Estimating advanced breast cancer risk in women undergoing annual or biennial mammography could identify women who may benefit from less or more intensive screening. We developed an actionable model to predict cumulative 6-year advanced cancer (prognostic pathologic stage II or higher) risk according to screening interval. We included 931 186 women aged 40-74 years in the Breast Cancer Surveillance Consortium undergoing 2 542 382 annual (prior mammogram within 11-18 months) or 752 049 biennial (prior within 19-30 months) screening mammograms. The prediction model includes age, race and ethnicity, body mass index, breast density, family history of breast cancer, and prior breast biopsy subdivided by menopausal status and screening interval. We used fivefold cross-validation to internally validate model performance. We defined higher than 95th percentile as high risk (>0.658%), higher than 75th percentile to 95th or less percentile as intermediate risk (0.380%-0.658%), and 75th or less percentile as low to average risk (<0.380%). Obesity, high breast density, and proliferative disease with atypia were strongly associated with advanced cancer. The model is well calibrated and has an area under the receiver operating characteristics curve of 0.682 (95% confidence interval = 0.670 to 0.694). Based on women’s predicted advanced cancer risk under annual and biennial screening, 69.1% had low or average risk regardless of screening interval, 12.4% intermediate risk with biennial screening and average risk with annual screening, and 17.4% intermediate or high risk regardless of screening interval. Most women have low or average advanced cancer risk and can undergo biennial screening. Intermediate-risk women may consider annual screening, and high-risk women may consider supplemental imaging in addition to annual screening.

Background Concurrent chemoradiation is the standard of care in non-operable stage III non-small cell lung cancer (NSCLC). Data has suggested a benefit of dose-escalation, however results from the randomized dose-escalation trial RTOG 0617 revealed a lower survival rate with high-dose radiation. To evaluate the impact of dose-escalation on overall survival (OS) in stage III NSCLC treated with chemoradiotherapy outside the controlled setting of a randomized trial, we performed an observational, population-based investigation of the National Cancer Data Base (NCDB). Patients and Methods A total of 33,566 patients with stage III NSCLC treated with chemoradiation from 2004 – 2012 and radiation doses between 59.4 -85 Gy were included. The primary end-point was OS, median survival calculated via Kaplan-Meier. Univariate, multivariable and propensity-score matching analyses were performed. Results Patients were stratified by dose with median OS of: 18.8, 19.8 and 21.6 months for cohorts receiving 59.4-60 Gy, 61-69 Gy, and≥70 Gy respectively (p<0.001). Granular dose analyses were performed demonstrating increased OS with increasing radiation dose: median survival of 18.8, 21.1, 22.0 and 21.0 months for 59.4-60, 66, 70 and≥71 Gy respectively. While 66, 70 and≥71 Gy resulted in increased OS in comparison to 59.4-60 Gy, no significant difference in OS was observed when comparing 66 to≥71 Gy (p=0.38). Conclusions Dose escalation above 60 Gy was associated with improved OS in this cohort of stage III NSCLC patients treated with chemoradiotherapy. A plateau of benefit was observed, with no additional improvement in OS with increased dose (≥ 71 Gy) compared to 66-70 Gy. With evidence suggesting worse OS and quality of life with increased dose, these data support investigation of the role of intermediate-dose radiation, and in the absence of randomized evidence, may be leveraged to justify utilization of intermediate-dose radiation.

Pancreatic ductal adenocarcinoma (PDAC) continues to be a major health problem. A ketogenic diet (KD), characterized by a very low carbohydrate and high fat composition, has gained attention for its antitumor potential. We evaluated the effect and mechanisms of feeding a strict KD alone or in combination with gemcitabine in the autochthonous LSL-KrasG12D/+; LSL-Trp53 R172H/+; Pdx1-Cre (KPC) mouse model. For this purpose, both male and female pancreatic tumor-bearing KPC mice were allocated to a control diet (CD; %kcal: 65% carb, 15% protein, 20% fat), a KD (%kcal: 1% carb, 15% protein, 84% fat), a CD + gemcitabine (CG), or a KD + gemcitabine (KG) group. Mice fed a KD alone or in combination with gemcitabine showed significantly increased blood β-hydroxybutyrate levels compared with mice fed a CD or CG. KPC mice fed a KG had a significant increase in overall median survival compared with KPC mice fed a CD (increased overall median survival by 42%). Interestingly, when the data were disaggregated by sex, the effect of a KG was significant in female KPC mice (60% increase in median overall survival), but not in male KPC mice (28% increase in median overall survival). Mechanistically, the enhanced survival response to a KD combined with gemcitabine was multifactorial, including inhibition of ERK and AKT pathways, regulation of fatty acid metabolism and the modulation of the gut microbiota. In summary, a KD in combination with gemcitabine appears beneficial as a treatment strategy in PDAC in KPC mice, deserving further clinical evaluation.Significance: This article is the first preclinical study to comprehensively evaluate the effect of a KD alongside chemotherapy using a standard autochthonous genetically modified mouse model (in both male and female KPC mice).