Citations

Abstract Background: The I-SPY 2 TRIAL enrolls women with locally advanced, molecular high-risk breast cancer. An integrated Residual Cancer Burden (iRCB), based on MRI volume change through treatment, is used to predict pathologic complete response (pCR) in the randomization/evaluation Bayesian engine. With the goal of effective de-escalation of treatment for patients exhibiting an early response, biomarkers are being assessed for their ability to predict pCR, alone or with MR data, during treatment. Here, we present the results of a pilot study to examine if invasive tumor cellularity in mid-treatment tissue core biopsies predicts pCR in a 40-patient cohort of I-SPY 2 patients. Other pathologic variables evaluated include Ki67, tumoral histologic features, and stromal tumor-infiltrating lymphocytes (sTILs). Methods: I-SPY 2 TRIAL pathologists (N=4) were provided images of H&E-stained and Ki67 IHC- labelled (DAKO/Agilent, clone MIB-1) core biopsy sections from 40 patients at the inter-regimen time point, ~12-weeks into treatment. Of the 40 patients, 35 had 4 cores, 3 had 3 cores, and 2 had 2 cores assessed. In total, images from 153 cores were evaluated. For each core, pathologists were asked to score the % area occupied by tumor bed (treatment changes and/or residual cancer), % of viable invasive tumor (0-100%) within tumor bed (with Nottingham grading, % Ki67 labelled, and % sTILs, using standardized guidelines). As decided by the pathologist group, only cores with identified tumor bed were included in the initial analysis. Concordance between pathologists was assessed for all scored criteria, using % agreement for dichotomous variables, and Pearson correlation (r)/standard deviation (sd) for continuous variables. The maximum and average cellularity recorded over all cores/patient, averaged over all pathologists, were analyzed for association with pCR using t- tests (significance threshold: p<0.05). Fisher’s Exact test was used for dichotomous variables, and Pearson’s correlation for association of continuous variables with the residual cancer burden (RCB) index. Results: Pathologist were in general agreement about the presence or absence of tumor bed, with greater than 82% agreement between any two (83-96%), and an overall agreement of 77%. For scoring the % of the tumor bed involved by invasive cancer, correlations between pairs of pathologists ranged from 0.79-0.95 (mean(r)=0.87, sd=5%), and agreement on a binary presence/absence of invasive cancer was 78%. Both the mean (t-test: p=7.59E-05) and maximum (t-test: p=0.0012) %invasive tumor at 12 weeks, scored as an average over all pathologists, were significantly higher in patients who did not achieve pCR than in responders. We also treated %invasive cellularity as a dichotomous variable (present/absent). 90% (9/10) of patients scored by all pathologists as 0% invasive tumor cells (absent) achieved a pCR, vs only 20% (6/30) of patients scored as >0% invasive cellularity by one or more pathologists (present) (OR=32, Fisher p=0.0005); yielding a positive predictive value for pCR of 0.9. Ki67 and sTILS at 12 weeks were fairly concordant across pathologists ((r,sd)=(0.92, 8.45%) and (0.82,5.5%), respectively), but did not associate with response (p>0.05 for pCR, RCB01, or RCB index). Tumor histologic grade at 12 weeks, assessed in 29/30 patients with non-zero cellularity, trended toward association (Fisher p=0.078): 44% (4/9) with Grade 3 went on to have a pCR, vs. 15% (2/13) with Grade 2 and 0 with Grade 1. These data demonstrate the utility of invasive tumor cellularity as a predictor of pCR in a clinical setting. Conclusion: In this pilot study we demonstrate that the absence of invasive cancer cells within identified tumor bed in mid-treatment core biopsy samples is highly predictive of pCR. Citation Format: Sara J Venters, Denise M Wolf, Lamorna Brown-Swigart, Christina Yau, Amy L Delson, Bev Parker, Ron Balassanian, Jodi Carter, Yunn-Yi Chen, Kimberly Cole, Laila Khazai, Molly Klein, Dina Kokh, Gregor Krings, Sunati Sahoo, Jane Wei, I-SPY 2 TRIAL Consortium, Laura J Esserman, Laura J van't Veer, W Fraser Symmans. Assessing biomarkers to inform treatment de-escalation: Mid-treatment biopsy cellularity predicts pCR in the I-SPY 2 Trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-10-02.

