Chemotherapy negatively impacts the tumor immune microenvironment in NSCLC: an analysis of pre- and post-treatment biopsies in the multi-center SAKK19/09 study.

BACKGROUND: Over the past few years, immune checkpoint inhibitors have changed the therapeutic landscape of non-small-cell lung cancer (NSCLC). Response to immune checkpoint inhibitors correlates with a pre-existing anti-tumoral immune response. Checkpoint inhibitors have been introduced as second-line therapy and are only very recently used as monotherapy or in combination with chemotherapy as first-line treatment of NSCLC. However, the effect of conventional first-line platinum-based chemotherapy on the immune infiltrate in the tumor is largely unknown. METHODS: We measured the gene expression of a custom set of 201 cancer- and immune-related genes in 100 NSCLC tumor biopsies collected before chemotherapy and 33 re-biopsies after platinum-based chemotherapy at the time point of progression. For 29 patients matched pre- and post-chemotherapy samples could be evaluated. RESULTS: We identified a cluster of 47 co-expressed immune genes, including PDCD1 (PD1) and CD274 (PD-L1), along with three other co-expression clusters. Chemotherapy decreased the average gene expression of the immune cluster while no effect was observed on the other three cluster. Within this immune cluster, CTLA4, LAG3, TNFRSF18, CD80 and FOXP3 were found to be significantly decreased in patient-matched samples after chemotherapy. CONCLUSION: Our results suggest that conventional platinum-based chemotherapy negatively impacts the immune microenvironment at the time point of secondary progression.

Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry.

BACKGROUND: Anti-PD1/PD-L1 directed immune checkpoint inhibitors (ICI) are widely used to treat patients with advanced non-small-cell lung cancer (NSCLC). The activity of ICI across NSCLC harboring oncogenic alterations is poorly characterized. The aim of our study was to address the efficacy of ICI in the context of oncogenic addiction. PATIENTS AND METHODS: We conducted a retrospective study for patients receiving ICI monotherapy for advanced NSCLC with at least one oncogenic driver alteration. Anonymized data were evaluated for clinicopathologic characteristics and outcomes for ICI therapy: best response (RECIST 1.1), progression-free survival (PFS), and overall survival (OS) from ICI initiation. The primary end point was PFS under ICI. Secondary end points were best response (RECIST 1.1) and OS from ICI initiation. RESULTS: We studied 551 patients treated in 24 centers from 10 countries. The molecular alterations involved KRAS (n = 271), EGFR (n = 125), BRAF (n = 43), MET (n = 36), HER2 (n = 29), ALK (n = 23), RET (n = 16), ROS1 (n = 7), and multiple drivers (n = 1). Median age was 60 years, gender ratio was 1 : 1, never/former/current smokers were 28%/51%/21%, respectively, and the majority of tumors were adenocarcinoma. The objective response rate by driver alteration was: KRAS = 26%, BRAF = 24%, ROS1 = 17%, MET = 16%, EGFR = 12%, HER2 = 7%, RET = 6%, and ALK = 0%. In the entire cohort, median PFS was 2.8 months, OS 13.3 months, and the best response rate 19%. In a subgroup analysis, median PFS (in months) was 2.1 for EGFR, 3.2 for KRAS, 2.5 for ALK, 3.1 for BRAF, 2.5 for HER2, 2.1 for RET, and 3.4 for MET. In certain subgroups, PFS was positively associated with PD-L1 expression (KRAS, EGFR) and with smoking status (BRAF, HER2). CONCLUSIONS: : ICI induced regression in some tumors with actionable driver alterations, but clinical activity was lower compared with the KRAS group and the lack of response in the ALK group was notable. Patients with actionable tumor alterations should receive targeted therapies and chemotherapy before considering immunotherapy as a single agent.

Focusing on cancer patients' intentions to use psychooncological support: A longitudinal, mixed-methods study.

