Citations

Abstract Background. DCIS consists of a molecularly heterogeneous group of premalignant lesions, with variable risk of invasive progression. Understanding biomarkers for invasive progression could help individualize treatment recommendations based upon tumor biology. As part of the NCI Human Tumor Atlas Network (HTAN), we conducted comprehensive genomic analyses on two large DCIS case-control cohorts. Methods. We performed smart3-seq and low-pass whole genome sequencing on two independent, retrospective, longitudinally sampled DCIS case-control cohorts. TBCRC 038 was a multicenter cohort diagnosed with DCIS between 1998 and 2016 at one of the Translational Breast Cancer Research sites; the RAHBT (Resource of Archival Human Breast Tissue) cohort included women identified through the St. Louis Breast Tissue Repository, and the Women’s Health Repository diagnosed between 1997 and 2001. We studied the spectrum of molecular changes present and sought genomic predictors of subsequent ipsilateral breast events (iBEs: DCIS recurrence or invasive progression) in both DCIS epithelium and stroma in formalin fixed paraffin embedded tissue. We generated de novo tumor and stroma-centric subtypes for DCIS that represents fundamental transcriptomic organization. Copy number analysis was performed using low-pass DNA sequencing. Non-negative matrix factorization (NMF) was applied to the RNA expression of all coding genes to identify clusters. A negative-binomial regression model was used to identify differentially expressed genes. Results. We analyzed 677 DCIS samples from 481 patients with 7.1 years median follow-up. In TBCRC samples, we identified three clusters via NMF in TBCRC referred to as ER low, quiescent, and ER high. The ER-low cluster had significantly higher levels of ERBB2 and lower levels of ESR1 compared to quiescent and ER-high clusters. Quiescent cluster lesions were less proliferative and less metabolically active than ER high and ER low subtypes. These findings were replicated in the RAHBT cohort. Focusing on the stromal component of DCIS from laser capture microdissection in RAHBT samples, we identified four distinct DCIS-associated stromal clusters. A “normal-like” stromal cluster with ECM organization and PI3K-AKT signaling; a “collagen-rich” stromal cluster; a “desmoplastic” stromal cluster with high fibroblast and total myeloid abundance, mostly associated with macrophages and myeloid dendritic cells (mDC); and an “immune-dense” stromal cluster. Further, we compared differentially expressed genes in patients with or without subsequent iBEs within 5 years of diagnosis. Hypothesizing that the resulting 812 DE genes (DESeq2) represent multiple routes to subsequent iBEs, we leveraged NMF to identify paths to progression. In both TBCRC and RAHBT cohorts, poor outcome groups exhibited increased ER, MYC signaling, and oxidative phosphorylation, supporting that these pathways are important for DCIS recurrence and progression. Conclusion. Comprehensive genomic profiling in two independent DCIS cohorts with longitudinal outcomes shows distinct DCIS stromal expression patterns and immune cell composition. RNA expression profiles reveal underlying tumor biology that is associated with later iBEs in both cohorts. These studies provide new insight into DCIS biology and will guide the design of diagnostic strategies to prevent invasive progression. Citation Format: Siri H Strand, Belén Rivero-Gutiérrez, Kathleen E Houlahan, Jose A Seoane, Lorraine M King, Tyler Risom, Lunden Simpson, Sujay Vennam, Aziz Khan, Timothy Hardman, Bryan E Harmon, Fergus J Couch, Kristalyn Gallagher, Mark Kilgore, Shi Wei, Angela DeMichele, Tari King, Priscilla F McAuliffe, Julie Nangia, Joanna Lee, Jennifer Tseng, Anna Maria Storniolo, Alastair Thompson, Gaorav Gupta, Robyn Burns, Deborah J Veis, Katherine DeSchryver, Chunfang Zhu, Magdalena Matusiak, Jason Wang, Shirley X Zhu, Jen Tappenden, Daisy Yi Ding, Dadong Zhang, Jingqin Luo, Shu Jiang, Sushama Varma, Cody Straub, Sucheta Srivastava, Christina Curtis, Rob Tibshirani, Robert Michael Angelo, Allison Hall, Kouros Owzar, Kornelia Polyak, Carlo Maley, Jeffrey R Marks, Graham A Colditz, E Shelley Hwang, Robert B West. The Breast PreCancer Atlas DCIS genomic signatures define biology and correlate with clinical outcomes: An analysis of TBCRC 038 and RAHBT cohorts [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS4-07.

