Immunologic Factors Associated with Differential Response to Neoadjuvant Chemoimmunotherapy in Triple-Negative Breast Cancer.

Background: KEYNOTE-522 resulted in FDA approval of the immune checkpoint inhibitor pembrolizumab in combination with neoadjuvant chemotherapy for patients with early-stage, high-risk, triple-negative breast cancer (TNBC). Unfortunately, pembrolizumab is associated with several immune-related adverse events (irAEs). We aimed to identify potential tumor microenvironment (TME) biomarkers which could predict patients who may attain pathological complete response (pCR) with chemotherapy alone and be spared the use of anti-PD-1 immunotherapy. Methods: Comprehensive immune profiling, including RNA-seq gene expression assessment of 395 immune genes, was performed on matched FFPE tumor samples from 22 stage I-III TNBC patients (14 patients treated with neoadjuvant chemotherapy alone (NAC) and 8 treated with neoadjuvant chemotherapy combined with pembrolizumab (NAC+I)). Results: Differential gene expression analysis revealed that in the NAC group, IL12B and IL13 were both significantly associated with pCR. In the NAC+I group, LCK and TP63 were significantly associated with pCR. Patients in both treatment groups exhibiting pCR tended to have greater tumor inflammation than non-pCR patients. In the NAC+I group, patients with pCR tended to have greater cell proliferation and higher PD-L1 expression, while in the NAC group, patients with pCR tended to have lower cancer testis antigen expression. Additionally, the NAC+I group trended toward a lower relative dose intensity averaged across all chemotherapy drugs, suggesting that more dose reductions or treatment delays occurred in the NAC+I group than the NAC group. Conclusions: A comprehensive understanding of immunologic factors could potentially predict pCR to chemotherapy alone, enabling the avoidance of the unnecessary treatment of these patients with checkpoint inhibitors.

Visceral Obesity in Non-Small Cell Lung Cancer.

While obesity measured by body mass index (BMI) has been paradoxically associated with reduced risk and better outcome for lung cancer, recent studies suggest that the harm of obesity becomes apparent when measured as visceral adiposity. However, the prevalence of visceral obesity and its associations with demographic and tumor features are not established. We therefore conducted an observational study of visceral obesity in 994 non-small cell lung cancer (NSCLC) patients treated during 2008-2020 at our institution. Routine computerized tomography (CT) images of the patients, obtained within a year of tumor resection or biopsy, were used to measure cross-sectional abdominal fat areas. Important aspects of the measurement approach such as inter-observer variability and time stability were examined. Visceral obesity was semi-quantified as visceral fat index (VFI), the fraction of fat area that was visceral. VFI was found to be higher in males compared to females, and in former compared to current or never smokers. There was no association of VFI with tumor histology or stage. A gene expression-based measure of tumor immunogenicity was negatively associated with VFI but had no bearing with BMI. Visceral obesity is appraisable in routine CT and can be an important correlate in lung cancer studies.

Obesity-Specific Association of Statin Use and Reduced Risk of Recurrence of Early Stage NSCLC.

INTRODUCTION: Statins, used for their lipid-lowering activity, have anti-inflammatory and anticancer properties as well. We evaluated this potential benefit of statin use in patients with NSCLC. METHODS: All 613 patients with pathologic stage 1 or 2 NSCLC who had lobectomy without neoadjuvant therapy at our institution during 2008 to 2015 were included. Association between presurgery statin use and overall survival and recurrence-free survival (RFS) was analyzed using Cox proportional hazards regression. Association of statin use with tumor transcriptome was evaluated in another 350 lung cancer cases. RESULTS: Univariable analyses did not reveal a statistically significant association of statin use with either overall survival or RFS, with hazard ratio equals to 1.19 and 0.70 (Wald p = 0.28 and 0.09), respectively. In subgroup analyses, significantly improved RFS was found in statin users, but only in overweight/obese patients (body mass index [BMI] > 25; n = 422), with univariable and multivariable hazard ratio of 0.49 and 0.46 (p = 0.005 and 0.002), respectively, but not in patients with BMI less than or equal to 25 (n = 191; univariable p = 0.21). Transcriptomes of tumor statin users had high expression of tumoricidal genes such as granzyme A and interferon-γ compared with those of nonusers among high- but not low-BMI patients with lung cancer. CONCLUSIONS: Our study suggests that statins may improve the outcome of early stage NSCLC but only in overweight or obese patients. This benefit may stem from a favorable reprogramming of the antitumor immune response that statins perpetrate specifically in the obese.

Visceral Obesity Promotes Lung Cancer Progression-Toward Resolution of the Obesity Paradox in Lung Cancer.

INTRODUCTION: Although obesity is associated with adverse cancer outcomes in general, most retrospective clinical studies suggest a beneficial effect of obesity in NSCLC. METHODS: Hypothesizing that this "obesity paradox" arises partly from the limitations of using body mass index (BMI) to measure obesity, we quantified adiposity using preoperative computed tomography images. This allowed the specific determination of central obesity as abdominal visceral fat area normalized to total fat area (visceral fat index [VFI]). In addition, owing to the previously reported salutary effect of metformin on high-BMI patients with lung cancer, metformin users were excluded. We then explored associations between visceral obesity and outcomes after surgical resection of stage I and II NSCLC. We also explored potential immunologic underpinnings of such association using complimentary analyses of tumor gene expression data from NSCLC tumors and the tumor transcriptome and immune microenvironment in an immunocompetent model of lung cancer with diet-induced obesity. RESULTS: We found that in 513 patients with stage I and II NSCLC undergoing lobectomy, a high VFI is associated with decreased recurrence-free and overall survival. VFI was also inversely related to an inflammatory transcriptomic signature in NSCLC tumors, consistent with observations made in immunocompetent murine models wherein diet-induced obesity promoted cancer progression while exacerbating elements of immune suppression in the tumor niche. CONCLUSIONS: In all, this study uses multiple lines of evidence to reveal the adverse effects of visceral obesity in patients with NSCLC, which align with those found in animal models. Thus, the obesity paradox may, at least in part, be secondary to the use of BMI as a measure of obesity and the confounding effects of metformin use.

VIABILITIES OF AMYLASE GENOTYPES IN DROSOPHILA PSEUDOOBSCURA ON STARCH AND MALTOSE FOOD.

In order to study the relationship between selection on an enzyme and the environment, viability was measured for genotypes at the α-amylase (Amy) locus of D. pseudoobscura on food containing either starch as the primary source of carbohydrates or, as a control, maltose, the breakdown product of starch by amylase. These conditions were chosen to reveal possible differences among these genotypes in their abilities to survive on starch food. Counted numbers of larvae were cultured on food with low or high levels of starch, or with maltose, at both 20°C and 25°C. Only under the most stressful environmental conditions, on food with a low starch concentration at 25°C, did the genotypes differ significantly in viability. Four population cages maintained on food with either maltose or starch as carbohydrate sources were set up to assay differences in overall fitness among the Amy genotypes. No selective differences were observed over 10 generations, and we infer that components of fitness other than viability also differed little among the Amy genotypes on the two types of food. Thus our efforts to manipulate the environmental levels of starch, the substrate of amylase, led to measurable selective differences only under very stressful conditions.