A computational approach to distinguish somatic vs. germline origin of genomic alterations from deep sequencing of cancer specimens without a matched normal.

A key constraint in genomic testing in oncology is that matched normal specimens are not commonly obtained in clinical practice. Thus, while well-characterized genomic alterations do not require normal tissue for interpretation, a significant number of alterations will be unknown in whether they are germline or somatic, in the absence of a matched normal control. We introduce SGZ (somatic-germline-zygosity), a computational method for predicting somatic vs. germline origin and homozygous vs. heterozygous or sub-clonal state of variants identified from deep massively parallel sequencing (MPS) of cancer specimens. The method does not require a patient matched normal control, enabling broad application in clinical research. SGZ predicts the somatic vs. germline status of each alteration identified by modeling the alteration's allele frequency (AF), taking into account the tumor content, tumor ploidy, and the local copy number. Accuracy of the prediction depends on the depth of sequencing and copy number model fit, which are achieved in our clinical assay by sequencing to high depth (>500x) using MPS, covering 394 cancer-related genes and over 3,500 genome-wide single nucleotide polymorphisms (SNPs). Calls are made using a statistic based on read depth and local variability of SNP AF. To validate the method, we first evaluated performance on samples from 30 lung and colon cancer patients, where we sequenced tumors and matched normal tissue. We examined predictions for 17 somatic hotspot mutations and 20 common germline SNPs in 20,182 clinical cancer specimens. To assess the impact of stromal admixture, we examined three cell lines, which were titrated with their matched normal to six levels (10-75%). Overall, predictions were made in 85% of cases, with 95-99% of variants predicted correctly, a significantly superior performance compared to a basic approach based on AF alone. We then applied the SGZ method to the COSMIC database of known somatic variants in cancer and found >50 that are in fact more likely to be germline.

Clinical Trial Authorisation: A Final Look Back to Better Appraise the New European Regulation.

The implementation of the new European Clinical Trial Regulation on 31 January 2022, is a major step to promote clinical research in Europe. The French National Agency for Medicines and Health Products Safety (ANSM) proposes to share some key aspects of the preparation for the application of the Regulation initiated in 2017 and to discuss shared indicators that should be considered to monitor clinical trials opportunities on a territory with regards to access to innovation for patients and attractiveness for sponsors. New criteria based on the time from the first request for authorisation to the first inclusion could be of particular interest to appraise the implementation of the European Clinical Trial Regulation.

Molecular analysis for refractory rare cancers: Sequencing battle continues - learnings for the MOSCATO-01 study.

BACKGROUND: For patients with metastatic rare cancers, treatments are limited. How systematic tumor sequencing can improve therapeutic possibilities in this population? PATIENTS AND METHODS: Patients with rare cancer were identified in the MOSCATO-01 trial. Patients' outcome was measured by progression-free survival (PFS) and overall survival (OS). RESULTS: The most frequently identified histologic subypes were ovarian adenocarcinoma (N = 13), carcinoma of unknown primary (N = 11), and leiomyosarcoma (N = 10). Ninety-nine (39%) of them had at least one targetable cancer molecular alteration Forty-nine patients (50%) received the therapy proposed by the molecular tumor board, and 13 patients (26%, 95%CI 15-41%) achieved a PFS2/PFS1 > 1.3. The median PFS2 on matched treatment subgroup was 2.3 months (95% CI 1.8-3.6) and the median OS was 11.4 months (95% CI 9-15.5). CONCLUSIONS: The molecular screening of patients with refractory, metastatic rare cancers might increase the therapeutic options. Facilitating access strategy to molecular-driven clinical trials or agnostic-approved treatment is crucial.

Biomarkers of response to immunotherapy in early stage non-small cell lung cancer.