Abstract Background We evaluated the time to progression (TTP) and survival outcomes of second-line therapy for metastatic colorectal cancer among adults aged 70 years and older compared with younger adults following progression on first-line clinical trials. Methods Associations between clinical and disease characteristics, time to initial progression, and rate of receipt of second-line therapy were evaluated. TTP and overall survival (OS) were compared between older and younger adults in first- and second-line trials by Cox regression, adjusting for age, sex, Eastern Cooperative Oncology Group Performance Status, number of metastatic sites and presence of metastasis in the lung, liver, or peritoneum. All statistical tests were 2-sided. Results Older adults comprised 16.4% of patients on first-line trials (870 total older adults aged >70 years; 4419 total younger adults aged ≤70 years, on first-line trials). Older adults and those with Eastern Cooperative Oncology Group Performance Status >0 were less likely to receive second-line therapy than younger adults. Odds of receiving second-line therapy decreased by 11% for each additional decade of life in multivariable analysis (odds ratio = 1.11, 95% confidence interval = 1.02 to 1.21, P = .01). Older and younger adults enrolled in second-line trials experienced similar median TTP and median OS (median TTP = 5.1 vs 5.2 months, respectively; median OS = 11.6 vs 12.4 months, respectively). Conclusions Older adults were less likely to receive second-line therapy for metastatic colorectal cancer, though we did not observe a statistical difference in survival outcomes vs younger adults following second-line therapy. Further study should examine factors affecting decisions to treat older adults with second-line therapy. Inclusion of geriatric assessment may provide better criteria regarding the risks and benefits of second-line therapy.

AbstractBackgroundHidradenitis suppurativa (HS) is a chronic inflammatory dermatosis with recurrent painful nodules and abscesses affecting the intertriginous areas. Patients often experience a significant negative impact on quality of life from associated pain, discharge, odor, scarring, and social stigma. Even with complex medical regimens, patients may report inadequate disease control. Lifestyle changes and complementary and alternative medicines (CAM) are used by a majority of HS patients. Conventional medicines and lifestyle and CAM modalities strategically incorporated together can increase treatment satisfaction and success.ObjectiveWe aim to highlight lifestyle and CAM treatment modalities to use alongside conventional treatment plans for HS patients.FindingsLifestyle modifications for HS patients include weight loss, reducing skin friction, smoking cessation, and stress reduction. Dietary modifications for HS patients include limiting foods containing dairy, Brewer's yeast, and simple carbohydrates, appropriate caloric reduction, and consuming foods in the Mediterranean diet. The CAM modalities studied in HS are vitamin D, niacinamide, vitamin B12, zinc, and magnesium. Potential CAM modalities for HS include probiotics, cannabinoids, turmeric, bathing regimens, and acupuncture.ConclusionThis review is a guide for clinicians to provide evidence‐based care for HS patients seeking non‐pharmacologic treatment modalities such as weight loss, clothing choices, dietary changes, and use of supplements and complementary medicine. Lifestyle and CAM modalities may be used in parallel with conventional medicines to synergistically improve patient disease outcomes.

Composite classic Hodgkin lymphoma and follicular lymphoma (CHLFL) is a rare and poorly characterized entity. Herein, we report the clinicopathologic features of 22 cases of CHLFL from 3 institutions and we assess 27 additional cases reported in the literature. In our cohort (n=22), patients with CHLFL had a median age of 61 years and an equal male to female incidence. Most cases (95%) arose de novo with the remaining patients having a history of non-Hodgkin lymphoma. CHLFL always involved lymph nodes (100%) and most cases (95%) revealed 2 distinct areas separately diagnostic for CHL and FL. The CHL component represented a variable proportion of the overall neoplasm (5% to 90%) and was either mixed cellularity (82%) or nodular sclerosis (18%) type. The Hodgkin/Reed-Sternberg cells expressed CD30 (100%), PAX5 (100%), CD15 (62%), BCL6 (47%), BCL2 (29%), and EBER (25%), in a polymorphous inflammatory background typical of CHL. The FL component was low-grade in 55%, grade 3A in 36%, and grade 3B in 9% of cases. All 3 cases investigated by cytogenetic methods for a clonal relationship between the CHL and FL components were clonally related. These clinicopathologic features of our cohort are similar to those of cases reported in the literature. The 5-year overall survival in combined patients with CHLFL (n=49) was 48%, comparable to CHL but worse than FL in the elderly. In summary, CHLFL is a rare entity that most often occurs in older adults, involves lymph nodes, and most commonly presents de novo. In the small number of cases assessed, the CHL and FL components are usually clonally related suggesting that the CHL and FL components may share a common progenitor B-cell, likely a mutated germinal center B-cell.

