Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA

Circulating tumour DNA (ctDNA) can be used to detect and profile residual tumour cells persisting after curative intent therapy1. The study of large patient cohorts incorporating longitudinal plasma sampling and extended follow-up is required to determine the role of ctDNA as a phylogenetic biomarker of relapse in early-stage non-small-cell lung cancer (NSCLC). Here we developed ctDNA methods tracking a median of 200 mutations identified in resected NSCLC tissue across 1,069 plasma samples collected from 197 patients enrolled in the TRACERx study2. A lack of preoperative ctDNA detection distinguished biologically indolent lung adenocarcinoma with good clinical outcome. Postoperative plasma analyses were interpreted within the context of standard-of-care radiological surveillance and administration of cytotoxic adjuvant therapy. Landmark analyses of plasma samples collected within 120 days after surgery revealed ctDNA detection in 25% of patients, including 49% of all patients who experienced clinical relapse; 3 to 6 monthly ctDNA surveillance identified impending disease relapse in an additional 20% of landmark-negative patients. We developed a bioinformatic tool (ECLIPSE) for non-invasive tracking of subclonal architecture at low ctDNA levels. ECLIPSE identified patients with polyclonal metastatic dissemination, which was associated with a poor clinical outcome. By measuring subclone cancer cell fractions in preoperative plasma, we found that subclones seeding future metastases were significantly more expanded compared with non-metastatic subclones. Our findings will support (neo)adjuvant trial advances and provide insights into the process of metastatic dissemination using low-ctDNA-level liquid biopsy

Lung adenocarcinoma promotion by air pollutants

A complete understanding of how exposure to environmental substances promotes cancer formation is lacking. More than 70 years ago, tumorigenesis was proposed to occur in a two-step process: an initiating step that induces mutations in healthy cells, followed by a promoter step that triggers cancer development1. Here we propose that environmental particulate matter measuring ≤2.5 μm (PM2.5), known to be associated with lung cancer risk, promotes lung cancer by acting on cells that harbour pre-existing oncogenic mutations in healthy lung tissue. Focusing on EGFR-driven lung cancer, which is more common in never-smokers or light smokers, we found a significant association between PM2.5 levels and the incidence of lung cancer for 32,957 EGFR-driven lung cancer cases in four within-country cohorts. Functional mouse models revealed that air pollutants cause an influx of macrophages into the lung and release of interleukin-1β. This process results in a progenitor-like cell state within EGFR mutant lung alveolar type II epithelial cells that fuels tumorigenesis. Ultradeep mutational profiling of histologically normal lung tissue from 295 individuals across 3 clinical cohorts revealed oncogenic EGFR and KRAS driver mutations in 18% and 53% of healthy tissue samples, respectively. These findings collectively support a tumour-promoting role for PM2.5 air pollutants and provide impetus for public health policy initiatives to address air pollution to reduce disease burden

Use of routinely available clinical, nutritional, and functional criteria to classify cachexia in advanced cancer patients.

Cachexia is a highly prevalent syndrome in cancer and chronic diseases. However, due to the heterogeneous features of cancer cachexia, its identification and classification challenge clinical practitioners. To determine the clinical relevance of a cancer cachexia classification system in advanced cancer patients. Beginning with the four-stage classification system proposed for cachexia [non-cachexia (NCa), pre-cachexia (PCa), cachexia (Ca) and refractory cachexia (RCa)], we assigned patients to these cachexia stages according to five classification criteria available in clinical practice: 1) biochemistry (high C-reactive protein or leukocytes, or hypoalbuminemia, or anemia), 2) food intake (normal/decreased), weight loss: 3) moderate (≤5%) or 4) significant (>5%/past six months) and 5) performance status (Eastern Cooperative Oncology Group Performance Status ≥ 3). We then determined if symptom severity, body composition changes, functional levels, hospitalizations and survival rates varied significantly across cachexia stages. Two-hundred and ninety-seven advanced cancer patients with primary gastrointestinal and lung tumors were included. Patients were classified into Ca (36%), PCa and RCa (21%, respectively) and NCa (15%). Significant (p < 0.05) differences were observed among cachexia stages for most of the outcome measures (symptoms, body composition, handgrip strength, emergency room visits and length of hospital stays) according to cachexia severity. Survival also differed between cachexia stages (except between PCa and Ca). Five clinical criteria can be used to stage cancer cachexia patients and predict important clinical, nutritional and functional outcomes. The lack of statistical difference between PCa and Ca in almost all clinical outcomes examined suggests either that the PCa group includes patients already affected by early cachexia or that more precise criteria are needed to differentiate PCa from Ca patients. More studies are required to validate these findings

