H2AX promotes replication fork degradation and chemosensitivity in BRCA-deficient tumours.

Histone H2AX plays a key role in DNA damage signalling in the surrounding regions of DNA double-strand breaks (DSBs). In response to DNA damage, H2AX becomes phosphorylated on serine residue 139 (known as γH2AX), resulting in the recruitment of the DNA repair effectors 53BP1 and BRCA1. Here, by studying resistance to poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA1/2-deficient mammary tumours, we identify a function for γH2AX in orchestrating drug-induced replication fork degradation. Mechanistically, γH2AX-driven replication fork degradation is elicited by suppressing CtIP-mediated fork protection. As a result, H2AX loss restores replication fork stability and increases chemoresistance in BRCA1/2-deficient tumour cells without restoring homology-directed DNA repair, as highlighted by the lack of DNA damage-induced RAD51 foci. Furthermore, in the attempt to discover acquired genetic vulnerabilities, we find that ATM but not ATR inhibition overcomes PARP inhibitor (PARPi) resistance in H2AX-deficient tumours by interfering with CtIP-mediated fork protection. In summary, our results demonstrate a role for H2AX in replication fork biology in BRCA-deficient tumours and establish a function of H2AX separable from its classical role in DNA damage signalling and DSB repair.

Clinical effectiveness and safety of olaparib in BRCA-mutated, HER2-negative metastatic breast cancer in a real-world setting: final analysis of LUCY.

PURPOSE: The interim analysis of the phase IIIb LUCY trial demonstrated the clinical effectiveness of olaparib in patients with germline BRCA-mutated (gBRCAm), human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (mBC), with median progression-free survival (PFS) of 8.11 months, which was similar to that in the olaparib arm of the phase III OlympiAD trial (7.03 months). This prespecified analysis provides final overall survival (OS) and safety data. METHODS: The open-label, single-arm LUCY trial of olaparib (300 mg, twice daily) enrolled adults with gBRCAm or somatic BRCA-mutated (sBRCAm), HER2-negative mBC. Patients had previously received a taxane or anthracycline for neoadjuvant/adjuvant or metastatic disease and up to two lines of chemotherapy for mBC. RESULTS: Of 563 patients screened, 256 (gBRCAm, n = 253; sBRCAm, n = 3) were enrolled. In the gBRCAm cohort, median investigator-assessed PFS (primary endpoint) was 8.18 months and median OS was 24.94 months. Olaparib was clinically effective in all prespecified subgroups: hormone receptor status, previous chemotherapy for mBC, previous platinum-based chemotherapy (including by line of therapy), and previous cyclin-dependent kinase 4/6 inhibitor use. The most frequent treatment-emergent adverse events (TEAEs) were nausea (55.3%) and anemia (39.2%). Few patients (6.3%) discontinued olaparib owing to a TEAE. No deaths associated with AEs occurred during the study treatment or 30-day follow-up. CONCLUSION: The LUCY patient population reflects a real-world population in line with the licensed indication of olaparib in mBC. These findings support the clinical effectiveness and safety of olaparib in patients with gBRCAm, HER2-negative mBC. CLINICAL TRIAL REGISTRATION: Clinical trials registration number: NCT03286842.

The clinical challenges of homologous recombination proficiency in ovarian cancer: from intrinsic resistance to new treatment opportunities.

Ovarian cancer is the most lethal gynecologic cancer. Optimal cytoreductive surgery followed by platinum-based chemotherapy with or without bevacizumab is the conventional therapeutic strategy. Since 2016, the pharmacological treatment of epithelial ovarian cancer has significantly changed following the introduction of the poly (ADP-ribose) polymerase inhibitors (PARPi). BRCA1/2 mutations and homologous recombination deficiency (HRD) have been established as predictive biomarkers of the benefit from platinum-based chemotherapy and PARPi. While in the absence of HRD (the so-called homologous recombination proficiency, HRp), patients derive minimal benefit from PARPi, the use of the antiangiogenic agent bevacizumab in first line did not result in different efficacy according to the presence of homologous recombination repair (HRR) genes mutations. No clinical trials have currently compared PARPi and bevacizumab as maintenance therapy in the HRp population. Different strategies are under investigation to overcome primary and acquired resistance to PARPi and to increase the sensitivity of HRp tumors to these agents. These tumors are characterized by frequent amplifications of Cyclin E and MYC, resulting in high replication stress. Different agents targeting DNA replication stress, such as ATR, WEE1 and CHK1 inhibitors, are currently being explored in preclinical models and clinical trials and have shown promising preliminary signs of activity. In this review, we will summarize the available evidence on the activity of PARPi in HRp tumors and the ongoing research to develop new treatment options in this hard-to-treat population.

