Background: Invasive lobular carcinoma (ILC) comprises 10-15% of breast tumors and is the second most common histological type after invasive ductal carcinoma (IDC). Patients with ILC are often diagnosed at an older age and more advanced stage than those with IDC. Late recurrences and worse long-term survival suggest the need for improved approaches to treatment optimization and exploration of molecular pathways unique to ILC. Although previous reports have described comprehensive transcriptomic profiling of ILC, these were limited by small sample sizes. Furthermore, differential gene expression between ILC and IDC within genomic risk groups and molecular subtypes has yet to be explored. Here we characterize differential gene expression between ILC and IDC in a large, age-matched patient subset categorized by 70-gene signature/MammaPrint (MP) risk and 80-gene signature/BluePrint (BP) subtype. Methods: The prospective FLEX Registry (NCT03053193) includes stage I-III primary invasive breast cancer patients who receive MP/BP testing and consent to full transcriptome and clinical data collection. This sub-analysis included 450 ILC patients enrolled from 2017 to present. Compared with a random selection of IDC patients (n=450, mean age, 60 years), ILC patients were older (mean, 63 years, p ± 1.0 were considered significant. Results: ILC represented 13% of FLEX cases (n=450/3562), and were 81% lymph node-negative, 99% ER+, 94% HER2-negative, and 68% MP Low Risk (LR). By BP, ILC were 99% Luminal, 1% HER2, and Conclusions: Here we report differential clinical and molecular characteristics between ILC and IDC in a large, age-matched patient subset. Regardless of MP risk, expression of CDH1 was lower in ILC compared with IDC. Approximately one-third of ILCs were MP HR, and we report a greater number and diversity of DEGs between HR ILC and HR IDC compared with LR tumors, in particular genes related to TGFβ signaling. TGFβ pathway genes play a variety of roles in the tumor microenvironment, including induction of angiogenesis, fibroblast growth factor stimulation, and inhibition and/or exclusion of an immune response. These results suggest that therapeutic strategies targeting the TGFβ pathway may be future avenues of exploration in ILC, although further studies are warranted to characterize underlying molecular mechanisms. Citation Format: Beth-Ann Lesnikoski, Jennifer A. Crozier, Gordan Srkalovic, Patricia Robinson, Clodia Osipo, Kaylan Banda, Heather M. Kling, Josien Haan, William Audeh, FLEX Investigators Group. Differential gene expression in luminal-type invasive lobular carcinoma and invasive ductal carcinoma by MammaPrint risk stratification [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-03.

Castleman disease (CD) includes a group of rare and heterogeneous disorders with characteristic lymph node histopathological abnormalities. CD can occur in a single lymph node station, which is referred to as unicentric CD (UCD). CD can also involve multicentric lymphadenopathy and inflammatory symptoms (multicentric CD [MCD]). MCD includes human herpesvirus-8 (HHV-8)-associated MCD, POEMS-associated MCD, and HHV-8-/idiopathic MCD (iMCD). The first-ever diagnostic and treatment guidelines were recently developed for iMCD by an international expert consortium convened by the Castleman Disease Collaborative Network (CDCN). The focus of this report is to establish similar guidelines for the management of UCD. To this purpose, an international working group of 42 experts from 10 countries was convened to establish consensus recommendations based on review of treatment in published cases of UCD, the CDCN ACCELERATE registry, and expert opinion. Complete surgical resection is often curative and is therefore the preferred first-line therapy, if possible. The management of unresectable UCD is more challenging. Existing evidence supports that asymptomatic unresectable UCD may be observed. The anti-interleukin-6 monoclonal antibody siltuximab should be considered for unresectable UCD patients with an inflammatory syndrome. Unresectable UCD that is symptomatic as a result of compression of vital neighboring structures may be rendered amenable to resection by medical therapy (eg, rituximab, steroids), radiotherapy, or embolization. Further research is needed in UCD patients with persisting constitutional symptoms despite complete excision and normal laboratory markers. We hope that these guidelines will improve outcomes in UCD and help treating physicians decide the best therapeutic approach for their patients.