OBJECTIVE: Distress screening programs aim to ensure appropriate psychooncological support for cancer patients, but many eligible patients do not use these services. To improve distress management, we need to better understand patients' supportive care needs. In this paper, we report the first key finding from a longitudinal study that focused on patients' intentions to use psychooncological support and its association with distress and uptake of the psychooncology service. METHODS: We conducted a prospective, observational study in an Oncology Outpatient Clinic and assessed distress, intention to use psychooncological support, and uptake of the psychooncology service by using the Distress Thermometer, a semistructured interview, and hospital records. We analyzed data with a mixed-methods approach. RESULTS: Of 333 patients (mean age 61 years; 55% male; 54% Distress Thermometer ≥ 5), 25% intended to use the psychooncology service (yes), 33% were ambivalent (maybe), and 42% reported no intention (no). Overall, 23% had attended the psychooncology service 4 months later. Ambivalent patients reported higher distress than patients with no intention (odds ratio = 1.18, 95% confidence interval [1.06-1.32]) but showed significantly lower uptake behavior than patients with an intention (odds ratio = 14.04, 95% confidence interval [6.74-29.24]). Qualitative analyses revealed that ambivalent patients (maybe) emphasized fears and uncertainties, while patients with clear intentions (yes/no) emphasized knowledge, attitudes, and coping concepts. CONCLUSIONS: We identified a vulnerable group of ambivalent patients with high distress levels and low uptake behavior. To optimize distress screening programs, we suggest addressing and discussing patients' supportive care needs in routine clinical practice.

Patterns of progression on first line osimertinib in patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC): A Swiss cohort study.

AIM: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) approved for patients with EGFR mutated non-small cell lung cancer as first-line treatment. However, treatment resistance inevitably emerges and may present as oligo-progressive disease (OPD) or systemic progressive disease (SPD). The incidence of OPD on first-line osimertinib is unknown. METHODS: We retrospectively analyzed patients who received first-line osimertinib at 13 Swiss centers. The rate of OPD (PD in ≤ 5 lesions) and treatment outcomes were analyzed. RESULTS: The median age of the 148 patients was 68.2 years (range. 38.0-93.3). There were 62 % females, 83 % with a PS ≤ 1, 59 % never smokers, 57 % of patients with an EGFR exon 19 deletion and 37 % with EGFR p.L858R exon 21. 77 % experienced OPD. Median overall survival (OS) was 51.6 months (95 % CI, 38.4-65.0). Median progression-free survival (PFS) was 19.2 (95 % CI, 14.3-23.5) and 8.7 (95 % CI, 2.8-15.6) months for patients with common and uncommon EGFR mutations. Patients with OPD compared to SPD had a significantly longer time to treatment failure and longer OS of (22.9 vs. 10.8 months, p < 0.001 and 51.6 vs. 26.4 months, p = 0.004, respectively). The most common organ sites of PD were lung (62 %), brain (30 %), lymph nodes (30 %), bone (27 %) and pleura (27 %). Twenty-six patients (45 %) with OPD received local ablative treatment (LAT). The OS of OPD patients with LAT was 60.0 (95 % CI, 51.6-NA) vs. 51.4 (95 % CI 38.4-65.3) months (p = 0.43) without LAT. CONCLUSION: The rate of OPD of patients receiving first line osimertinib was 77 %. Patients with OPD had a significantly better OS compared to patients with SPD (51.6 vs. 26.4 months). Patients with OPD receiving LAT had the longest median OS (60.0 months).

Immune checkpoint blockers in solid organ transplant recipients and cancer: the INNOVATED cohort.

BACKGROUND: Patients with solid organ transplant (SOT) and solid tumors are usually excluded from clinical trials testing immune checkpoint blockers (ICB). As transplant rates are increasing, we aimed to evaluate ICB outcomes in this population, with a special focus on lung cancer. METHODS: We conducted a multicenter retrospective cohort study collecting real data of ICB use in patients with SOT and solid tumors. Clinical data and treatment outcomes were assessed by using retrospective medical chart reviews in every participating center. Study endpoints were: overall response rate (ORR), 6-month progression-free survival (PFS), and grade ≥3 immune-related adverse events. RESULTS: From August 2016 to October 2022, 31 patients with SOT (98% kidney) and solid tumors were identified (36.0% lung cancer, 19.4% melanoma, 13.0% genitourinary cancer, 6.5% gastrointestinal cancer). Programmed death-ligand 1 expression was positive in 29% of tumors. Median age was 61 years, 69% were males, and 71% received ICB as first-line treatment. In the whole cohort the ORR was 45.2%, with a 6-month PFS of 56.8%. In the lung cancer cohort, the ORR was 45.5%, with a 6-month PFS of 32.7%, and median overall survival of 4.6 months. The grade 3 immune-related adverse events rate leading to ICB discontinuation was 12.9%. Allograft rejection rate was 25.8%, and risk of rejection was similar regardless of the type of ICB strategy (monotherapy or combination, 28% versus 33%, P = 1.0) or response to ICB treatment. CONCLUSIONS: ICB could be considered a feasible option for SOT recipients with some advanced solid malignancies and no alternative therapeutic options. Due to the risk of allograft rejection, multidisciplinary teams should be involved before ICB therapy.