344 Background: ICI with anti-PD-1 therapy was approved by the US FDA as 1st/2nd-line treatment of advanced GEC regardless of PD-L1 status. It is argued that patients (pts) with PD-L1-low GEC do not benefit from ICI. To avoid spurious exclusion of pts, we systematically reviewed phase 3 trials to assess the magnitude and consistency of PD-L1 to predict benefit from ICI. We also examined other potential predictive factors to understand their magnitude and consistency in comparison with PD-L1 status. Methods: MEDLINE, Embase, Scopus, Web of Science, and Cochrane Central Register were searched for all randomized clinical trials (RCT; 2000-2021) in advanced GEC comparing ICI, alone or with chemotherapy, vs standard of care (SOC). The primary endpoint was overall survival (OS). Study screening, data abstraction, and bias assessment were done independently by two reviewers per PRISMA guidelines. The mean HR for ICI vs SOC was calculated by random effects model. The predictive value of a factor was quantified using relative magnitude and consistency (table). Results: 14 RCTs at low risk of bias were included (N = 9,210 pts; KN62, CM649, CM648, ESCORT1st, KN590, ATT4, JAV100, KN181, KN61, ATT3, ESCORT, RATIONALE302, JAV300, ATT2). 6 trials were 1st-line, 8 were after 1st-line. Treatment comparisons were ICI + chemo vs chemo (6 trials), ICI vs chemo (9 trials), and ICI vs placebo (1 trial). ICI was always anti-PD-1/-L1 (1 trial also had anti-CTLA-4). Table shows primary results. To enable head to head comparisons, subgroup analyses of trials containing both levels of a factor or having similar design were done and generally yielded consistent results. Conclusions: PD-L1 CPS is the strongest predictive biomarker, after MSI, for OS benefit from ICI-containing therapy vs SOC. Additional research on gender is warranted.[Table: see text]

101 Background: Colorectal cancer (CRC) incidence and mortality have decreased since the 1970s, but the incidence in young adults (20-49 years, named early-onset CRC, eoCRC) has been increasing. eoCRC patients with metastatic disease are treated with the same standard regimens as late-onset CRC (loCRC, age ≥ 50 years) although detailed response data for eoCRC are largely missing. Methods: Individual patient data on 7,604 subjects with metastatic eoCRC from 11 first line randomized bevacizumab studies between 2000 and 2012 in the ARCAD advanced colorectal cancer database were pooled. The distributions of demographics, clinicopathological features, biomarkers, and outcome data were summarized by age groups. Progression-free survival (PFS) and overall survival (OS) were assessed by Kaplan-Meier curves and Cox models stratified by treatment arms within studies, adjusting for potential confounders. Predictive value of age group was evaluated by testing interaction effect between treatment and age variables. Results: Female eoCRC are more commonly seen compared to loCRC (46.8% vs. 38.7%, p<0.0001). Patients with eoCRC (n=1,289) were significantly more likely to have had prior metastasectomy (17.5% vs. 13.5%, p=0.043) and lung metastatic disease (67% vs. 59.8%, p<0.001), but less likely to have distant lymph node metastatic disease (58.8 vs. 62.9%, p=0.036) or KRAS mutation (29.2% vs. 34.4%, p=0.042) compared to those with loCRC (n=6,315). eoCRC and loCRC patients had similar distributions according to PS, primary tumor sidedness, prior primary tumor resection, liver involvement, peritoneal involvement, number of metastatic sites, NRAS and BRAF. Age of disease onset was not a statistically significant prognostic factor for PFS in univariate and multivariate analysis (seen in table). Bevacizumab in addition to chemo improved PFS in eoCRC population (9.9 vs. 6.8 months, HR = 0.66, p<0.001), which was similar to the findings in loCRC population (9.4 vs. 7.3 months, HR= 0.73, p<0.001, interaction p=0.54). By multivariate analysis, a greater improvement in PFS was noted for the addition of bevacizumab in eoCRC relative to LoCRC patients (HR = 0.62 vs. HR = 0.82). Conclusions: Treatment naive eoCRC patients with metastatic disease derive similar benefit from bevacizumab relative to their average age counterparts.[Table: see text]