Immunotherapy in Urological, Gynecological and Gastrointestinal Cancers - Current Landscape.

Immunotherapy is becoming increasingly important in the management of urological, gynecological, and gastrointestinal cancers. Immune checkpoint inhibitor-based combinations have become a standard of care for patients with metastatic renal and liver cancers, as well as for many patients with bladder, cervical, gastric, and esophageal cancers, based on various biomarkers. Some tumor types are less responsive to immunotherapy, such as prostate and colon cancer. In these tumors, however, a subgroup of patients with a microsatellite-instability-high/DNA-mismatch repair deficient molecular phenotype significantly benefits from immunotherapy. Molecular characterization is therefore essential to identify patients who may benefit from these treatments. One of the major challenges is the search for new predictive biomarkers and novel combinations or strategies to further improve patient outcome.

Changes of health-related quality of life 6 months after high-risk oncological upper gastrointestinal and hepatobiliary surgery: a single-centre prospective observational study (ChangeQol Study).

INTRODUCTION: Postoperative health-related quality of life (HRQoL) is an essential outcome in oncological surgery, particularly for elderly patients undergoing high-risk surgery. Previous studies have suggested that, on average, HRQoL returns to premorbid normal levels in the months following major surgery. However, the averaging of effect over a studied cohort may hide the variation of individual HRQoL changes. The proportions of patients who have a varied HRQoL response (stable, improvement, or a deterioration) after major oncological surgery is poorly understood. The study aims to describe the patterns of these HRQoL changes at 6 months after surgery, and to assess the patients and next-of-kin regret regarding the decision to undergo surgery. METHODS AND ANALYSIS: This prospective observational cohort study is carried out at the University Hospitals of Geneva, Switzerland. We include patients over 18 years old undergoing gastrectomy, esophagectomy, pancreas resection or hepatectomy. The primary outcome is the proportion of patients in each group with changes in HRQoL (improvement, stability or deterioration) 6 months after surgery, using a validated minimal clinically important difference of 10 points in HRQoL. The secondary outcome is to assess whether patients and their next-of-kin may regret their decision to undergo surgery at 6 months. We measure the HRQoL using the EORTC QLQ-C30 questionnaire before and 6 months after surgery. We assess regret with the Decision Regret Scale (DRS) at 6 months after surgery. Key other perioperative data include preoperative and postoperative place of residence, preoperative anxiety and depression (HADS scale), preoperative disability (WHODAS V.2.0), preoperative frailty (Clinical Frailty Scale), preoperative cognitive function (Mini-Mental State Examination) and preoperative comorbidities. A follow-up at 12 months is planned. ETHICS AND DISSEMINATION: The study was first approved by the Geneva Ethical Committee for Research (ID 2020-00536) on 28 April 2020. The results of this study will be presented at national and international scientific meetings, and publications will be submitted to an open-access peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT04444544.

Nab-PIPAC: a phase IB study protocol of intraperitoneal cisplatin and nab-paclitaxel administered by pressurised intraperitoneal aerosol chemotherapy (PIPAC) in the treatment of advanced malignancies confined to the peritoneal cavity.

INTRODUCTION: Intraperitoneal dissemination is a major problem resulting in very poor prognosis and a rapid marked deterioration in the quality of life of patients. Pressurised intraperitoneal aerosol chemotherapy (PIPAC) is an emergent laparoscopic procedure aiming to maximise local efficacy and to reduce systemic side effects. METHODS AND ANALYSIS: Nab-PIPAC, a bicentre open-label phase IB, aims to evaluate safety of nab-paclitaxel and cisplatin association using in patients with peritoneal carcinomatosis (PC) of gastric, pancreatic or ovarian origin as ≥1 prior line of systemic therapy. Using a 3+3 design, sequential intraperitoneal laparoscopic application of nab-paclitaxel (7.5, 15, 25, 37.5, 52.5 and 70 mg/m2) and cisplatin (10.5 mg/m2) through a nebuliser to a high-pressure injector at ambient temperature with a maximal upstream pressure of 300 psi. Treatment maintained for 30 min at a pressure of 12 mm Hg and repeated4-6 weeks intervals for three courses total.A total of 6-36 patients are expected, accrual is ongoing. Results are expected in 2024.The primary objective of Nab-PIPAC trial is to assess tolerability and safety of nab-paclitaxel and cisplatin combination administered intraperitoneally by PIPAC in patients with PC of gastric, pancreatic or ovarian origin. This study will determine maximum tolerated dose and provide pharmacokinetic data. ETHIC AND DISSEMINATION: Ethical approval was obtained from the ethical committees of Geneva and Vaud (CCER-2018-01327). The study findings will be published in an open-access, peer-reviewed journal and presented at relevant conferences and research meetings. TRIAL REGISTRATION NUMBER: NCT04000906.