Neoadjuvant treatment does not influence PD-L1 expression in stage III non-small-cell lung cancer: a retrospective analysis of tumor samples from the trials SAKK 16/96, 16/00, 16/01, and 16/14.

BACKGROUND: The inclusion of immune checkpoint inhibitors (ICIs) in the treatment of operable stage III non-small-cell lung cancer is becoming a new standard. Programmed death-ligand 1 (PD-L1) protein expression on tumor cells has emerged as the most important biomarker for sensitivity to ICIs targeting the programmed cell death protein 1 (PD-1)-PD-L1 axis. Little is known about the impact of neoadjuvant treatment on PD-L1 expression. PATIENTS AND METHODS: We assessed PD-L1 expression by immunohistochemistry (Ventana SP263 assay) on tumor cells in treatment-naive diagnostic tumor samples and matched lung resections from patients with stage III non-small-cell lung cancer included in the Swiss Group for Clinical Cancer Research (SAKK) trials 16/96, 16/00, 16/01, and 16/14. All patients received neoadjuvant chemotherapy (CT) with cisplatin/docetaxel, either as single modality (CT), with sequential radiotherapy [chemoradiation therapy (CRT)] or with the PD-L1 inhibitor durvalumab (CT + ICI). RESULTS: Overall, 132 paired tumor samples were analyzed from patients with neoadjuvant CT (n = 69), CRT (n = 33) and CT + ICI (n = 30). For CT and CRT, PD-L1 expression before and after neoadjuvant treatment did not differ significantly (Wilcoxon test, P = 0.94). Likewise, no statistically significant difference was observed between CT and CRT for PD-L1 expression after neoadjuvant treatment (P = 0.97). For CT + ICI, PD-L1 expression before and after neoadjuvant treatment also did not differ significantly (Wilcoxon test, P > 0.99). Event-free survival and overall survival for patients with downregulation or upregulation of PD-L1 expression after neoadjuvant treatment were similar. CONCLUSIONS: In our cohort of patients neoadjuvant treatment did not influence PD-L1 expression, irrespective of the specific neoadjuvant treatment protocol. Dynamic change of PD-L1 expression did not correlate with event-free survival or overall survival.

[Chemotherapy for malignant tumors of lung and pleura]. / Chemotherapie bei Tumoren der Lunge und Pleura - was darf von welchem Therapieansatzerwartet werden.

Lung Cancer is the leading cause of cancer-related mortality worldwide, with nearly 1.4 million deaths each year. There has been an overall decrease in the incidence of lung cancer in men, although in women this trend has only been noted very recently in the United States and in many countries in Western Europe. In contrast, in many parts of the world the number of cases and deaths related to lung cancer is on the rise. These increased death rates are in close correlation to smoking habits in the different countries. It is also increasingly becoming a disease of the elderly, with a median age at diagnosis of 70 years. In Switzerland about 2'500 men and 1'200 women are yearly diagnosed with lung cancer. Lung cancer is diagnosed at an advanced stage in a majority of patients, which explains the high mortality rate associated with this disease. In the current review we give on overview on the current treatment practice for small cell lung cancer (SCLC) as well as on non-small cell lung cancer (NSCLC). The main focus is on the novel treatment options for advanced, metastatic NSCLC and the current use of predictive biomarkers in order to personalize therapy. Malignant pleural mesothelioma is a rare cancer occurring mainly in older men who have been exposed to asbestos, although it occurs decades after exposure (20 - 40 years later). The disease is difficult to treat and median overall survival is only about one year.

[Cancer immunotherapy - novel perspectives]. / Neue Perspektiven in der immunologischen Krebstherapie.