Immunotherapy with immune-checkpoint inhibitors (ICIs) targeting programmed cell death 1 or programmed death-ligand 1 has revolutionised the treatment of advanced non-small cell lung cancer (NSCLC) and has been investigated in early NSCLC, alone or in combination with chemotherapy, anti-CTLA-4 antibodies and radiotherapy. Although more mature data are needed before setting a change of paradigm in early stages, reports of pathological response rates and disease-free survival are promising, especially with neoadjuvant multimodality approaches. Nevertheless, major pathological response rates for neoadjuvant anti-PD-(L)1 monotherapy rarely exceed 40%, and biomarkers for characterising patients who may benefit the most from ICIs are lacking. These biomarkers have a distinct value from the metastatic setting, with highly different tumour biologies. Among the most investigated so far in this context, programmed death-ligand 1 expression and, to a lesser extent, tumour mutational burden seem to correlate better with higher pathological response rates and survival. Epidermal growth factor receptor, Serine/Threonine Kinase 11and Kelch-like ECH-associated protein 1 mutations rise as essential determinations for the treatment selection in early-stage NSCLC. Emerging and promising approaches comprise evaluation of blood-based ratios, microbiota, and baseline intratumoural TCR clonality. Circulating tumour DNA will be of great help in the near future when selecting best candidates for adjuvant ICIs, monitoring the tumour response to the neoadjuvant treatment in order to improve the rates of complete resections in the early stage.

Prevention and management of health products shortages by the French national agency (ANSM), 10 years of experience.

Shortages of drugs and medical devices have tended to increase in France and worldwide, with consequences for patients and healthcare professionals. Preventing shortages of health products has become a priority for regulatory authorities, including the French National Agency for Medicines and Health Products Safety (ANSM). To highlight perspectives for a better prevention, we described and analyzed the management of shortages in the availability of health products in France over the last 10 years. The supply chain was mapped to identify the main causes of shortages and stakeholders involved in managing shortages throughout the supply chain. National and European initiatives and regulatory measures were reviewed. A retrospective nationwide data analysis from the French reporting system of health product shortage reports was conducted over 10 years for drugs (2013-2022) and over an 18-month period for medical devices, from 1st March 2022 to 31st August 2023. An increase in drug shortage reports was observed, rising from 404 in 2013 to 3,761 in 2022 for drugs, with a relatively constant distribution of affected therapeutic classes. In 2022, the main reported causes of drug shortage risk were insufficient production capacity (27.1%), increased sales volume (21.5%), or lack of supply (13.6%). Over half of the reports on medical devices (55.4%) were objectified as indispensable, and their causes were mainly due to a lack of supply (48.2%), discontinuation of marketing (14.9%), increased sales volume (13.2%), and regulatory reasons (9.6%). ANSM and French authorities have engaged a public health policy for prevention and management of health product shortages including financial penalties, minimum safety stocks for Major Therapeutic Interest drugs, and a shortage management plan. Based on 10 years of experience, four priority measures have been identified to anticipate the risk of heath products shortages based: the importance of a national coordination from raw materials to local market, the implementation of new prevention and management actions in the supply chain, strengthening European cooperation and regulation including the establishment of a list of critical drugs, and promoting transparency and information.

Authorization of COVID-19 clinical trials: lessons from 2 years of experience of a national competent authority.

The COVID-19 pandemic was immediately marked by strong clinical research activity. The French national competent authority presents the data on request for authorization during the first 2 years of COVID-19 pandemic to inform discussions on future clinical research issues. Applications for authorization of interventional COVID-19 trials submitted between March 2020 and February 2022 were analysed. Trials on medicinal products were classified according to market authorization status, mechanism of action of the investigational product, target population and clinical context. In 2 years, 208 clinical trials were submitted. 75% were authorized, 3% refused, 22% withdrawn by the sponsor. Among medicinal products trials, 6% were adaptative, 28% included outpatients and 2% were focused on post COVID-19 symptoms. Vaccines were evaluated in 9% of trials, antivirals in 38% and immunomodulators in 35%; 63% of antiviral and 60% of immunomodulation trials included a drug with a marketing authorization in another indication. The dynamics of authorization prove the involvement of stakeholders but also illustrates the risk of dispersion of research efforts and the risk of decorrelation between trials and the epidemic evolution. The high rate of withdrawal of applications could be explained by changes in the sanitary context and by the dropping of some therapeutic approaches. Most of clinical trials evaluate drugs authorized in another indication and assessment procedures by authorities have to mitigate between the knowledge of safety profile of those drugs and the uncertainty in a new clinical context with rapidly evolving knowledge. COVID-19 experience should now support future evolution in clinical research practices.