Selumetinib in Combination With Dacarbazine in Patients With Metastatic Uveal Melanoma: A Phase III, Multicenter, Randomized Trial (SUMIT)

Experimentele farmacotherapi

Mode de vie et cancer du sein: quels conseils pour la prise en charge de l’après cancer ?

National audienceIt is widely admitted that after adjuvant therapy, about one half of women with localized breast cancer experience a weight gain of 3 kg. It can however reach 8 to 10 kg in numerous cases. Risk factors associated with weight gain are unclear, but women undergoing chemotherapy seem to have an increased risk, especially before the menopause. Retrospective studies suggest that post-treatment weight gain mightincrease the risk of relapse. Furthermore, the only intervention trial in adjuvant breast cancer, though impaired by methodological pitfalls, suggests that limiting weight gain could increase disease free survival. The use of nutritional complements by cancer patients is usually underestimated. Several compounds, such as vitamins C and, E, selenium or carotenoids, have been investigated in clinical trials whose quality is usually poor. Available date nevertheless suggest a deleterious effect of supplementation with anti-oxydants, in particular at supraphysiological doses. The WHEL trial is the only large randomised trial investigating an healthy diet with vegetables, fruits and fiber after localized breast cancer. An effect of survival is observed in the experimental arm only in patients with sufficient level of physical activity. Physical activity, when practiced regularly, improves asthenia, quality of life and even survival, without any detrimental effect. It should however be initiated after an evaluation of patient’s ability and comorbidities, and be realized in specific centers with careful medical follow-up. Its mechanisms of action include regulation of estrogen, insulin, IGF1 and adipokines. Adapted physical activity should be proposed to patients fulfilling precise inclusion criteria.On estime que près de la moitié des femmes traitées pour un cancer du sein localisé sont affectées par un gain de l’ordre de 3 kg, mais des prises de poids de l’ordre de 8 à 10 kg ne sont pas exceptionnelles. Les facteurs de risque ne sont pas clairement individualisés, mais les patientes recevant une chimiothérapie semblent plus concernées, en particulier avant la ménopause. Les études rétrospectives montrent que la prise de poids pourrait être un facteur de risque de rechute, qui plus est, le seules said’ intervention actuellement publié dans le cancer du sein, bien que sujet à des critiques d’ordre méthodologique, suggère un effet positif de la réduction du surpoids sur la survie sans récidive. L’utilisation de compléments nutritionnels par les patients est, quant à elle, largement sous-estimée. De nombreux composés ont fait l’objet d’essais cliniques dont la méthodologie est globalement peu convaincante (vitamines C et E, sélénium, caroténoïdes). Les données disponibles suggèrent un effet négatif de la supplémentation en antioxydants(en particulier à des doses supra-physiologiques) pouvant éventuellement affecter l’efficacité du traitement antitumoral. L’essai WHEL (Women’s Healthy Eating and Living) est le seul grand essai randomisé d’intervention, basé sur une supplémentation en fruits et légumes après traitement d’un cancer du sein localisé : il suggère un effet positif de la supplémentation uniquement si elle est associée à une activité physique suffisante. L’ activité physique régulière lors des soins en cancérologie améliore la qualité de vie, la fatigue, la survie, enparticulier pour les patientes por-teuses de cancer du sein, et ce, sans effet secondaire à condition d’être mise en place après un bilan précis des capacités, des comorbidités, d’être réalisée dans des structures adaptées avec un suivi médical des progrès et des difficultés. Les mécanismes d’action passent par des modifications de sécrétion d’estrogène, d’insuline, d’IGF1 et des adipokines. L’activité physique adaptée en cancérologie doit être proposée aux malades répondant à des critères d’inclusion précis