The concept of cancer immune surveillance dates back decades and is based on the hypothesis that the immune system can suppress the development or progression of spontaneous malignancies. Immunotherapy strategies include antitumor monoclonal antibodies, cancer vaccines, adoptive transfer of ex vivo activated T and natural killer cells, and administration of antibodies that either costimulate immune cells or block immune inhibitory pathways. Sipuleucel-T is the first anticancer vaccine that improved overall survival in a randomized clinical study in patients with metastatic castration-resistant prostate cancer. Similarly, ipilimumab, a monoclonal antibody blocking cytotoxic T-lymphocyte antigen 4 (CTLA-4), showed an overall survival benefit and durable tumor responses in pretreated and previously untreated patients with metastatic melanoma. In Switzerland, ipilimumab is approved for second line treatment in metastatic melanoma. These recent positive results of clinical trials with novel immunoactive drugs raised expectations that immunotherapy will play a crucial role in the anticancer treatment of the next decade.

How to read a next-generation sequencing report-what oncologists need to know.

Next-generation sequencing (NGS) of tumor cell-derived DNA/RNA to screen for targetable genomic alterations is now widely available and has become part of routine practice in oncology. NGS testing strategies depend on cancer type, disease stage and the impact of results on treatment selection. The European Society for Medical Oncology (ESMO) has recently published recommendations for the use of NGS in patients with advanced cancer. We complement the ESMO recommendations with a practical review of how oncologists should read and interpret NGS reports. A concise and straightforward NGS report contains details of the tumor sample, the technology used and highlights not only the most important and potentially actionable results, but also other pathogenic alterations detected. Variants of unknown significance should also be listed. Interpretation of NGS reports should be a joint effort between molecular pathologists, tumor biologists and clinicians. Rather than relying and acting on the information provided by the NGS report, oncologists need to obtain a basic level of understanding to read and interpret NGS results. Comprehensive annotated databases are available for clinicians to review the information detailed in the NGS report. Molecular tumor boards do not only stimulate debate and exchange, but may also help to interpret challenging reports and to ensure continuing medical education.

Long-term outcomes of operable stage III NSCLC in the pre-immunotherapy era: results from a pooled analysis of the SAKK 16/96, SAKK 16/00, SAKK 16/01, and SAKK 16/08 trials.

BACKGROUND: Chemoradiotherapy with durvalumab consolidation has yielded excellent results in stage III non-small-cell lung cancer (NSCLC). Therefore, it is essential to identify patients who might benefit from a surgical approach. MATERIAL AND METHODS: Data from 437 patients with operable stage III NSCLC enrolled in four consecutive Swiss Group for Clinical Cancer Research (SAKK) trials (16/96, 16/00, 16/01, 16/08) were pooled and outcomes were analyzed in 431 eligible patients. All patients were treated with three cycles of induction chemotherapy (cisplatin/docetaxel), followed in some patients by neoadjuvant radiotherapy (44 Gy, 22 fractions) (16/00, 16/01, 16/08) and cetuximab (16/08). RESULTS: With a median follow-up time of 9.3 years (range 8.5-10.3 years), 5- and 10-year overall survival (OS) rates were 37% and 25%, respectively. Overall, 342 patients (79%) underwent tumor resection, with a complete resection (R0) rate of 80%. Patients (n = 272, 63%) with R0 had significantly longer OS compared to patients who had surgery but incomplete resection (64.8 versus 19.2 months, P < 0.001). OS for patients who achieved pathological complete remission (pCR) (n = 66, 15%) was significantly better compared to resected patients without pCR (86.5 versus 37.0 months, P = 0.003). For patients with pCR, the 5- and 10-year event-free survival and OS rates were 45.7% [95% confidence interval (CI) 32.8% to 57.7%] and 28.1% (95% CI 15.2% to 42.6%), and 58.2% (95% CI 45.2% to 69.2%) and 45.0% (95% CI 31.5% to 57.6%), respectively. CONCLUSION: We report favorable long-term outcomes in patients with operable stage III NSCLC treated with neoadjuvant chemotherapy with cisplatin and docetaxel ± neoadjuvant sequential radiotherapy from four prospective SAKK trials. Almost two-third of the patients underwent complete resection after neoadjuvant therapy. We confirm R0 resection and pCR as important predictors of outcome.

Second-line therapy improves overall survival in primary refractory non-small cell lung cancer (NSCLC) patients.

