Type I interferon signaling pathway enhances immune-checkpoint inhibition in KRAS mutant lung tumors.

Lung cancer is the leading cause of cancer mortality worldwide. KRAS oncogenes are responsible for at least a quarter of lung adenocarcinomas, the main subtype of lung cancer. After four decades of intense research, selective inhibitors of KRAS oncoproteins are finally reaching the clinic. Yet, their effect on overall survival is limited due to the rapid appearance of drug resistance, a likely consequence of the high intratumoral heterogeneity characteristic of these tumors. In this study, we have attempted to identify those functional alterations that result from KRAS oncoprotein expression during the earliest stages of tumor development. Such functional changes are likely to be maintained during the entire process of tumor progression regardless of additional co-occurring mutations. Single-cell RNA sequencing analysis of murine alveolar type 2 cells expressing a resident Kras oncogene revealed impairment of the type I interferon pathway, a feature maintained throughout tumor progression. This alteration was also present in advanced murine and human tumors harboring additional mutations in the p53 or LKB1 tumor suppressors. Restoration of type I interferon (IFN) signaling by IFN-ß or constitutive active stimulator of interferon genes (STING) expression had a profound influence on the tumor microenvironment, switching them from immunologically "cold" to immunologically "hot" tumors. Therefore, enhancement of the type I IFN pathway predisposes KRAS mutant lung tumors to immunotherapy treatments, regardless of co-occurring mutations in p53 or LKB1.

Comparisons of assessment pathways after abnormal mammography screening in Denmark, Norway, and Spain.

PURPOSE: To ensure high-quality screening programmes and effective utilization of resources, it is important to monitor how cancer detection is affected by different strategies performed at recall assessment. This study aimed to describe procedures performed at recall assessment and compare and evaluate the performance of the assessment in Denmark, Norway, and Spain in terms of screen-detected cancer (SDC) and interval cancer (IC) rates. METHODS: We included women aged 50-69 years from Denmark, Norway, and Spain, who were recalled for assessment after screening mammography, and recorded all procedures performed during six months after diagnosis, and the timing of the procedures. Women were followed for two years and screen-detected and interval cancer, and sensitivity of recall was calculated and compared. RESULTS: In total, data from 24,645 Danish, 30,050 Norwegian, and 41,809 Spanish women were included in the study. Most of the women had some assessment within 2 months in all three countries. SDC rates were higher in Denmark (0.57) and Norway (0.60) compared to Spain (0.38), as were the IC rates, i.e. 0.25 and 0.18 vs. 0.12, respectively. The sensitivity of the diagnostic follow-up was somewhat higher in Denmark (98.3%) and Norway (98.2%), compared to Spain (95.4%), but when excluding non-invasive assessment pathways, the sensitivities were comparable. CONCLUSION: This comparison study showed variation in the assessment procedures used in the three countries as well as the SDC and IC rates and the sensitivity of recall.

The promoting physical activity in regional and remote cancer survivors (PPARCS) trial: Physical activity maintenance.

INTRODUCTION: The study examined whether increased physical activity (PA) in nonmetropolitan cancer survivors was maintained 12 weeks following the PPARCS intervention. METHODS: PA outcomes were assessed using an accelerometer at baseline, end of the intervention, and at 24 weeks. Linear mixed models were used to examine between-group changes in PA outcomes. RESULTS: The increased moderate-to-vigorous PA (MVPA) following intervention was maintained with significantly higher MVPA in the intervention group at 24 weeks (vs. controls) compared to baseline nett change of 52.5 min/week (95% CI 11.0-94.0.4). CONCLUSIONS: Distance-based interventions using wearables and health coaching may produce MVPA maintenance amongst nonmetropolitan cancer survivors.

Cumulative risk of a false-positive screening result: A retrospective cohort study using empirical data from 10 biennial screening rounds in BreastScreen Norway.