Abstract Background Prior epidemiologic studies have shown an inverse relationship of aspirin and NSAID use with breast cancer (BC) risk in the general population. Women with benign breast disease (BBD) are at an increased BC risk compared with women in the general population, and we have shown that BBD biopsies contain increased numbers of immune cells compared with normal breast tissues donated for research in the Komen Tissue Bank. We hypothesized that NSAID use among women with BBD is associated with reduced risk of BC. Methods We evaluated BC risk in relation to aspirin and NSAID use in a single institution retrospective cohort of 4,498 women who received a biopsy diagnosis of BBD between 1/1/1992 and 12/31/2001. Information on usual medication use, including average number of days used per month (0, 1-7, 8-28 and >28), was collected via questionnaires mailed after identification of participants. NSAIDs were categorized into three classes: 1) Aspirin, 2) Ibuprofen (plus other prostaglandin synthesis inhibitors), and 3) COX inhibitors. BC events were captured via medical record, questionnaires, and Tumor Registry records. Medication use was evaluated for associations with clinical and pathology features. Hazard ratios (HR) and 95% confidence intervals (CI) examining associations between medication use and BC risk were estimated using Cox regression analyses, with adjustment for age and BMI at biopsy, years between biopsy and questionnaire, and pathologic features related to BC risk (severity of BBD and degree of involution in background lobules). Tests for trend examining frequency of use were calculated from ordered values (lowest to highest) in Cox models with a one degree-of-freedom linear term. We assessed BC associations with any type of NSAID use, as well as the three subclasses. Results Information on NSAID use was available for 3,089 (69%) of the participants in the cohort; these women had a median age of 49 and did not differ in BC risk from women who did not provide data on NSAID use (p=0.46). Of the 3,089 respondents, 313 (10.1%) subsequently developed BC with median follow-up of 17 years. Age was significantly associated with use of all types of NSAIDs, with increasing use in older women. BMI at the time of biopsy, severity of BBD findings, and involution in background lobules were also associated with NSAID use; thus these factors and age were adjusted for in risk association analyses. Ever users of NSAIDs (any type) had a significantly lower risk of BC than never users (HR 0.76, CI 0.59-0.98, p=0.03), and increasing frequency of NSAID use was significantly associated with lower BC risk (HRs 0.81, 0.79, and 0.70 for regular use 1-7, 8-28, and >28 days/month), trend p=0.02. Analyses of drug classes revealed that ever use of ibuprofen (HR 0.61, CI 0.42-0.89, p=0.01) and ever use of COX inhibitors (HR 0.59, CI 0.39-0.89, p=0.01) were associated with decreased BC risk. COX inhibitors in particular showed a strong dose response effect with increasing use (HRs 0.97, 0.52, and 0.47 for regular use 1-7, 8-28, and >28 days/month), trend p<0.01. Use of aspirin was not associated with BC risk (HR 0.88, CI 0.64-1.21, p=0.44). Conclusions In this exploratory analysis, we found use of ibuprofen and other NSAIDs to be associated with decreased BC risk among women who had undergone a BBD biopsy. These findings suggest that anti-inflammatory approaches may have value in chemoprevention among women with BBD. Citation Format: Amy Degnim, Robert Vierkant, Stacey Winham, Marlene Frost, Daniel Visscher, Jodi Carter, Suneetha Kaggal, Julie Cunningham, Teresa Allers, Tanya Hoskin, Ethan Heinzen, Celine Vachon, Keith Knutson, Keith Knutson, Derek Radisky, Mark Sherman. NSAID use and breast cancer risk in a retrospective cohort of women with benign breast disease [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-08-06.

