 1 (25) 0 (0) Number of previous treatments 2.4 ± 2 5 ± 2 1.8 ± 1 1.5 ± 1 TMB (mt/Mb, Min-Max)(N=16) 36.2 (2-385) 5 (4-9) 3 (2-4) 114 (25-385) ORR at 12 weeks (CR+PR) 37%(N=7/19) 0%(N=0/5) 50%(N=2/4) 46%(5/10) DCR at 12 weeks (CR+PR+SD) 58%(N=11/19) 0%(N=0/5) 75%(N=3/4) 80%(8/10) Median Progresssion-Free survival (months) 5.6 2.3 10.3vs POLEnp: HR=0.2 IC95% 0.1-0.7 Median Overall Survival (months) 9.1 5.0 Not Reachedvs POLEnp:HR=0.1 IC95% 0.02-0.7 Citation Format: Benoît Rousseau, Ivan Bieche, Eric Pasmant, Nadim Hamzaoui, Nicolas Leulliot, Lucas Michon, Aurelien de Reynies, Mike Foote, Julien Masliah-Planchon, Magali Svrcek, Romain Cohen, Victor Simmet, Paule Augereau, David Malka, Antoine Hollebecque, Damien Pouessel, Carlos Gomez-Roca, Rosine Guimbaud, Amandine Bruyas, Marielle Guillet, Muriel Duluc, Sophie Cousin, Christelle de la Fourchardiere, Frederic Rolland, Sandrine Hiret, Esma Saada-Bouzid, Olivier Bouche, Thierry Andre, Diane Pannier, Farid El Hajbi, Stephane Oudard, Christophe Tournigand, Jean-Charles Soria, Drew Gerber, Dennis Stephens, Michelle Lamandola-Essel, Steven B Maron, Bill Diplas, Guillem Argiles, Asha Krishnan, Neil Segal, Andrea Cercek, Nathalie Hoog-Labouret, Frederic Legrand, Clotide Simon, Assia Lamrani-Ghaouti, Luis A. Diaz, Pierre Saintigny, Sylvie Chevret, Aurelien Marabelle. PD-1 blockade in solid tumors with defects in polymerase epsilon [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT021.

Resume Introduction La neutropenie febrile (NF) est une complication severe de l’administration de chimiotherapie. A partir des donnees issues de la base PMSI, l’objectif de ce travail est d’estimer l’impact clinique induit par les hospitalisations pour NF, en termes de nombre de patients hospitalises, nombre de sejours et mortalite hospitaliere. Methodes Un algorithme a ete utilise pour selectionner dans la base PMSI les patients traites par chimiotherapie (1 re annee de traitement) et ayant ete hospitalises pour NF au cours des 30 jours suivants l’administration de chimiotherapie. Le nombre, les caracteristiques et les comorbidites des patients hospitalises pour NF ont ete decrits, ainsi que le nombre et la duree de sejours et la mortalite hospitaliere. Resultats En 2010–2011, une hospitalisation pour NF a concerne 10 229 patients, representant un taux d’hospitalisation de 7,4 % chez les patients nouvellement diagnostiques d’un cancer et traites par chimiotherapie. Au total, 13 559 sejours ont ete generes, d’une duree moyenne de 6,3 ± 8,7 jours. Au total, 720 deces hospitaliers sont survenus, correspondant a un taux de mortalite de 7 %. Quatorze pour cent des patients hospitalises pour NF chimio-induite souffrent de diabete, 8 % d’insuffisance cardiaque, 34 % d’hypertension et 41 % d’au moins une de ces 3 comorbidites. Discussion L’impact clinique induit par la neutropenie febrile chez les patients atteints de cancer et traites par chimiotherapie est considerable au cours de la premiere annee de traitement, induisant une hospitalisation chez 10 299 patients et 13 559 sejours hospitaliers.

Acute pancreatitis is an inflammatory disorder of the pancreas characterized by upper abdominal pain, nausea, and vomiting, with elevated serum amylase or lipase. Gallstones and alcohol are the two main etiologies; drug-induced pancreatitis is uncommon. Paclitaxel associated with pancreatitis is very rare and since that time, only seven case reports have been published. We report a case of a 54-year-old female who developed an acute pancreatitis after administration of the first cycle of neoadjuvant chemotherapy with paclitaxel (175 mg/m2 over 3 h) and carboplatin (AUC 6) for ovarian adenocarcinoma. After conservative management, pancreatitis was resolved. The patient received an additional five cycles of carboplatin with no complication. Because Paclitaxel is used in many chemotherapy protocols, it is important for clinicians to be aware that paclitaxel can induce acute pancreatitis, as early diagnosis can be vital.