Idiopathic multicentric Castleman disease (iMCD) is a rare immunologic disorder characterized by systemic inflammation, multicentric lymphadenopathy, and organ dysfunction. Enlarged lymph nodes demonstrate a spectrum of characteristic but variable histopathologic features historically categorized into hyaline vascular (HV) (or hypervascular [HyperV] more recently), plasmacytic, or “mixed.” Though the etiology is unknown, a pro‐inflammatory cytokine storm, often involving interleukin‐6 (IL‐6), contributes to pathogenesis. Anti‐IL‐6 therapy with siltuximab is the only FDA‐ or EMA‐approved treatment based on efficacy and safety in multiple studies. Importantly, no patients considered to have HV histopathology achieved the primary endpoint in the Phase II study. NCCN currently recommends siltuximab first‐line for iMCD, except for patients considered to have HV histopathology. We investigated whether histopathologic subtype should guide siltuximab treatment decisions. Secondary analyses of clinical trial and real‐world data revealed similar clinical benefit across histopathologic subtypes. Notably, only 18 of 79 patients in the Phase II study were consistently classified into histopathologic subtype by three independent review panels, demonstrating limited reliability to guide treatment decisions. Real‐world data further demonstrate siltuximab's effectiveness in patients considered to have HV (or HyperV). Though histopathology is a critical component for diagnosis, there is insufficient evidence to guide treatment based solely on lymph node histopathologic subtype.

The ECOG‐ACRIN Cancer Research Group trial E2511 recently demonstrated a potential benefit for the addition of veliparib to cisplatin‐etoposide (CE) in patients with extensive stage small cell lung cancer (ES‐SCLC) in a phase II randomized controlled trial. Secondary trial endpoints included comparison of the incidence and severity of neurotoxicity, hypothesized to be lower in the veliparib arm, and tolerability of the addition of veliparib to CE. Physician‐rated and patient‐reported neurotoxicity was also compared.

8548Background: Castleman disease (CD) describes a group of lymphoproliferative disorders that share characteristic histopathology. Unicentric CD (UCD) and idiopathic multicentric CD (iMCD) are dif...

e19291 Background: Invasive lobular carcinoma (ILC), the second most common histological breast cancer type, comprises 10-15% of breast tumors. Although ILC is thought to have a low risk of relapse, patient survival data vary. ILC treatment guidelines mirror those for invasive ductal carcinoma (IDC); however, these were extrapolated from trials that included predominantly IDC. The FLEX Registry captures data from real-world breast cancer patients; the current sub-study evaluated molecular profiles and treatment recommendations in ILC. Methods: The FLEX Registry (NCT03053193) includes stage I-III primary invasive breast cancer patients who receive 70-gene signature (70-GS)/80-gene signature (80-GS) testing and consent to full transcriptome and clinical data collection. This sub-analysis includes 335 ILC patients and 2,179 IDC patients enrolled from 2017 to present. 70-GS stratified tumors by risk of distant metastasis [High (HR), Low (LR), Ultralow (UL) Risk], and 80-GS classified tumors by molecular subtype (Luminal, HER2, or Basal type). Genomic and clinical data were compared for ILC and IDC using chi-square or Fisher’s exact test. Results: ILC represented 13% of FLEX cases (n = 335/2752); 81% were lymph node-negative, 99% ER-positive, and 94% HER2-negative. Clinical risk assessment (MINDACT criteria) classified 61% of ILC and 53% of IDC as low risk (p = 0.03). 70-GS risk distribution in ILC (18% UL, 51% LR, 31% HR) differed from IDC (13% UL, 34% LR, 53% HR; p < 0.01). Discordance between 70-GS and clinical risk was greater in ILC (43%) than IDC (30%, p < 0.01). 80-GS results also differed between ILC (98% Luminal, 1.6% HER2, 0.3% Basal) and IDC (85% Luminal, 3% HER2, 11% Basal; p < 0.01). Inclusion of chemotherapy (CT) in treatment plans was associated with 70-GS risk (p < 0.01); treatment plans that disagreed with 70-GS results were associated with discordant clinical risk (p < 0.05). Treatment plans disagreed with 70-GS in 15% of ILC and 12% of IDC total cases (p = 0.08), and more frequently in HR cases (25% in ILC, 14% in IDC; p < 0.01). Conclusions: The FLEX Registry includes patients with ILC consistent with real-world breast cancer frequencies. ILC demonstrated genomic risk and subtype profiles distinct from IDC. Treatment plans largely agreed with 70-GS results; however, discordance was more frequent in HR ILC than IDC. Future studies will evaluate clinical outcomes; however, these results demonstrate the added value of molecular profiling in ILC and the utility of real-world registry data in evaluating uncommon breast tumor types. Clinical trial information: NCT03053193 .