[Intraperitoneal therapy for carcinomatosis in ovarian cancer: proposed treatment algorithm]. / Traitements intrapéritonéaux de la carcinose ovarienne : proposition d'algorithmes décisionnels.

Ovarian cancer is the first cause of death by gynecological cancer. Most of the patients are diagnosed with peritoneal carcinomatosis that represents a therapeutic challenge. Its management implies maximal cytoreductive surgery with survival benefit. Over the last three decades, several strategies of intra-peritoneal chemotherapy have been investigated. This includes intra-peritoneal adjuvant chemotherapy that is used mainly in North America, hyperthermic intraperitoneal chemotherapy (HIPEC) and more recently pressurized intraperitoneal aerosol chemotherapy (PIPAC). In the current article, we review the evidence in favor of each therapeutic approach, and we propose treatment algorithms depending on the clinical situation of ovarian cancer patients: upfront, platinum-sensitive and platinum-resistant relapse.

Le cancer de l'ovaire est la première cause de décès par cancer gynécologique. La plupart des patientes sont diagnostiquées au stade de carcinose péritonéale qui représente un défi thérapeutique. Sa prise en charge chirurgicale implique une cytoréduction maximaliste. Au cours des 30 dernières années, plusieurs stratégies de chimiothérapie intrapéritonéale ont été testées afin d'améliorer le contrôle de la carcinose péritonéale. Il s'agit des chimiothérapies intrapéritonéale adjuvante utilisée surtout en Amérique du Nord, hyperthermique intrapéritonéale (CHIP) et intrapéritonéale pressurisée en aérosols (PIPAC). Dans cet article, nous reprenons les données de la littérature sur chacune de ces trois approches thérapeutiques et proposons des algorithmes décisionnels selon la situation clinique des patientes traitées pour un cancer de l'ovaire : au diagnostic, récidive platine-sensible et platine-résistante.

Humoral and cellular immunogenicity two months after SARS-CoV-2 messenger RNA vaccines in patients with cancer.

Little is known on the long-lasting humoral response and the T cell activation induced by SARS-CoV-2 mRNA vaccines in patients with cancer. The study assessed the efficacy of the SARS-CoV-2 mRNA vaccines through measuring the seroconversion rate at pre-specified time points and the effect on the T cell immunity in patients with cancers. The study included 131 adult patients with solid or hematological cancer, who received SARS-CoV-2 mRNA vaccines. 96.2% of them exhibited adequate antibody response to the SARS-CoV-2 mRNA vaccines 2 months after the booster dose. SARS-CoV-2 mRNA vaccines could induce T cell activation; however, this is more likely in patients who have a positive seroconversion (94%) compared with the patients who did not (50%). Further research into the clinical relevance of low antibodies titers and lack of T cell activity is required to set up an effective vaccination strategy within this group of patients.

Immunogenicity of SARS-CoV-2 messenger RNA vaccines in patients with cancer.

Patients with cancer experience a higher burden of SARS-CoV-2 infection, disease severity, complications, and mortality, than the general population. SARS-CoV-2 mRNA vaccines are highly effective in the general population; however, few data are available on their efficacy in patients with cancer. Using a prospective cohort, we assessed the seroconversion rates and anti-SARS-CoV-2 spike protein antibody titers following the first and second dose of BNT162b2 and mRNA-1273 SARS-CoV-2 vaccines in patients with cancer in US and Europe from January to April 2021. Among 131 patients, most (94%) achieved seroconversion after receipt of two vaccine doses. Seroconversion rates and antibody titers in patients with hematological malignancy were significantly lower than those with solid tumors. None of the patients with history of anti-CD-20 antibody in the 6 months before vaccination developed antibody response. Antibody titers were highest for clinical surveillance or endocrine therapy groups and lowest for cytotoxic chemotherapy or monoclonal antibody groups.

Clinical effectiveness of olaparib monotherapy in germline BRCA-mutated, HER2-negative metastatic breast cancer in a real-world setting: phase IIIb LUCY interim analysis.