BACKGROUND: The effect of palliative chemotherapy for non-small cell lung cancer (NSCLC) is well established. Recently, immune checkpoint inhibitors have shown promising efficacy in NSCLC patients. However, little is known about the efficacy of cytotoxic chemotherapy in patients whose tumors are refractory to first-line chemotherapy. We investigated the outcome of all consecutive and unselected patients receiving palliative chemotherapy in a single institution to assess the efficacy of second-line chemotherapy in primary refractory NSCLC. PATIENTS AND METHODS: Patients with metastatic NSCLC diagnosed between 1990 and 2016 were assessed. Outcome parameters were collected and patients were characterized as either having primary progressive disease or clinical benefit [CB; defined as complete/partial remission (CR, PR) or stable disease (SD)]. Probabilities of survival were calculated using the Kaplan-Meier estimator. The log-rank test was used for comparing groups. Cox models were used to explore the prognostic value of covariables. RESULTS: The analysis included 576 patients. Median overall survival (OS) was 9.5 months [95% confidence interval (CI) 8.47-10.47]; 62.7% of patients were treated with a platinum-based first-line therapy. Two hundred twenty-two patients (38.5%) were primary refractory to first-line therapy. Median OS was significantly shorter for those patients [7.4 versus 11.5 months, hazard ratio (HR) 1.61 (95% CI 1.34-1.93), P < 0.0001]. Poorer initial performance status was significantly associated with primary refractory disease (P = 0.015). Eighty-one (36.5%) primary refractory patients received a second-line therapy. Median OS was significantly longer for refractory patients receiving second-line therapy versus best supportive care [10.1 versus 5.0 months, HR 0.53 (95% CI 0.40-0.72), P < 0.0001]. CONCLUSIONS: Nearly 40% of patients are primary refractory to palliative first-line therapy and have a poor prognosis. Active second-line therapy can significantly improve the outcome. Therefore, patients with primary refractory NSCLC should be offered further active therapy. These real-life data for primary refractory patients form the basis for further research in sequencing of current palliative treatment options.

Patterns of progression on osimertinib in EGFR T790M positive NSCLC: A Swiss cohort study.

INTRODUCTION: Osimertinib is an EGFR tyrosine kinase inhibitor (TKI) with antitumor activity in non-small cell lung cancer (NSCLC) with EGFR T790 M mutations. The incidence of oligo-progression (PD) on osimertinib is unknown. METHODS: We retrospectively analyzed 50 pre-treated EGFR T790M-positive NSCLC patients treated with osimertinib at seven Swiss centers. Oligo-PD was defined as PD in ≤ 5 lesions. Mutational profiling of pre- and post-osimertinib tumor samples was performed. RESULTS: Median age was 62 years (37-89), 64% were females, 86% had a PS ≤ 1, 54%/13% were never/current smokers. Median follow-up was 15.3 (IQR: 8.6-21.6) months. Overall response rate was 80%, median progression-free survival 12.1 months (95% CI 8.3-18.3), median overall survival 28 months (95% CI 20.2-not reached [NR]) and median treatment duration 18.8 months (95%CI 16-8-NR). PD occurred in 36 patients (72%). 73% had oligo-PD. Median osimertinib treatment duration in patients with oligo-PD was 19.6 vs. 7 months if systemic PD (p = 0.007). The number of progressive lesions in patients with oligo-PD was 1 (27%), 2 (35%) and 3-5 (39%). Sites of PD included lungs (56%), bones (44%), and brain (17%). Sixteen patients with oligo-PD continued treatment with osimertinib for a median of 6.7 months beyond PD. Thirteen received local ablative treatment (LAT). In pre- and post-PD tumor tissue multiple molecular alterations were detected. CONCLUSION: In patients with acquired resistance to osimertinib, we observed a high rate (73%) of oligo-PD. Outcomes of patients receiving LAT were favorable, supporting the concept of osimertinib treatment beyond progression in combination with LAT of progressing lesions.

BRIGHTEN Heart: Design and baseline characteristics of a randomized controlled trial for minority older adults with depression and cardiometabolic syndrome.