Pulmonary toxicity related to systemic treatment of nonsmall cell lung cancer.

Physicians who are responsible for the delivery of systemic treatment in lung cancer should be aware of the potential risk of drug-induced pulmonary toxicity (DIPT), because such toxicity may develop in the context of a multifactorial clinical condition. First, most patients with lung cancer may suffer from other non-neoplastic, smoking-related lung diseases, such as emphysema and chronic obstructive lung disease, which may generate pathologic changes in lung parenchyma. In addition, lung cancer itself may worsen the respiratory function, inducing atelectasis and lymphangitic carcinomatosis. The superimposed iatrogenic damage may lead to respiratory failure and, sometimes, death. The risk of DIPT from chemotherapeutic agents has been widely examined in the past; and, currently, the potential for lung toxicity has been extended by the introduction of molecular targeted therapies. Because there are no univocal criteria with which to recognize DIPT, the diagnosis often is made by exclusion; consequently, it is hard to establish an early diagnosis. The objective of this review was to describe the major DIPTs associated with antineoplastic agents against nonsmall cell lung cancer to help physicians with this difficult diagnostic challenge.

[Potential value of CA125 kinetic monitoring in the initial management of advanced epithelial ovarian cancer]. / Intérêt potentiel du suivi de cinétique du CA125 dans la prise en charge initiale des cancers épithéliaux de l'ovaire de stade avancé

Ovarian carcinoma is account for 4% of all women cancer deaths because of late diagnosis at advanced stage. During chemotherapy, survey includes repeated assays of antigen carbohydrate 125 (CA125), which is a membrane glycoprotein belonging to the mucin family and secreted by 80% of the serous ovarian tumours. The aim of this study was to analyze the clinical relevance of a follow-up of CA125 kinetics of five ovarian carcinoma patients at advanced stages and under neoadjuvant chemotherapy. CA125 was assayed on a Kryptor(®) (Thermo-Fisher BRAHMS) and CA125 kinetics on semi-logarithmic curve with the software "Cinetic System". This software calculates the half-life and the doubling time between two points and can detect a line of tendency. It can also point out the nadir value. Kinetics are followed during 1 or 2 years. For all patients, we observe a very good agreement between kinetics, clinical and radiological issues (tumor size reduction). For three patients, after the first chemotherapy, the lines of tendency are decreasing. In one case with peritoneal carcinomatosis, the retrospective study of the pattern showed a biphasic curve anticipating the radiological modifications. For the two other patients, the normalisation of the CA125 is never obtained with no possible surgery. A greatest study could confirm the interest of associating this graphic approach to the clinical and radiological elements in order to optimize the medico-surgical assumption of responsibility of these patients with ovarian carcinoma at advanced stages, under first adjuvant treatment.

Potential predictive markers of response to EGFR-targeted therapies in colorectal cancer.

The importance of the epidermal growth factor receptor (EGFR) axis in tumorigenesis and tumor progression makes it an attractive target for the development of anticancer therapies. Strategies aimed at inhibiting the EGFR pathway included different classes of compounds, with monoclonal antibodies and tyrosine kinase inhibitors being the most widely-investigated agents in colorectal cancer. Although anti-EGFR therapies are active in some patients, disease will become refractory to therapy in nearly all patients. Identification of specific markers likely to predict which patients will best respond to anti-EGFR therapy is a major challenge. While the occurrence of rash is associated with greater likelihood of response, EGFR staining by immunohistochemistry at baseline is not. Among biological predictors, some studies indicate that activated EGFR, EGFR amplification, absence of KRAS mutations, PTEN expression, and low VEGFR expression are implicated in response to anti-EGFR monoclonal antibodies. Moreover, germinal gene polymorphisms, such as dinucleotide repeats polymorphism or FcgammaR polymorphism, have been shown to be associated with response to anti-EGFR therapy. Since most available data come from retrospective studies, there is a need to validate these results in prospective trials.