BACKGROUND: In the phase III OlympiAD trial, olaparib significantly increased progression-free survival (PFS) compared with chemotherapy of physician's choice in patients with germline BRCA-mutated (gBRCAm), human epidermal growth factor 2 (HER2)-negative metastatic breast cancer (mBC). The phase IIIb LUCY trial assessed the clinical effectiveness of olaparib in similar patients, in a setting reflecting clinical practice. METHODS: This open-label, single-arm trial of olaparib (300 mg, twice daily) enrolled patients with BRCAm, HER2-negative mBC who had received taxane and/or anthracycline in the (neo)adjuvant/metastatic setting and not more than two lines of prior chemotherapy for mBC. Patients with hormone receptor-positive mBC had progressed on at least one line of endocrine therapy in an adjuvant/metastatic setting and were unsuitable for further endocrine treatment. This interim analysis was planned after 160 PFS events. RESULTS: Of 563 patients screened, 252 patients with gBRCAm were enrolled and received at least one dose of olaparib. The median investigator-assessed PFS was 8.11 months (95% confidence interval [CI], 6.93-8.67; 166/252 events [65.9% maturity]). The investigator-assessed clinical response rate was 48.6%, and median time to first subsequent treatment or death was 9.66 months (95% CI, 8.67-11.14). The most common treatment-emergent adverse events (TEAEs; >20% patients) were nausea, anaemia, asthenia, vomiting and fatigue. Eleven patients (4.4%) discontinued treatment because of a TEAE. Grade 3 or higher TEAEs occurred in 64 patients (25.4%), including anaemia (33 patients; 13.1%). CONCLUSION: Olaparib was clinically effective in patients with gBRCAm, HER2-negative mBC with safety outcomes consistent with previous findings. ClinicalTrials.gov identifier: NCT03286842.

Redefining cancer of unknown primary: Is precision medicine really shifting the paradigm?

The concept of Cancer of Unknown Primary (CUP) has evolved with the advent of medical oncology. CUP can be difficult to diagnose and represents 2 to 5% of new cancers, therefore not exceptionally rare. Within CUPs can be identified a subset of favourable prognosis tumours, however the vast majority of CUP patients belongs to a poor prognosis group. CUP features significant oncological challenges, such as unravelling biological and transversal issues, and most importantly, improving patient's outcomes. In that regard, CUP patients' outcomes regrettably showed minimal improvement for decades and CUP remains a cancer group of very poor prognosis. The biology of CUP has two main hypotheses. One is that CUP is a subgroup of a given primary cancer, where the primary is present but cannot be seen due to its small size. The other, the "true" CUP hypothesis, states that CUP share features that make them a specific entity, whatever their tissue of origin. A true biological signature has not yet been described, but chromosomal instability is a hallmark of poor prognosis CUP group. Precision oncology, despite achieving identifying the putative origin of the CUP, so far failed to globally improve outcomes of patients. Targeting molecular pathways based on molecular analysis in CUP management is under investigation. Immunotherapy has not shown ground-breaking results, to date. Accrual is also a crucial issue in CUP trials. Herein we review CUP history, biological features and remaining questions in CUP biology, the two main approaches of molecular oncology in CUP management, in order to draw perspectives in the enormous challenge of improving CUP patient outcomes.

Immunologic Clearance of a BK Virus-associated Metastatic Renal Allograft Carcinoma.

BACKGROUND: Metastatic carcinoma of a renal allograft is a rare but life threatening event with a difficult clinical management. Recent reports suggested a potential role of BK polyomavirus (BKPyV) in the development of urologic tract malignancies in kidney transplant recipients. METHODS: We investigated a kidney-pancreas female recipient with an history of BKPyV nephritis who developed a rapidly progressive and widely metastatic donor-derived renal carcinoma 9 years after transplantation. RESULTS: Histology and fluorescence in situ hybridization analysis revealed a donor-derived (XY tumor cells) collecting (Bellini) duct carcinoma. The presence of BKPyV oncogenic large tumor antigen was identified in large amount within the kidney tumor and the bowel metastases. Whole genome sequencing of the tumor confirmed multiple genome BKPyV integrations. The transplanted kidney was removed, immunosuppression was withdrawn, and recombinant interleukin-2 (IL-2) was administered for 3 months, inducing a complete tumor clearance, with no evidence of disease at 6-year follow-up. The immunological profiling during IL-2 therapy revealed the presence of donor-specific T cells and expanded cytokine-producing bright natural killer cells but no donor-specific antibodies. Finally, we found persistently elevated anti-BK virus IgG titers and a specific anti-BKPyV T cell response. CONCLUSIONS: This investigation showed evidence for the potential oncogenic role of BKPyV in collecting duct carcinoma in renal allografts and demonstrated that immunosuppression withdrawal and IL-2 therapy can lead to an efficient antitumor cellular mediated rejection possibly via 3 distinct mechanisms including (1) host-versus-graft, (2) host-versus-tumor, and (3) anti-BKPyV responses.