BACKGROUND: False-positive screening results are an inevitable and commonly recognized disadvantage of mammographic screening. This study estimated the cumulative probability of experiencing a first false-positive screening result in women attending 10 biennial screening rounds in BreastScreen Norway, which targets women aged 50 to 69 years. METHODS: This retrospective cohort study analyzed screening outcomes from 421,545 women who underwent 1,894,523 screening examinations during 1995-2019. Empirical data were used to calculate the cumulative risk of experiencing a first false-positive screening result and a first false-positive screening result that involved an invasive procedure over 10 screening rounds. Logistic regression was used to evaluate the effect of adjusting for irregular attendance, age at screening, and number of screens attended. RESULTS: The cumulative risk of experiencing a first false-positive screening result was 18.04% (95% confidence interval [CI], 18.00%-18.07%). It was 5.01% (95% CI, 5.01%-5.02%) for experiencing a false-positive screening result that involved an invasive procedure. Adjusting for irregular attendance or age at screening did not appreciably affect these estimates. After adjustments for the number of screens attended, the cumulative risk of a first false-positive screening result was 18.28% (95% CI, 18.24%-18.32%), and the risk of a false-positive screening result including an invasive procedure was 5.11% (95% CI, 5.11%-5.22%). This suggested that there was minimal bias from dependent censoring. CONCLUSIONS: Nearly 1 in 5 women will experience a false-positive screening result if they attend 10 biennial screening rounds in BreastScreen Norway. One in 20 will experience a false-positive screening result with an invasive procedure. LAY SUMMARY: A false-positive screening result occurs when a woman attending mammographic screening is called back for further assessment because of suspicious findings, but the assessment does not detect breast cancer. Further assessment includes additional imaging. Usually, it involves ultrasound, and sometimes, it involves a biopsy. This study has evaluated the chance of experiencing a false-positive screening result among women attending 10 screening examinations over 20 years in BreastScreen Norway. Nearly 1 in 5 women will experience a false-positive screening result over 10 screening rounds. One in 20 women will experience a false-positive screening result involving a biopsy.

Comparison of technical parameters and women's experience between self-compression and standard compression modes in mammography screening: a single-blind randomized clinical trial.

OBJECTIVES: We compared the compression force, breast thickness, and glandular dose, as well as the severity of discomfort and women's experience between the patient-assisted compression (PAC) and standard compression (SC) modes. MATERIALS AND METHODS: We conducted a prospective randomized controlled study at Hospital del Mar in Barcelona, Spain. We included 448 asymptomatic women aged 50 to 69 years old, attending their screening round from December 2017 to December 2019. Mammograms included the two bilateral views. In each woman, one breast was studied with SC and the other with PAC. The mode used in each breast was selected following a randomized list. Compression force, breast thickness, and average glandular dose were obtained for each of the 1792 images. We also recorded the degree of discomfort and women's experience, after mammogram acquisitions, using a predefined survey. RESULTS: Higher compression forces were obtained with PAC than with SC (99.27 N vs 83.25 N, p < 0.001). Breast thickness mode (56.11 mm vs 57.52 mm, p = 0.015) and glandular dose (1.34 mGy vs 1.37 mGy, p = 0.018) were lower in PAC. The discomfort score was slightly higher with PAC (mean 3.94 vs 3.69, p = 0.042), but in the satisfaction survey, more women reported that PAC caused less discomfort. Additionally, 63.2% of women (289/448) preferred PAC. CONCLUSION: PAC achieved higher compression forces without impairing the other technical imaging parameters and enhanced women's experience of screening mammography. We believe there were no clinically significant differences in the severity of discomfort between the two modes. KEY POINTS: • Self-compression allows higher compression forces than the standard compression mode. • Self-compression does not affect technical imaging parameters. • Self-compression improved women's experience of screening mammography when standard compression was used on one breast and self-compression on the other.

Does the patient-assisted compression mode affect the mammography quality? A within-woman randomized controlled trial.