International audience; PURPOSE: Age induces a progressive decline in functional reserve and impacts cancer treatments. Telomere attrition leads to tissue senescence. We tested the hypothesis that telomere length (TL) could predict patient vulnerability and outcome with cancer treatment. PATIENTS AND METHODS: An ancillary study in the Elderly Women GINECO Trial 3 was performed to evaluate the impact of geriatric covariates on survival in elderly advanced ovarian cancer patients receiving six cycles of carboplatin. TL was estimated from peripheral blood at inclusion using standard procedures. RESULTS: TL (in base pairs) was estimated for 109/111 patients (median 6.1 kb; range [4.5-8.3 kb]). With a cut-off of 5.77 kb, TL discriminated two patient groups, long telomere (LT) and short telomeres (ST), with significantly different treatment completion rates of 0.80 (95% CI [0.71-0.89]) and 0.59 (95% CI [0.41-0.76]), respectively (odds ratio [OR]=2.8, p=0.02). ST patients were at higher risk of serious adverse events (SAE, OR=2.7; p=0.02) and had more unplanned hospital admissions (OR=2.1; p=0.08). After adjustment on FIGO stage, TL shorter than 6 kb was a risk factor of premature death (HR=1.57; p=0.06). CONCLUSION: This exploratory study identifies TL as predictive factor of decreased treatment completion, SAE risk, unplanned hospital admissions and OS after adjustment on FIGO stage.

Febrile neutropenia (FN) is a severe complication of chemotherapy in terms of morbidity and mortality. Using data from the PMSI database, the objective of this work was to estimate the clinical burden caused by hospitalization for FN in France, assessed by number of patients, number of stays and hospital mortality.Using the PMSI database (which includes all hospitalizations occurring annually in France), an algorithm was used to select newly-diagnosed patients treated by chemotherapy in 2010/2011 who were hospitalized for FN within the 30 days following each administration of chemotherapy during their first year of treatment. The number, characteristics and comorbidities of patients were described, as well as the number and length of stay and mortality in hospitalized patients.In 2010-11, 10,229 patients were hospitalized for FN, representing a hospitalization rate of 7.4% in newly-diagnosed patients receiving chemotherapy. A total of 13,559 stays were identified, with an average duration of 6.3±8.7 days (median=4 days). A total of 720 deaths occurred during the hospital stays, corresponding to a mortality rate of 7%. Among patients hospitalized for FN, there were 14% of patients with diabetes, 8 % with heart failure, 34% with hypertension and 41% with at least one of these three comorbidities.With 10,299 hospitalized patients and 13,559 stays in 2010-11, the clinical burden induced by febrile neutropenia in cancer patients treated with chemotherapy is considerable.

Occasionally, patients with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) present atypical features such as confusion, coma, or nonconvulsive status epilepticus. Acute focal neuropsychological syndrome revealing the disease has been poorly documented. We report the atypical presentation of two patients in whom CADASIL was revealed by an episode of headache followed by focal neuropsychological impairment.

Olivia Le Saux,1 Bertrand Ripamonti,2 Amandine Bruyas,3,4 Olivier Bonin,4 Gilles Freyer,1,4 Marc Bonnefoy,4,5 Claire Falandry4,51Medical Oncology Unit, Lyon Sud University Hospital, Hospices Civils de Lyon, Pierre-Bénite, 2Gynaecology-Obstetrics Department, University Hospital, Saint-Etienne, 3Croix Rousse University Hospital, Hospices Civils de Lyon, Pierre-Bénite, 4Lyon University, Lyon, 5Geriatric Unit, Lyon Sud University Hospital, Hospices Civils de Lyon, Pierre-Bénite, FranceAbstract: Breast cancer (BC) is the most common female malignancy in the world and almost one third of cases occur after 70 years of age. Optimal management of BC in the elderly is a real challenge and requires a multidisciplinary approach, mainly because the elderly population is heterogeneous. In this review, we describe the various possibilities of treatment for localized or metastatic BC in an aging population. We provide an overview of the comprehensive geriatric assessment, surgery, radiotherapy, and adjuvant therapy for early localized BC and of chemotherapy and targeted therapies for metastatic BC. Finally, we attempt to put into perspective the necessary balance between the expected benefits and risks, especially in the adjuvant setting.Keywords: elderly, breast cancer, geriatric assessment, surgery, chemotherapy, radiotherapy