OBJECTIVES: African American and Hispanic elderly are at elevated risk of both depression and cardiovascular disease, relative to non-Hispanic whites. Effective interventions are therefore needed to address depressive symptoms and to reduce these disparities. BRIGHTEN Heart was a behavioral randomized controlled trial to test the efficacy of a virtual team intervention in reducing depressive symptoms in minority elderly as measured by the 9-item Patient Health Questionnaire (PHQ9). STUDY DESIGN: 250 African American and Hispanic adults, age ≥60 years, with comorbid depression and overweight/obesity were randomized. Participants randomized to the Intervention condition received a social work evaluation, team-based electronic consultation, case management, and psychotherapy over a 12 month period. Control participants were enrolled in a membership program that provided health classes and other services to support chronic disease self-management. Blinded research assistants completed assessments at baseline, and 6 and 12 months postrandomization. RESULTS: The study population was characterized by low socioeconomic status, with 81.4% having a household income of less than $20,000. Although median depression scores were in the mild range, 25% of participants had scores showing moderate to severe depression at baseline. 75% of participants had four or more chronic conditions. Significant demographic and clinical differences were observed between the African American and Hispanic populations. CONCLUSIONS: BRIGHTEN Heart was designed to rigorously test the efficacy of a multi-level intervention to reduce comorbid depressive symptoms and cardiovascular risk in minority elderly. Investigators successfully recruited a cohort well suited to testing the study hypothesis.

Biochemical abnormalities in patients with slipped capital femoral epiphysis and chondrolysis.

A prospective clinical and laboratory study was performed in thirty-four patients (twenty-two blacks, ten Puerto Ricans, and two whites) who had slipped capital femoral epiphysis in fifty-two hips. Although the majority of the laboratory studies were normal, all patients showed significant elevations of the serum immunoglobulins and C3 component of complement, with the highest values recorded for IgA. Urinary glycosaminoglycans were elevated in the few patients studied and increased proportionally with the duration of the disease. Nine (25 per cent) of the thirty-four patients had chondrolysis in thirteen hips. The male:female ratio in these nine patients was 0.8:1, compared with the ratio of 1.4:1 in all thirty-four patients. No additional biochemical abnormality was found in the patients with chondrolysis except for a greater elevation of the IgM fraction. These preliminary and tentative data suggest either that slipping of an epiphysis produces an antigen which induces an autoimmune state or that slipping is a localized manifestation of a generalized process resembling some form of connective-tissue disorder or inflammatory state. There is presumably a genetically determined sub-group of patients with this disorder who may have chondrolysis.

Cross-cultural issues in primary care medicine.

A generation ago, the experience of practicing medicine across cultural lines was far less common than it is today. In contemporary American society, the population is much more diverse in race, culture, language, religion, and ethnicity. Although health care is increasingly guided by scientific, evidence-based models, individual patients are increasingly seeking health care that addresses their personal beliefs and needs. Physicians must develop the knowledge and the skills to engage patients from different cultures and to understand the beliefs and the values of those cultures. If physicians focus only on a narrowly defined biomedical approach to the treatment of disease, they will often misunderstand their patients, miss valuable diagnostic cues, and experience higher rates of patient noncompliance with therapies. Such miscommunication will also result in greater patient dissatisfaction and more malpractice suits. This article reviews the role of culture in primary care medicine and the effect of health beliefs on decisions to seek care. Other influences, including the patient's family, language, and socioeconomic status, are examined. The possible effects of the physician's own culture are looked at as well. Methods of eliciting the patient's explanatory model are reviewed, and guidance is given on strategies to avoid miscommunication or misunderstandings. Additionally, the physician is given guidance on how to draw on the patient's beliefs and values as resources in health promotion and the treatment of disease. Specifically, the use of interpreters to overcome language barriers is reviewed. Behaviors are identified that can maximize the accuracy of communication when interpreters are needed. Physicians who actively seek to understand their patients' cultures will find their simple efforts amply rewarded by improved patient access to health care, increased patient satisfaction, and greater clinical effectiveness.

The family with a member who has cancer.

Optimal medical care for persons with chronic illnesses such as cancer cannot be provided unless the physician adopts a family-oriented approach to patient care. Such an approach requires little additional time or effort but profoundly affects the ability of patient and family to cope with cancer. Physicians should routinely gather data about the family system of their patients with cancer and make use of that data in understanding the unique issues the patient will face in adapting to their illness. The physician's goal should be to anticipate how the illness will affect the family at its current stage of the life cycle and recognize how the patient's family is currently affecting the patient's experience of the illness. The maintenance of clear, open communication among patient, family, and physician is critical to successful adaptation.