80 Background: Higher baseline body mass index is associated with improved survival in metastatic CRC (mCRC). Whether weight gain or loss after mCRC diagnosis is associated with survival remains largely unknown. Methods: We analyzed individual patient data from 3504 patients with previously untreated mCRC enrolled in five phase III randomized trials (AVF2017g, AVF2192g, CRYSTAL, N9741, OPUS) conducted between 2000 and 2006. Weight measurements were prospectively collected at 3 months after diagnosis and then up to 5 years. Patients were categorized into three groups based on the percent weight change at 3 months: stable weight or gain, weight loss up to 5% of baseline weight, and ≥5% weight loss of baseline weight. Cox models were used to assess the prognostic associations of weight change at 3 months with overall survival (OS) and progression-free survival (PFS), adjusting for baseline BMI, age, sex, performance score, chemotherapy backbone (oxaliplatin vs. irinotecan), and biologics type (cetuximab vs. bevacizumab). Sub-analyses included Cox models adjusted for additional clinical-pathological factors (primary tumor sidedness [right colon vs. left colon-rectum], and BRAF status; N=1,511). Results: Median percent weight change at 3 months was -0.5% (IQR -4.0 to+1.6%). OS was better in patients with weight stability or gain than in those with weight loss (up to 5% or ≥5%; (Table). Results were consistent for PFS for patients with ≥5% weight loss of baseline weight, as well as for sub-analyses. Conclusions: Patients losing weight during the first 3 months of systemic therapy for metastatic colorectal cancer have significantly shorter overall survival than those with stable or increasing weight. Degree of weight loss is proportional to the observed increased risk of death and remains evident among underweight, normal weight and obese individuals. Further studies examining possible usefulness of on-treatment early weight loss as a novel intermediary end-point are needed.[Table: see text]

11 Background: Six months of oxaliplatin-based adjuvant chemotherapy in patients with stage III colon cancer (CC) remains a standard in high-risk stage III patients. Early treatment discontinuation (ETD) could worsen the prognosis. In addition, there is current lack of data on the prognostic impact of early oxaliplatin only discontinuation (EOD). Methods: We studied the prognostic impact of ETD and EOD in patients with stage III CC who participated in 11 relevant clinical trials of the ACCENT and IDEA databases, where patients were planned to receive 6 months of adjuvant fluoropyrimidine plus oxaliplatin (FOLFOX or CAPOX). ETD was defined as discontinuation of treatment before 75% of cycles of chemotherapy. EOD was defined as discontinuation of oxaliplatin only, while continuing the fluoropyrimidine, before 75% of cycles of oxaliplatin. Association between ETD/EOD and overall survival (OS) and disease-free survival (DFS) was assessed by Cox model adjusted for prognostic factors. Results: ETD analysis included 10,444 patients (FOLFOX n = 7,033; CAPOX n = 3,411), with 20.9% of patients with ETD (17.8% with FOLFOX and 27.2% with CAPOX, p < 0.001). Out of 7,243 patients, 18.8% experienced EOD (17.4% FOLFOX versus 21.4% with CAPOX, p < 0.001). Compared to patients without ETD or EOD, patients with ETD or EOD were statistically more likely to be women, older, with higher ECOG-PS ≥ 1, and in addition for ETD, a Body Mass Index (BMI) < 18.5 kg/m2. In multivariate analyses, ETD was associated with a decrease in DFS and OS in the overall population (HR: 1.40 95%CI 1.23-1.58, p < 0.001 and HR: 1.51 95%CI 1.31-1.74, p < 0.001, respectively). The same pattern was present with FOLFOX and CAPOX regimen, and also in low-risk and high-risk groups for each regimen with the exception of the CAPOX regimen in the low-risk group for DFS and OS. By contrast, EOD was not associated with reduced DFS or OS in the overall population (HR: 1.10 95%CI 0.77-1.58, p = 0.6 and HR: 0.97 95%CI 0.62-1.52, p = 0.9, respectively), in the low-risk group (HR: 0.97 95%CI 0.56-1.66, p = 0.9 and HR: 0.97 95%CI 0.51-1.82, p = 0.9, respectively) and high-risk group (HR: 1.22 95%CI 0.74-2.02, p = 0.4 and HR: 1.05 95%CI 0.53-2.08, p = 0.9, respectively) and for all subgroups of regimen. Conclusions: In patients treated with 6 months of oxaliplatin-based adjuvant chemotherapy for stage III CC, ETD was associated with a decrease in DFS and OS. By contrast, EOD was not significantly associated with poorer outcomes. In case of relevant neurotoxicity during a 6 months schedule, these data are not in favor of continuing oxaliplatin beyond 75% of planned cycles of adjuvant chemotherapy, and demonstrate that fluoropyrimidines remain the cornerstone of adjuvant chemotherapy in localized CC.