[Hot topics about early clinical trials at ASCO congress 2018: News pathways, new targets, new associations]. / Actualité des essais thérapeutiques précoces au congrès de l'ASCO 2018 : nouveaux mécanismes, nouvelles cibles, nouvelles associations.

Looking at the results of the early trials presented at the 2018 American Society of Clinical Oncology (ASCO) conference can help identify the molecules and strategies that will potentially enter the practices of tomorrow. It is in this spirit that this subject has justified the attention of residents in oncology and the writing of this synthesis. Molecules that can represent breakthrough innovations are presented as well as new therapeutics under development acting on targets already validated in clinical practice and early data of checkpoint inhibitors in combination with different immunomodulators, as well as new strategies for immunotherapies (vaccines and cell therapy).

Should Adjuvant Radiation Therapy Be Systematically Proposed for Male Breast Cancer? A Systematic Review.

BACKGROUND: Guidelines for radiotherapy in male breast cancer (MBC) are lacking. Some extrapolate the results from female breast cancer trials, while others advocate systematic adjuvant irradiation. We evaluated clinical practices and outcomes with respect to radiation therapy in MBC treated with locoregional irradiation in the adjuvant setting using a systematic literature review. MATERIAL AND METHODS: We included studies with data about adjuvant radiotherapy published between 1984 and 2017 and including at least 40 patients. RESULTS: We found 29 retrospective series, 10,065 men were diagnosed with breast cancer; 3-100% (mean=54%) received adjuvant radiotherapy. Tumor size and nodal involvement were the strongest prognostic factors. Approximatively half of all cases had nodal metastases. Radiation therapy improved locoregional control in six series, overall survival in three and distant metastasis-free survival in one. CONCLUSION: MBC is diagnosed at a highly advanced stage and may be linked with poorer outcomes. Adjuvant radiation therapy must, at least, be proposed to men with positive nodes. Despite the large number of cases gathered here, arguments for radiotherapy in other prognostic subgroups (especially in pN0) may exist but are not well supported.

[HBV infection: Screening and treatment for oncology patients]. / Hépatite B : dépistage et traitement en oncologie.

Patients with chronic hepatitis B infection are at risk of viral reactivation when treated by immuno- or chemotherapy, with potentially serious or even fatal consequences. This article proposes an overview on screening strategies and antiviral treatment recommendations for oncology patients. We have learned in hematology that reactivations are commun with rituximab and prophylactic treatment is recommanded for any patient who has been in contact with the virus. The risk appears to be lower with cytotoxics but has been far less studied. The recommandations are not formally consensual and upcoming studies will help to establish clearer practice guidelines.

[Immune checkpoints inhibitors: Recent data from ASCO's meeting 2017 and perspectives]. / Actualités autour des inhibiteurs de checkpoints immunitaires : enseignements issus du congrès ASCO 2017 et perspectives.

Immune checkpoint inhibitors anti-PD-1, anti-PD-L1 and anti-CTLA-4 have been in development in several indications and have changed the face of cancer patients' management. Cancer immunotherapy was central in ASCO's meeting 2017. The identification of patients who could benefit most from immune checkpoint inhibitors is essential. The predictive value of PD-L1 status remains insufficient to select patients who could respond to immunotherapy. An extended search for new biomarkers predictive of response (INF-γ, mutational load) is ongoing, in order to better select responders. Immune checkpoint inhibitors have mainly been developed as monotherapy. However, the low response rate, between 10 and 30%, and the occurrence of resistance, contributes to the increment of new therapeutic strategies. This review summarizes the results of combination trials of two immune checkpoint inhibitors, combination of immunotherapy with conventional chemotherapy, radiotherapy or targeted therapies active on the oncogenic addiction pathway.