Background Human herpes-virus 8-negative/idiopathic multicentric Castleman disease (iMCD) is a rare inflammatory disorder involving multicentric lymphadenopathy with characteristic histopathology. Clinical presentation is heterogenous and includes cytokine-driven constitutional symptoms, cytopenias, systemic inflammation, and multi-organ dysfunction. International consensus treatment guidelines are based on a large cohort of case studies and a few clinical trials, but the available evidence is limited. Siltuximab, an anti-IL-6 therapy, is the only FDA-approved treatment for iMCD; 34% of patients achieved durable symptomatic and tumor response in the phase II trial. Tocilizumab, an anti-IL-6 receptor therapy, is frequently used off label and demonstrated promising results in an open-label study in Japan. The treatment guidelines recommend siltuximab ± corticosteroids (CS) as first-line therapy for all iMCD patients and tocilizumab as a substitute when siltuximab is not available. Rituximab, a CD20 antibody, is recommended as an alternate first-line therapy in patients who are non-severe and do not exhibit marked cytokine-driven symptoms. In all other patients, rituximab is recommended second-line; however, it has never been systematically evaluated in iMCD. Chemotherapies, immunosuppressants, and immunomodulators are recommended second- or third-line, but again, effectiveness is not well described. Better understanding of treatment effectiveness is urgently needed. Herein, we describe treatment and response in a real-world cohort of iMCD patients. Methods Data were collected and abstracted for 68 patients enrolled in an on-going IRB-approved natural history study of Castleman disease. Diagnosis is graded by an expert panel of clinicians and pathologists on an on-going basis; patients unlikely to have iMCD were excluded from analysis (N=12). Of the 56 patients included, 37 (66%) are expert panel-confirmed and 19 (34%) are awaiting confirmation. Durable response is defined as achieving ≥50% improvement in the proportion of abnormal iMCD minor clinical and laboratory diagnostic criteria sustained for ≥1 year. Small sample size prevented statistical comparisons. Results Median age at diagnosis is 33 years (range: 1-65 years). The cohort is 52.9% female, 63% white, and 4 (7%) patients died. Thirty-three unique drugs, including anti-IL-6 therapies, CS, chemotherapies, immunosuppressants, and others have been administered across the 56 patients. Rituximab is the most frequently used drug, administered to 39 (70%) patients. Siltuximab (29 patients, 52%) and tocilizumab (19 patients, 34%) are the next two most frequently used targeted therapies. There was a 52% response (15/29) to regimens inclusive of siltuximab, 50% response (9/18) to those inclusive of tocilizumab, and 25% response (9/26) to those inclusive of rituximab. Siltuximab±CS induced response in 15/24 (63%) patients, tocilizumab±CS in 4/7 (57%), and rituximab±CS in 2/13 (15%). Among the 37 expert-confirmed iMCD patients, we found a 58% response (11/19) to regimens inclusive of siltuximab, 47% (8/17) to those inclusive of tocilizumab, and 27% (7/26) to those inclusive of rituximab. Further, in these patients, siltuximab±CS induced response in 11/16 (69%), tocilizumab±CS in 3/6 (50%), and rituximab±CS in 1/6 (17%) patients. Of note, 3 of 4 deceased patients received both anti-IL-6 therapy and rituximab and all 4 received chemotherapies and immunosuppressants but did not respond to any drug. Discussion These data reveal that despite there being one FDA-approved treatment, iMCD is treated with a variety of agents. Among the full cohort, siltuximab±CS demonstrated a 63% durable response, which was higher than the response reported in the clinical trial (not statistically compared). This may reflect differences in response criteria and/or disease activity of patients in clinical trials versus real world settings. Siltuximab and tocilizumab have never been systematically compared; in this cohort they demonstrated similar response. Considering the morbidity and mortality of iMCD, these data suggest that current therapies demonstrate important activity. However, additional agents are needed for refractory patients, who have few options and are at risk of death due to disease progression. Further data are needed to compare groups and identify optimal treatment protocols. Liu: BridgeBio Pharma: Employment, Equity Ownership. Gibson:EUSA Pharma: Employment. Kanhai:EUSA Pharma: Employment. Martin:EUSA Pharma: Employment. Srkalovic:Takeda: Speakers Bureau; Janssen: Speakers Bureau; Foundation Medicine: Speakers Bureau; EUSA Pharma: Speakers Bureau. Uldrick:Patent: Patents & Royalties: co-inventor on US Patent 10,001,483 entitled ; Celgene: Other: research support from Celgene through a CRADA at the NCI; Roche: Other: commercial research support through a CTA with Fred Hutchinson Cancer Research Center; Merck: Other: drug for a clinical trial from Merck through a CRADA with the NCI. van Rhee:Takeda: Consultancy; Sanofi Genzyme: Consultancy; Karyopharm Therapeutics: Consultancy; EUSA: Consultancy; Adicet Bio: Consultancy; Kite Pharma: Consultancy; Castleman Disease Collaborative Network: Consultancy. Fajgenbaum:Janssen Pharmaceuticals: Research Funding. Tocilizumab, a monoclonal antibody directed against IL-6-receptor, is approved for use in rheumatoid arthritis in the US. It is frequently used off-label in idiopathic multicentric Castleman disease (iMCD) and is recommended as a substitute first-line therapy in the International Consensus iMCD treatment guidelines. Rituximab, a monoclonal antibody directed against CD20, is used in rheumatoid arthritis and other autoimmune and cancerous disorders. It is frequently used off-label in iMCD and is recommended as an alternate first-line or a second-line therapy in the International Consensus iMCD treatment guidelines. Corticosteroids are used broadly in iMCD and are recommended as needed as useful adjunctive therapy in the International Consensus iMCD treatment guidelines.