OBJECTIVES: Evaluate the image quality of a mammography screening device using the patient-assisted compression (PAC) compared with the standard compression (SC) mode. METHODS: This prospective within-woman, randomized controlled trial was conducted between September 2017 and December 2019. Participants were asymptomatic women aged 50 to 69 years attending their second or subsequent screening mammography round. By random assignment, one breast underwent the SC and the other breast, the PAC. Image quality was evaluated as perfect, good, moderate, or inadequate (PGMI) on 10 criteria for the craniocaudal (CC) view and 8 criteria for the mediolateral oblique (MLO) view. Pearson's chi-square test, with Yates' correction if pertinent, was performed to compare image quality between compression modes. RESULTS: A total of 444 participants were included (mean [± standard deviation] age, 60 [± 4.9] years). There were no differences in the percentages of PGMI between the PAC and SC modes for the CC view (perfect, 37% [162/444] vs 37% [163/444]; good, 1% [5/444] vs 2% [9/444]; moderate, 62% [277/444] vs 61% [271/444]; inadequate, 0% vs 0.2% [1/444]; p = .88) or for the MLO view (perfect, 53% [237/444] vs 56% [247/444]; good, 22% [99/444] vs 22% [97/444]; moderate, 23% [102/444] vs 22% [98/444]; inadequate, 1% [6/444] vs 0.5% [2/444]; p = .72). No differences were found when we stratified by laterality or when analyzed by PGMI criteria. CONCLUSION: PAC does not seem to impair mammographic image quality. Future research should focus in a daily practice setting. KEY POINTS: No differences were found in the distribution of the PGMI classification, a tool for quality assessment, between patient-assisted compression and standard compression. Similar results were found on stratification of image quality by mammographic view and breast laterality for both types of compression. None of the PGMI criteria had significantly more errors in patient-assisted compression than in standard compression.

Mammographic features of benign breast lesions and risk of subsequent breast cancer in women attending breast cancer screening.

OBJECTIVES: To evaluate the mammographic features in women with benign breast disease (BBD) and the risk of subsequent breast cancer according to their mammographic findings. METHODS: We analyzed data from a Spanish cohort of women screened from 1995 to 2015 and followed up until December 2017 (median follow-up, 5.9 years). We included 10,650 women who had both histologically confirmed BBD and mammographic findings. We evaluated proliferative and nonproliferative BBD subtypes, and their mammographic features: architectural distortion, asymmetries, calcifications, masses, and multiple findings. The adjusted hazard ratios (aHR) and 95% confidence intervals (95% CI) for breast cancer were estimated using a Cox proportional hazards model. We plotted the adjusted cumulative incidence curves. RESULTS: Calcifications were more frequent in proliferative disease with atypia (43.9%) than without atypia (36.8%) or nonproliferative disease (22.2%; p value < 0.05). Masses were more frequent in nonproliferative lesions (59.1%) than in proliferative lesions without atypia (35.1%) or with atypia (30.0%; p value < 0.05). Multiple findings and architectural distortion were more likely in proliferative disease (16.1% and 4.7%) than in nonproliferative disease (12.8% and 1.9%). Subsequent breast cancer occurred in 268 (2.5%) women. Compared with women who had masses, the highest risk of subsequent breast cancer was found in those with architectural distortions (aHR, 2.21; 95% CI, 1.16-4.22), followed by those with multiple findings (aHR, 1.89; 95% CI, 1.34-2.66), asymmetries (aHR, 1.66; 95% CI, 0.84-3.28), and calcifications (aHR, 1.60; 95% CI, 1.21-2.12). CONCLUSION: BBD subtypes showed distinct mammographic findings. The risk of subsequent breast cancer was high in those who have shown architectural distortion, multiple findings, asymmetries, and calcifications than in women with masses. KEY POINTS: • The presence of mammographic findings in women attending breast cancer screening helps clinicians to assess women with benign breast disease (BBD). • Calcifications were frequent in BBDs with atypia, which are the ones with a high breast cancer risk, while masses were common in low-risk BBDs. • The excess risk of subsequent breast cancer in women with BBD was higher in those who showed architectural distortion compared to those with masses.

Factors that Influence Treatment Delay for Patients with Breast Cancer.