Abstract Background: Local antitumor immunity—as assessed by quantifying tumor-infiltrating immune cells—is increasingly recognized as a critical factor influencing prognosis and therapy response in TNBC. However, an understanding of systemic antitumor immune responses occurring in peripheral blood, and their influence on prognosis and chemotherapy response has not been rigorously studied. Methods: Cytometry by time-of-flight (CyTOFTM, Fluidigm) was used to examine viably cryopreserved peripheral blood mononuclear cell (PBMC) suspensions prospectively collected from patients with early-stage TNBC prior to initiation of standard neoadjuvant paclitaxel followed by doxorubicin and cyclophosphamide (NACT) as part of the BEAUTY study [1]. Samples were stained using a panel of metal-tagged antibodies, recognizing 30 surface proteins optimized for immune monitoring of human peripheral blood. Differential abundance analysis of immune cell subsets was carried out to evaluate differences between patients who achieved pCR versus those with residual disease after NACT, and between patients with known luminal androgen receptor (LAR) versus basal TNBC subtypes defined by bulk tumor RNA sequencing. Results: Viably cryopreserved PBMC samples from 40 treatment-naive TNBC patients were available for analysis. The median age was 52 years (range 32 - 73), with 6 (15%) patients having tumors classified as LAR TNBC, and the remaining 34 (85%) as basal TNBC. Overall, 21 (53%) patients achieved pCR after NACT. After acquisition on the mass cytometer, the median yield per sample was 626,815 single-cell events (range 42,786 - 1,035,575), with a median percent debris of 13.7% (range 14 - 58). Across the 40 PBMC samples, the total yield was 23,507,094 single-cell events. The median frequencies of major circulating immune cell subsets across the 40 TNBC patients were: T cells 53.9% (range 25.4 - 71.3), with 33.4% CD4+ T cells (range 11.4 - 46.7) and 10.3% CD8+ T cells (range 5.8 - 19.9); B cells 10.8% (3.3 - 32.6), NK cells 8.6% (1.7 - 17.0) and monocytes 10.6% (2.7 - 29.8). Examining pre-treatment blood samples, patients with residual disease after NACT exhibited a higher median frequency of baseline CD14+CD16- classical monocytes (7.5% vs. 4.1%, p=0.025) and a lower frequency of terminally-differentiated effector memory cytotoxic (CD8+) T cells (0.6% vs. 1.7%, p=0.038) compared to patients who achieved pCR. Patients with LAR TNBC also exhibited a higher frequency of CD14+CD16- classical monocytes (11.5% vs 4.3%, p=0.058), and in addition exhibited a lower frequency of central memory CD4+ T cells (10.4% vs 15.2%, p=0.048). No difference in CD8+ T cells was seen by LAR status. Additional associations of peripheral blood immune cell subsets and classic tumor pathological features will be presented at the meeting. Conclusion: To our knowledge, this is the first study focused on TNBC to demonstrate variation in peripheral blood immune cell populations by molecular TNBC subtype (LAR vs. basal), and by chemotherapy response. A higher frequency of circulating classical monocytes—which can infiltrate into tissues and give rise to macrophages—appears to be detrimental; whereas a higher frequency of circulating antigen-experienced memory CD8+ T cells seems to be protective, suggesting a putative role of this cell subset in TNBC anti-tumoral immunity. Reference: [1] Goetz MP et al. JNCI 2017, PMID:28376176 Citation Format: Roberto A Leon-Ferre, Kaitlyn McGrath, Jodi M Carter, Krishna R Kalari, Vera J Suman, Richard Weinshilboum, Liewei Wang, Keith L Knutson, Stephen M Ansell, Judy C Boughey, J C Villasboas, Matthew P Goetz. Deep phenotyping using CyTOF identifies peripheral blood immune signatures associated with clinical outcomes and molecular subtypes in patients with early-stage triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-04-09.