Circulating microRNA profiling in patients with advanced non-squamous NSCLC receiving bevacizumab/erlotinib followed by platinum-based chemotherapy at progression (SAKK 19/05).

OBJECTIVES: Molecular subclassification of non small-cell lung cancer (NSCLC) is essential to improve clinical outcome. This study assessed the prognostic and predictive value of circulating micro-RNA (miRNA) in patients with non-squamous NSCLC enrolled in the phase II SAKK (Swiss Group for Clinical Cancer Research) trial 19/05, receiving uniform treatment with first-line bevacizumab and erlotinib followed by platinum-based chemotherapy at progression. MATERIALS AND METHODS: Fifty patients with baseline and 24 h blood samples were included from SAKK 19/05. The primary study endpoint was to identify prognostic (overall survival, OS) miRNA's. Patient samples were analyzed with Agilent human miRNA 8x60K microarrays, each glass slide formatted with eight high-definition 60K arrays. Each array contained 40 probes targeting each of the 1347 miRNA. Data preprocessing included quantile normalization using robust multi-array average (RMA) algorithm. Prognostic and predictive miRNA expression profiles were identified by Spearman's rank correlation test (percentage tumor shrinkage) or log-rank testing (for time-to-event endpoints). RESULTS: Data preprocessing kept 49 patients and 424 miRNA for further analysis. Ten miRNA's were significantly associated with OS, with hsa-miR-29a being the strongest prognostic marker (HR=6.44, 95%-CI 2.39-17.33). Patients with high has-miR-29a expression had a significantly lower survival at 10 months compared to patients with a low expression (54% versus 83%). Six out of the 10 miRNA's (hsa-miRN-29a, hsa-miR-542-5p, hsa-miR-502-3p, hsa-miR-376a, hsa-miR-500a, hsa-miR-424) were insensitive to perturbations according to jackknife cross-validation on their HR for OS. The respective principal component analysis (PCA) defined a meta-miRNA signature including the same 6 miRNA's, resulting in a HR of 0.66 (95%-CI 0.53-0.82). CONCLUSION: Cell-free circulating miRNA-profiling successfully identified a highly prognostic 6-gene signature in patients with advanced non-squamous NSCLC. Circulating miRNA profiling should further be validated in external cohorts for the selection and monitoring of systemic treatment in patients with advanced NSCLC.

MicroRNA-29b is involved in the Src-ID1 signaling pathway and is dysregulated in human lung adenocarcinoma.

The c-Src kinase regulates cancer cell invasion through inhibitor of DNA binding/differentiation 1 (ID1). Src and ID1 are frequently overexpressed in human lung adenocarcinoma. The current study aimed at identifying microRNAs (miRNAs) involved in the Src-ID1 signaling in lung cancer. Incubation of lung cancer cells with the Src inhibitor saracatinib led to the upregulation of several miRNAs including miR-29b, which was the most highly upregulated miRNA with predicted binding to the ID1 3'-untranslated region (UTR). Luciferase reporter assays confirmed direct binding of miR-29b to the ID1 3'-UTR. Expression of miR-29b suppressed ID1 levels and significantly reduced migration and invasion. Expression of antisense-miR-29b (anti-miR-29b), on the other hand, enhanced ID1 mRNA and protein levels, and significantly increased lung cancer cell migration and invasion, a hallmark of the Src-ID1 pathway. The ectopic expression of ID1 in miR-29b-overexpressing cells was able to rescue the migratory potential of these cells. Both, anti-miR-29b and ID1 overexpression diminished the effects of the Src inhibitors saracatinib and dasatinib on migration and invasion. Saracatinib and dasatinib decreased c-Myc transcriptional repression on miR-29b and led to increased ID1 protein levels, whereas forced expression of c-Myc repressed miR-29b and induced ID1. In agreement, we showed direct recruitment of c-Myc to the miR-29b promoter. miR-29b was significantly downregulated in primary lung adenocarcinoma samples compared with matched alveolar lung tissue, and miR-29b expression was a significant prognostic factor for patient outcome. These results suggest that miR-29b is involved in the Src-ID1 signaling pathway, is dysregulated in lung adenocarcinoma and is a potential predictive marker for Src kinase inhibitors.