INTRODUCTION: The diagnosis or treatment of breast cancer is sometimes delayed. A lengthy delay may have a negative psychological impact on patients. The aim of our study was to evaluate the sociodemographic, clinical and pathological factors associated with delay in the provision of surgical treatment for localised breast cancer, in a prospective cohort of patients. METHODS: This observational, prospective, multicentre study was conducted in ten hospitals belonging to the Spanish national public health system, located in four Autonomous Communities (regions). The study included 1236 patients, diagnosed through a screening programme or found to be symptomatic, between April 2013 and May 2015. The study variables analysed included each patient's personal history, care situation, tumour history and data on the surgical intervention, pathological anatomy, hospital admission and follow-up. Treatment delay was defined as more than 30 days elapsed between biopsy and surgery. RESULTS: Over half of the study population experienced surgical treatment delay. This delay was greater for patients with no formal education and among widows, persons not requiring assistance for usual activities, those experiencing anxiety or depression, those who had a high BMI or an above-average number of comorbidities, those who were symptomatic, who did not receive NMR spectroscopy, who presented a histology other than infiltrating ductal carcinoma or who had poorly differentiated carcinomas. CONCLUSIONS: Certain sociodemographic and clinical variables are associated with surgical treatment delay. This study identifies factors that influence surgical delays, highlighting the importance of preventing these factors and of raising awareness among the population at risk and among health personnel.

Breast density, benign breast disease, and risk of breast cancer over time.

OBJECTIVES: Assessing the combined effect of mammographic density and benign breast disease is of utmost importance to design personalized screening strategies. METHODS: We analyzed individual-level data from 294,943 women aged 50-69 years with at least one mammographic screening participation in any of four areas of the Spanish Breast Cancer Screening Program from 1995 to 2015, and followed up until 2017. We used partly conditional Cox models to assess the association between benign breast disease, breast density, and the risk of breast cancer. RESULTS: During a median follow-up of 8.0 years, 3697 (1.25%) women had a breast cancer diagnosis and 5941 (2.01%) had a benign breast disease. More than half of screened women had scattered fibroglandular density (55.0%). The risk of breast cancer independently increased with the presence of benign breast disease and with the increase in breast density (p for interaction = 0.84). Women with benign breast disease and extremely dense breasts had a threefold elevated risk of breast cancer compared with those with scattered fibroglandular density and without benign breast disease (hazard ratio [HR] = 3.07; 95%CI = 2.01-4.68). Heterogeneous density and benign breast disease was associated with nearly a 2.5 elevated risk (HR = 2.48; 95%CI = 1.66-3.70). Those with extremely dense breast without a benign breast disease had a 2.27 increased risk (95%CI = 2.07-2.49). CONCLUSIONS: Women with benign breast disease had an elevated risk for over 15 years independently of their breast density category. Women with benign breast disease and dense breasts are at high risk for future breast cancer. KEY POINTS: • Benign breast disease and breast density were independently associated with breast cancer. • Women with benign breast disease had an elevated risk for up to 15 years independently of their mammographic density category.

Effect of an information leaflet on breast cancer screening participation: A cluster randomized controlled trial.

OBJECTIVE: To evaluate the impact of an information leaflet about the risk-benefit balance of breast cancer screening on women's participation. METHODS: This cluster randomized controlled trial was conducted within a population-based breast cancer screening program and included women from the catchment areas of two hospitals in Barcelona, Spain. We evaluated women aged 50-69 years invited to screening between September 2019 and January 2020. The intervention group received an information leaflet on the benefits and harms of mammography screening. The control group received the usual invitation letter. The clusters consisted of the processing days of the invitation letter, assigned to the intervention with a simple random allocation scheme. We compared the participation rate at the individual level between groups, stratified by hospital and by per-protocol and intention-to-treat analyses. RESULTS: We included 11,119 women (137 clusters): 5416 in the intervention group (66 clusters) and 5703 in the control group (71 clusters). A total of 36% (1964/5393) of the women in the intervention group and 37% (2135/5694) of those in the control group attended screening, respectively. Overall, we found no differences in participation among groups (difference in participation - 1.1%; 95%CI; - 2.9 to 0.7%). In a hospital attending a population with a low socioeconomic status, attendance was lower in the intervention group (- 1.4, 95%CI: - 5.7% to - 0.03%). CONCLUSIONS: Overall participation in our program was unaffected by a new information leaflet on the risk-benefit balance of breast cancer screening. However, participation was lower in certain populations with lower socioeconomic status TRIAL REGISTRATION: Trial registration number ISRCTN13848929 .