[Screening of ovarian cancer : not for tomorrow]. / Dépistage du cancer de l'ovaire : ce n'est pas pour demain.

As the worldwide incidence of cancer continuously rises, one of the measures to reduce mortality is early diagnosis while the disease is still curable. Colonoscopy screening and PAP-smears are worthwhile examples illustrating the impact of early diagnosis on mortality. Ovarian cancer is the first cause of mortality by gynecological cancers in Switzerland (incidence of 600 new cases / year), mostly diagnosed at advanced stages with a poor prognosis. Could surveillance measures improve survival ? Three large-scale randomized control trials failed to show mortality reduction from ovarian cancer with the methods currently available. A better comprehension of pathogenesis can allow the development of new strategies of screening.

L'incidence des cancers ne cesse d'augmenter partout dans le monde. L'une des mesures les plus efficaces pour réduire la mortalité par cancer est le diagnostic précoce, à un stade permettant de proposer un traitement curatif. La colonoscopie ou le frottis du col utérin illustrent la réduction de la mortalité par des méthodes de dépistage efficaces. Première cause de décès par cancer gynécologique en Suisse, le cancer de l'ovaire y est diagnostiqué 600 fois par année, le plus souvent à un stade avancé, synonyme de pronostic réservé. Des mesures de surveillance peuvent-elles le détecter à temps ? Trois études randomisées ont démontré l'absence de bénéfice sur la mortalité du dépistage du cancer de l'ovaire avec les méthodes actuellement disponibles. Une meilleure compréhension de la pathogenèse permettrait le développement de nouvelles stratégies.

Lymphopenia combined with low TCR diversity (divpenia) predicts poor overall survival in metastatic breast cancer patients.

Lymphopenia (< 1Giga/L) detected before initiation of chemotherapy is a predictive factor for death in metastatic solid tumors. Combinatorial T cell repertoire (TCR) diversity was investigated and tested either alone or in combination with lymphopenia as a prognostic factor at diagnosis for overall survival (OS) in metastatic breast cancer (MBC) patients. The combinatorial TCR diversity was measured by semi quantitative multi-N-plex PCR on blood samples before the initiation of the first line chemotherapy in a development (n = 66) and validation (n = 67) MBC patient cohorts. A prognostic score, combining lymphocyte count and TCR diversity was evaluated. Univariate and multivariate analyses of prognostic factors for OS were performed in both cohorts. Lymphopenia and severe restriction of TCR diversity called "divpenia" (diversity ≤ 33%) were independently associated with shorter OS. Lympho-divpenia combining lymphopenia and severe divpenia accurately identified patients with poor OS in both cohorts (7.6 and 10.6 vs 24.5 and 22.9 mo). In multivariate analysis including other prognostic clinical factors, lympho-divpenia was found to be an independent prognostic factor in the pooled cohort (p = 0.005) along with lack of HER2 and hormonal receptors expression (p = 0.011) and anemia (p = 0.009). Lympho-divpenia is a novel prognostic factor that will be used to improve quality of MBC patients' medical care.

Bevacizumab plus microtubule targeting agents in heavily pre-treated ovarian cancer patients: a retrospective study.

OBJECTIVES. As vascular endothelial growth factor (VEGF) is expressed in ovarian cancer, we assessed the efficacy and safety of bevacizumab (a monoclonal antibody targeting VEGF) plus microtubule targeting agents for heavily pre-treated ovarian carcinoma patients. METHODS. We retrospectively reviewed 43 patients with recurrent epithelial ovarian carcinoma. Combined treatment included bevacizumab with paclitaxel in 32 (74%), docetaxel in 10 (23%), and vinorelbine in one (2.3%) patients, respectively. RESULTS. The median number of combined treatment was six cycles (range 1-29). On RECIST criteria, the objective response rate (ORR) was 40% (16% CR and 24% PR). Clinical benefit (complete response [CR] plus partial response [PR] and stable disease [SD] lasting ≥ 3 months) was 74% (CI95%: 46.7-77%). Median duration of treatment and overall survival were 3.9 months (range 0.2-14.4 months) and 20.1 months (CI95%: 13.8-20.1) respectively. No toxic death was reported. Grade 3-4 toxicity occurred in 30% of patients. Gastrointestinal perforations and fistula occurred in 3 (7%) and 6 (14%) patients, respectively. CONCLUSION. Although being active in terms of ORR, bevacizumab plus microtubule targeting agents - mainly taxanes - leads to a high rate of gastro-intestinal perforations and fistula in heavily pre-treated ovarian carcinoma patients.