Abstract Background The Circulating Cell-free Genome Atlas (CCGA; NCT02889978) study is a prospective, multi-center, observational, case-control study with longitudinal follow-up to support the development of a plasma cfDNA-based multi-cancer early detection assay. We previously reported that the fraction of tumor-derived cfDNA fragments in plasma (estimated tumor fraction [TF]) is associated with detection of multiple cancer types using a prototype whole-genome bisulfite sequencing (WGBS) assay in a pre-specified substudy. In addition, detectability of breast cancer varied by hormone-receptor (HR) status: HR negative (HR-) breast cancer had a higher detection rate than the overall breast cancer cohort. Here, we performed a planned in-depth analysis of the breast cancer cohort to understand the main clinical and biological determinants of detectability using our WGBS assay. Methods Blood samples were prospectively collected from participants (pts) with newly-diagnosed, untreated breast cancer. In a pre-specified CCGA substudy, 511 (31.4%) of 1,628 pts had a clinicopathologic diagnosis of breast cancer (any stage, excluding stage 0) and a WGBS result. Pre-specified biological and clinical factors were assessed for correlation with TF: clinical stage, pathologic N stage, lesion size (by imaging), T stage, histologic grade, hormone receptor (HR) status, and proliferative rate (Ki-67 by IHC [MIB-1 clone]) via univariate and multivariate analyses. Ki-67 was obtained from pathology reports provided by enrollment sites and also assessed centrally (Mayo Clinic [Rochester, MN]). Stage-specific differences in detection rates between HR positive (HR+) and HR- breast cancers due to biological differences such as histologic grade and/or proliferative rate was also assessed. Results Of 511 pts, 94 (18.4%; 48.9% HR- and 12.3% in HR+) had WGBS-detected cancer. Higher TF was significantly associated with cancer detection (p<0.001). In univariate analyses, the variables significantly associated with TF were clinical stage, pathological N stage, and histologic grade (p<0.001 each). Primary lesion size was modestly correlated with TF (all stages combined: Spearman's correlation coefficient rs=0.4, p<0.001), and when grouped by early and late stages (stages I/II: rs=0.27, p<0.01; stages III/IV: rs=0.50, p<0.01); clinical T stage was significantly associated with TF only when all stages were combined (p<0.001). Proliferative rate (Ki-67) was positively correlated with TF at stages I/II (rs=0.29, p<0.05) but not III/IV (rs=-0.24, p=0.34); Ki-67 results obtained through Mayo were similar to that from enrollment sites (Pearson’s correlation coefficient rp=0.68, p<0.001). HR- breast cancers had significantly higher TF versus HR+ breast cancers only at stage II (p<0.001). In addition, compared to HR+ breast cancers, HR- breast cancers had a significantly higher proportion of high histologic grade (p<0.001 at stages I and II) and proliferative rate at earlier stages (p<0.05 at stages I, II, and III). In the multivariate analysis, clinical stage (stage III vs I and IV vs I) and HR status remained the most significantly associated with TF (p<0.001 each). Conclusions Using a prototype methylation-based plasma cfDNA cancer detection assay, TF was found to be associated with detection, and with clinical and biological features of breast cancer. Features routinely used to assess clinical aggressiveness (eg, HR- status and histologic grade) also demonstrated stage-specific associations with TF. Given the known relationship between TF and detection, these data suggest that clinical and biological cancer features may also provide insight into the variability of cancer detection using plasma-based cfDNA tests. Citation Format: Minetta C. Liu, Jodi M. Carter, Daniel W. Visscher, Karla Kopp, Rita Shaknovich, Xiaoji Chen, Kathryn N. Kurtzman, Shilpen Patel, Jacqueline D. Brooks, Carlo R. Cosenza, Jafi A. Lipson, Donald A. Richards, Fergus J. Couch, Zhao Dong, Hai Liu, Oliver Venn, Joerg Bredno, Eric T. Fung, Anne-Renee Hartman. Blood-based cancer detection in plasma cell-free DNA (cfDNA): Evaluating clinical and pathologic tumor characteristics in participants with breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-01-01.