[Radiation therapy in inflammatory breast cancer]. / Radiothérapie des cancers du sein inflammatoires.

BACKGROUND: Inflammatory breast cancer accounts for 1-5% of all breast cancers. It is associated with a poor prognosis, because of an increased risk to develop metastases in comparison with all breast malignancies. The treatment is multimodal. We have evaluated the role of radiotherapy: indications, techniques and impact for local control and overall survival. METHOD: The series of the literature with more than 40 patients irradiated for inflammatory breast cancer published since 1995 were analyzed. RESULTS: Chemotherapy was always delivered first. Adjuvant radiotherapy was associated with local control and overall survival at 10 years of 63-92% and 51-64 respectively. Without surgery, local control was 65% and overal survival 38% at 10years. Results of concomitant radiochemotherapy were reported: the studies were heterogenous. Modalities of radiotherapy were detailed with respect to dose and fractionation, target-volumes and technical considerations (including bolus). CONCLUSION: The multimodal strategy comprises systematically radiotherapy with an evaluation of tumor response to maximise resecability.

[Hot topics in 2017 in oncology and hematology. A selection by the editorial board of Bulletin du Cancer]. / Les points chauds de l'actualité en 2017. Une sélection du comité de rédaction du Bulletin du Cancer.

Actuality was dense in 2017 for oncology and hematology. The editorial board of the Bulletin du Cancer proposes a selection of key data distinguishing four trends: precision medicine, immunotherapy, focus on early stages and global management of metastatic disease. A summary of results which have been published or presented in congresses is proposed and the impact on daily practices is discussed.

[Obesity and cancer]. / Obésité et cancer.

The proportion of people affected by obesity is increasing and this finding emphasizes several issues in oncology: obesity as a risk factor for cancer, prognostic value of obesity in cancer patients, nutritional assessment in overweight patients and impact of obesity on treatment management. It is important to remember the common underevaluation of malnutrition in overweight or obese patients. Every caregiver must be especially careful about the management of comorbidities in these patients.

[What biomarkers for the future? The point of view of the residents in oncology after the ESMO 2016 Congress]. / Quels biomarqueurs d'avenir ? Le point de vue des internes en oncologie à l'issue du congrès de l'ESMO 2016.

Since the advent of the HER2 biomarker allowing access to treatment with trastuzumab, we observe an explosion in research for biomarkers, in which the economic pressure linked to the costs of developing new products must not be overlooked, in order to better select the molecules to be developed and the patients who can benefit from them. Personalized medicine takes a little more space each year in the overall care of our patients and the search for specific indicators, has become unavoidable. Rapid identification of oncogenic changes, their therapeutic targeting and the anticipation of resistance or toxicity mechanisms is a challenge. From blood markers, proteins to tumor genomic profiling and new markers in medical imaging, clinicians, researchers, and patients all are looking for the Holy Grail. This article synthetizes oncology resident's reflexions during the ESMO congress which took place in Copenhagen from 7 to 11 October 2016. The aim was to select the most relevant or promising results for future clinical practice.

[The breakthrough of personalized medicine, new hopes and new challenges]. / Quelle vision des biomarqueurs en 2017 ? Promesses et défis de la médecine personnalisée en oncologie.

The development of personalized medicine in oncology is based on biomarkers that help select populations for more efficient and less toxic therapies. The onset of molecular biology led to new paradigms in drug development, with efficacy data reported in early clinical trials and accelerated approvals. Multiple clinical trials, including SHIVA, SAFIR-01 and MOSCATO-01, have been developed to evaluate the interest of treatment decision-making based on tumor molecular profiling, with the ambition to replace historical clinical and pathological classifications. Targeted molecular therapies have also drastically enhanced the prognosis of patients in several cancer subtypes, with increased use in the context of advanced palliative care. Breaking through those boundaries might lead to a true precision medicine in oncology, which implementation in clinical routine is now expected by patients and physicians.