Abstract Background: Patients who achieve a pathological complete response (pCR- defined as no invasive cancer) after neoadjuvant chemotherapy (NAC) for breast cancer (BC) have improved outcomes, but there is still controversy about the significance of residual ductal carcinoma in situ (DCIS) on local recurrence rate (LRR). The I-SPY 2 TRIAL is an adaptive neoadjuvant platform trial evaluating novel experimental regimens in comparison to standard chemotherapy in women with high-risk breast cancer. The purpose of this study is to determine if residual DCIS after NAC in early BC affects LRR in patients with or without residual invasive disease in the I-SPY 2 TRIAL. Methods: 933 I-SPY 2 patients with residual cancer burden (RCB) and follow-up data were included in this analysis. Residual DCIS was defined as any carcinoma in situ > 0% on RCB evaluation. Local recurrence was defined as recurrence in breast, chest wall or locoregional nodes and/or skin and subcutaneous tissue. We stratified our cohort into four groups: those without residual invasive disease (defined as RCB0) ± residual DCIS, and those with residual invasive disease (RCB>0) ± residual DCIS. We estimated LRR within each group using the Kaplan Meier method; and used Cox proportional hazards models to assess LRR differences between groups, with: patients with no residual disease (invasive or in situ) as reference group. Results: Among 933 patients assessed, median follow up time was 3.9 years. RCB 0 status was achieved in 337 patients (36%). Of these, 267 (29%) had no residual DCIS, which represents our reference group, and 70 (7%) had residual DCIS. Among 596 (64%) patients who had RCB>0, 296 (32%) had residual DCIS. For patients with RCB0 without DCIS and RCB0 with DCIS, the LRR at 3 years were similar: 2% vs 3% respectively (Hazard ratio: 1.29 [0.26-6.39]). Results were also similar in the RCB>0 group, with a LRR of 10% at 3 years in those without residual DCIS, and 11% in those with residual DCIS. Both RCB>0 groups had significantly higher LRR when compared to the patients with RCB0 without DCIS (Hazard ratio: 5.25 [2.20-12.5]) and HR 5.85 [2.47-13.9] respectively). Conclusion: There was no association between residual DCIS and LRR after neoadjuvant chemotherapy, regardless of resolution of invasive disease. Further work is needed to determine whether residual DCIS should drive locoregional therapy decisions after neoadjuvant chemotherapy for invasive breast cancer. Citation Format: Marie Osdoit, Christina Yau, W. Fraser Symmans, Judy C. Boughey, Smita M. Asare, Ron Balassanian, Jodi M. Carter, Yunn-Yi Chen, Kimberly Cole, Laila Khazai, Molly Klein, Dina Kokh, Gregor Krings, Sunati Sahoo, Gretchen Ahrendt, Akiko Chiba, Cheryl Ewing, Constantine Godellas, Nora Jaskowiak, Brigid Killelea, Helen Krontiras, Rachael Lancaster, Julie Lang, M. Catherine Lee, Arpana Naik, Roshni Rao, Julia Tchou, Shannon Tierney, Eleni Tousimis, Tod Tuttle, Anne Wallace, I-SPY 2 TRIAL Consortium, Bev Parker, Laura J. Esserman, Rita A. Mukhtar. The impact of residual ductal carcinoma in situ on breast cancer recurrence in the neoadjuvant I-SPY2 TRIAL [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-16.

Abstract Background: Achieving a pathologic complete response (pCR) has been shown on the patient level to predict excellent long-term event-free survival outcomes. Residual cancer burden (RCB) quantifies the extent of residual disease for patients who did not achieve pCR. A high proportion of metastatic events to the central nervous system (CNS), a known chemotherapy sanctuary site, was previously observed among the small number of relapses in patients achieving a pCR (Symmans et al 2017), raising the possibility that these CNS events may be independent of response in the breast. I-SPY2 is an adaptively randomized, phase II, platform trial that evaluates new drugs and combinations in the neoadjuvant setting for women with high-risk primary breast cancer. In this study, we evaluated the type and sites of recurrences by RCB classes in the I-SPY 2 TRIAL. Methods: I-SPY 2 patients enrolled prior to 11/2016 across 9 experimental and control arms, with available RCB and event-free survival (EFS) data were included in this analysis. The median follow-up is 3.8 years. We summarized the EFS event type, further sub-dividing the distant recurrence events by their site of relapse (CNS-only, CNS and other sites, Non-CNS). We estimated the overall and site-specific distant recurrence incidence in each RCB class at 3 years using a competing risk (Fine-Gray) model. In addition, we assessed the association between RCB and distant recurrence free survival including all distant recurrences (DRFS), as well as excluding the CNS-only recurrences (non-CNS DRFS) using a Cox model. Our statistics do not adjust for multiplicities beyond variables evaluated in this study. Results: Among 938 subjects, there were 180 EFS events, including 28 (16%) local recurrences (without distant recurrence and/or death) and 152 DRFS events. Among the DRFS events, 25 patients died without a distant recurrence. 127 experienced distant recurrences, including 22 (17.3%) with CNS-only, 16 (12.6%) with CNS and other sites, 87 (68.5%) with non-CNS distant recurrence; 2 (1.6%) patients had missing recurrence site information. Incidence of CNS-only recurrences are low and are similar across RCB classes (pCR/RCB-0 (n=338): 1%, RCB-I (n=129): 3%, RCB-II (n=328): 2%, RCB-III (n=143): 2% at 3 years). In contrast, the incidence of non-CNS recurrences increase with increasing RCB (RCB-0: 2%, RCB-I: 4%, RCB-II: 11%, RCB-III: 19% at 3 years). DRFS of RCB-I patients do not significantly differ from those achieving a pCR/RCB-0 (DRFS at 3 years: 92% vs. 95%, hazard ratio: 1.77 (0.87-3.63)); the small numerical difference is further reduced when the CNS-only recurrences are excluded (non-CNS DRFS at 3 years: 95% vs. 96%, hazard ratio: 1.48 (0.61-3.58)). CNS recurrences among DRFS events are proportionally higher within the pCR (5/16 (31%)) and RCB-I (5/12 (42%)) than in the RCB-II (8/57 (14%)) and RCB-III (4/42 (9%)) groups largely because of the relative low frequency of non-CNS recurrence events. Conclusions: In our high-risk I-SPY 2 cohort, CNS-only recurrences are uncommon but appear similar across RCB groups, independent of response, suggesting that the CNS is a treatment sanctuary site. In contrast, non-CNS recurrence rates increase as RCB increases. These findings, if confirmed, support the use of RCB to identify patients with excellent outcomes beyond those achieving a pCR; and suggest that inclusion of CNS only recurrences as an outcome event may impact the association between neoadjuvant therapy response and long-term outcome. Citation Format: Christina Yau, Angela DeMichele, W. Fraser Symmans, Lajos Pusztai, Douglas Yee, Amy S. Clark, Christos Hatzis, Jeffrey B. Matthews, Jodi Carter, Yunn-Yi Chen, Kimberly Cole, Laila Khazai, Molly Klein, Dina Kokh, Gregor Krings, Sunati Sahoo, Kathy S. Albain, A. Jo Chien, Kirsten K. Edmiston, Anthony D. Elias, Erin D. Ellis, David M. Euhus, Heather S. Han, Claudine Isaacs, Qamar J. Khan, Julie E. Lang, Janice Lu, Jane L. Meisel, Zaha Mitri, Rita Nanda, Donald W. Northfelt, Tara Sanft, Erica Stringer-Reasor, Rebecca K. Viscusi, Anne M. Wallace, Rachel Yung, Nola M. Hylton, Judy C. Boughey, Michelle E. Melisko, Jane Perlmutter, Hope S. Rugo, Richard Schwab, Laura J. van' t Veer, Donald A. Berry, Laura J. Esserman. Site of recurrence after neoadjuvant therapy: Clues to biology and impact on endpoints [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-20-02.

e19065 Background: Treatment decisions for patients with advanced stage (stages IIIB and IV) non-small cell lung cancer (AS NSCLC) are influenced by comorbidity at time of diagnosis. We studied the effects of comorbidity on survival and whether effects differ for short-term (120 days) vs. for long-term (>120 days) survival. Methods: Data were from surveys and medical records of 1498 patients withnewly diagnosed AS NSCLC in the Cancer Care Outcomes Research and Surveillance Consortium (CanCORS). Respiratory disease severity and comorbidities at diagnosis were measured from the Adult Comorbidity Evaluation (ACE-27) index and model fitting used the Akaike Information Criteria. The log-rank test was used for univariable survival models, and Cox proportional hazards regression for multivariable survival models. Results: Five comorbidities were significantly associated with survival and 437 (29.2%) patients had one or more of these. Survival to 120 days was significantly poorer for patients with a baseline diagnosis of stroke [hazard ratio (HR) 1.92; 95% confidence interval (CI) 1.26–2.93], diabetes (HR 1.33, 95% CI 1.08–1.65), or congestive heart failure (HR 1.45, 95% CI 1.07–1.96), controlling for age, gender, smoking status, stage, severe respiratory disease, and brain metastases. Given survival to 120 days (885 pts, 59%), survival beyond that was significantly poorer only for patients with baseline arrhythmia (HR 1.47, 95% CI 1.15–1.87) or end stage renal disease (HR 1.82, 95% CI 1.09–3.04), controlling for the covariates above. Adjustment for chemotherapy use had no effect on these associations. Conclusions: Several comorbidities present at diagnosis affected survival for AS NSCLC, with some comorbidities having a more immediate relationship to survival than others. Our finding provides information that could be used to tailor treatment decisions to patients’ comorbidities at diagnosis.

AbstractThe dense formation of abnormal scar tissue after total knee arthroplasty results in arthrofibrosis, an unfortunate sequela of inflammation. The purpose of this study was to use a validated rabbit model to assess the effects on surgically‐induced knee joint contractures of two combined pharmacological interventions: celecoxib (CXB) loaded on an implanted collagen membrane, and subcutaneously (SQ) injected ketotifen. Thirty rabbits were randomly divided into five groups. The first group received no intervention after the index surgery. The remaining four groups underwent intra‐articular implantation of collagen membranes loaded with or without CXB at the time of the index surgery; two of which were also treated with SQ ketotifen. Biomechanical joint contracture data were collected at 8, 10, 16, and 24 weeks. At the time of necropsy (24 weeks), posterior capsule tissue was collected for messenger RNA and histopathologic analyses. At 24 weeks, there was a statistically significant increase in passive extension among rabbits in all groups treated with CXB and/or ketotifen compared to those in the contracture control group. There was a statistically significant decrease in COL3A1, COL6A1, and ACTA2 gene expression in the treatment groups compared to the contracture control group (P < .001). Histopathologic data also demonstrated a trend towards decreased fibrous tissue density in the CXB membrane group compared to the vehicle membrane group. The present data suggest that intra‐articular placement of a treated collagen membrane blunts the severity of contracture development in a rabbit model of arthrofibrosis, and that ketotifen and CXB may independently contribute to the prevention of arthrofibrosis. Statement of clinical significance: Current literature has demonstrated that arthrofibrosis may affect up to 5% of primary total knee arthroplasty patients. For that reason, novel pharmacologic prophylaxis and treatment modalities are critical to mitigating reoperations and revisions while improving the quality of life for patients with this debilitating condition.

Abstract Stearoyl‐CoA desaturases (SCD) are endoplasmic reticulum (ER)‐associated enzymes that catalyze the synthesis of the monounsaturated fatty acids (MUFAs). As such, SCD play important roles in maintaining the intracellular balance between saturated fatty acid (SFAs) and MUFAs. The roles of SCD in CD4 + T‐helper cell responses are currently unexplored. Here, we have found that murine and human follicular helper T (T FH ) cells express higher levels of SCD compared to non‐T FH cells. Further, the expression of SCD in T FH cells is dependent on the T FH lineage‐specification transcription factor BCL6. We found that the inhibition of SCD impaired T FH cell maintenance and shifted the balance between T FH and follicular regulatory T (T FR ) cells in the spleen. Consequently, SCD inhibition dampened germinal center B‐cell responses following influenza immunization. Mechanistically, we found that SCD inhibition led to increased ER stress and enhanced T FH cell apoptosis in vitro and in vivo. These results reveal a possible link between fatty acid metabolism and cellular and humoral responses induced by immunization or potentially, autoimmunity.

AbstractImmune checkpoint inhibitor therapies targeting PD‐1/PD‐L1 are now the standard of care in oncology across several hematologic and solid tumor types, including triple negative breast cancer (TNBC). Patients with metastatic or locally advanced TNBC with PD‐L1 expression on immune cells occupying ≥1% of tumor area demonstrated survival benefit with the addition of atezolizumab to nab‐paclitaxel. However, concerns regarding variability between immunohistochemical PD‐L1 assay performance and inter‐reader reproducibility have been raised. High tumor‐infiltrating lymphocytes (TILs) have also been associated with response to PD‐1/PD‐L1 inhibitors in patients with breast cancer (BC). TILs can be easily assessed on hematoxylin and eosin–stained slides and have shown reliable inter‐reader reproducibility. As an established prognostic factor in early stage TNBC, TILs are soon anticipated to be reported in daily practice in many pathology laboratories worldwide. Because TILs and PD‐L1 are parts of an immunological spectrum in BC, we propose the systematic implementation of combined PD‐L1 and TIL analyses as a more comprehensive immuno‐oncological biomarker for patient selection for PD‐1/PD‐L1 inhibition‐based therapy in patients with BC. Although practical and regulatory considerations differ by jurisdiction, the pathology community has the responsibility to patients to implement assays that lead to optimal patient selection. We propose herewith a risk‐management framework that may help mitigate the risks of suboptimal patient selection for immuno‐therapeutic approaches in clinical trials and daily practice based on combined TILs/PD‐L1 assessment in BC. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.