Abstract Background BRAF genomic alterations (GA) occur in multiple tumor types and BRAF/MEK targeted therapies are approved in melanoma and NSCLC. Diverse mechanisms of AR to these therapies have been proposed but have not been comprehensively assessed. Methods Hybrid-capture based comprehensive genomic profiling (CGP) was performed on FFPE (n = 228,629) or blood-based cell free DNA (cfDNA, n = 15,069) samples for 222,952 patients (pts). Tumor mutational burden (TMB) was determined on 0.8-1.1 Mbp of sequenced DNA. Samples without evidence of tumor DNA or known to have not received RAF/MEK inhibitors were excluded. Paired samples were collected >60 days apart (median 523, range 71-5571). Results Paired samples with BRAF V600E (64%) or other activating BRAF GA (36%) were available for 154 pts with NSCLC (20%), melanoma (19%), CRC (15%) myeloma (8.4%) glioma (7.1%) or other (30%) cancers. Acquired GA previously described preclinically or clinically including in BRAF, KRAS, NRAS, MEK1, PIK3CA, PTEN, MET, and CCND1 occurred in 34 cases (Table). 56 additional cases had reportable acquired GA in other genes (eg. STK11, NF1). Median TMB was 4.0 vs 5.2 mut/Mb in the first vs second sample (p = 0.23). In 12% of cases (9 tissue, 9 cfDNA) a BRAF GA was not detected in the second sample. Most AR mechanisms (MET amp, KRAS mut, secondary BRAF GA) were tumor agnostic, but PIK3CA and PTEN GA were enriched in brain samples and absent in CRC, and NRAS mut were exclusive to melanoma (Table). Treatment status was available for a subset of cases. Notably V600E CRC, NSCLC and melanoma each had acquired MET amp post-dabrafenib + trametinib, and a V600E myeloma had acquired MEK C121S post-trametinib + vemurafenib. Additional clinical data will be presented. Table: 1878PD . Potential AR mechanism No. cases# AR subtypes Disease Histologies Associated Primary BRAF GA Biopsy location * KRAS mut 7 G12D (2), G12R, G12V, G13D, Q61H, K117N CRC (2), NSCLC (2), cholangiocarcinoma, multiple myeloma, CLL V600E (6), G466A omentum (2), liver NRAS mut 4 G12C, G13R, G13R/Q61H, Q61H/K melanoma (4) V600E (2), V600R, G469A brain (1), lymph node (1), soft tissue (1) NRAS amp 1 amp estimated copies: 41 NSCLC V600E pericardial fluid Secondary BRAF GA 10 N-terminal deletion exons 2-8 (6), duplications exons 10-18, L505H, N581I/D594G, amp estimated copies: 6 NSCLC (4), CRC (2), melanoma (2), multiple myeloma, pancreatic V600E (9), G466A liver (3), lymph node (2), lung, abdominal wall, brain MEK1 mut 1 C121S multiple myeloma V600E NA PIK3CA mut 5 H1047R (2), G1049R, R88Q, S405F glioma (3), NSCLC, thyroid V600E (3), N486_T491>K, R506_K507insVLR brain (4), lung PTEN GA 5 E7fs * , R130 * , G129R, splice site 165-1G>A, loss melanoma (2), glioma, NSCLC, UP neuroendocrine V600E, V600K, R506_K507insVLR, KHDRBS2-BRAF fusion brain (2), abdomen, soft tissue CCND1 amp 2 amp estimated copies: 9, 10 NSCLC, thyroid V600E, G464V brain, pleural fluid MET amp 4 amp estimated copies: 12, 14, 15, 56 NSCLC, CRC, melanoma, UP adenocarcinoma V600E (4) lymph node, colon, brain, liver * Indicated for tissue samples only (NA= not applicable); #5 cases had AR alterations in multiple genes included here; NSCLC: non-small cell lung cancer, CRC: colorectal carcinoma; CLL: chronic lymphocytic leukemia; UP: unknown primary; AR: acquired resistance; mut: mutation; amp: amplification. Conclusions Novel and previously observed potential AR alterations in paired BRAF altered clinical samples were detected using CGP. Most AR mechanisms appeared independent of tumor type and biopsy site. Additional clinical studies to explore effective treatments for these AR subsets are needed. Legal entity responsible for the study The authors. Funding Foundation Medicine. Disclosure F. Pietrantonio: Advisory / Consultancy: Roche; Advisory / Consultancy: Amgen; Advisory / Consultancy: Eli-Lily; Advisory / Consultancy: Bayer; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Servier; Advisory / Consultancy: Merck Serono. J. Lee: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. L. Boussemart: Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre. G. Srkalovic: Speaker Bureau / Expert testimony: Foundation Medicine. R. Madison: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. J.S. Ross: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. V.A. Miller: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche; Advisory / Consultancy: Revolution Medicines. B.M. Alexander: Leadership role, Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. S.M. Ali: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. A.B. Schrock: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. All other authors have declared no conflicts of interest.

Patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) may benefit from salvage chemoimmunotherapy (CIT). To explore further the use of CIT in the pre-novel agent era, ECOG-ACRIN undertook a phase 2 trial (E2903) for R/R CLL utilizing pentostatin, cyclophosphamide, and rituximab (PCR) followed by a consolidation course of alemtuzumab. This trial enrolled 102 patients with a median age of 64 years. Treatment consisted of 6 cycles of PCR followed by alemtuzumab for either 4 or 18 weeks depending on the initial response to PCR. The overall response after PCR (complete remission, CR, nodular partial remission, nPR, and partial remission, PR) was 55%. Major responses (CR or nPR) were achieved in 6%. The median overall survival (OS) and the median progression-free survival were 28 and 12 months, respectively. The most serious nonlethal adverse events were myelosuppression, febrile neutropenia, fatigue, nausea, and hyponatremia. PCR is an effective and well-tolerated nucleoside-based regimen for heavily pretreated CLL patients with R/R disease. The addition of alemtuzumab to CLL patients with a minor response (PR) or stable disease did not result in a significant number of higher responses (CR or nPR) nor an improvement in OS.

No abstract available.

The current paper discusses the use of genomics in the context of the changing landscape of clinical practice and modern medicine. Medical practice has shifted considerably over the past few decades, from empirical to evidence-based to personalized medicine, and the transition from reliance on observation to measureable parameters. Scientific innovation is required to collect an ever-increasing number and variety of data points and sophisticated analyses capable of distilling vast datasets into meaningful information. The next phase of innovation seeks to personalize disease management, in particular through genomics in oncology. With expanding use of genomics in medicine, and several initiatives collecting genomic data at the population level, education of patients and physicians is critical for data utility. By combining genomic and clinical data, bioinformatics approaches can be applied to developing individualized or targeted therapies. Breast cancer provides an example through which to understand the evolution of genomic data from pure science to clinical utility. From intrinsic subtype classification to development of multigene panels estimating recurrence risk, new studies, such as the FLEX trial, will expand to evaluate the whole transcriptome of tumours. This approach will enable discovery of novel gene signatures and ultimately pave the way toward a personalized approach to breast cancer management. CONCLUSION: Despite the potential for genomics to personalize treatments, a number of challenges remain to fully integrate these types of large datasets in a manner that provides clinicians and patients with meaningful, actionable information. However, if challenges are addressed, precision medicine has the capacity to transform patient care.

MammaPrint was the first genomic assay in breast cancer to be validated with a prospective randomized trial, the MINDACT trial. The 70 gene MammaPrint assay was developed to determine the risk of distant metastasis in early stage breast cancer through gene expression analysis and was the first FDA cleared genomic assay for breast cancer. The assay identifies primary breast cancers likely to metastasize within the first five years of diagnosis and has clinical utility for helping to determine the expected benefit from adjuvant chemotherapy. The MINDACT Trial was the first trial of a genomic assay in breast cancer to provide prospective, randomized evidence of clinical utility for this important clinical question, identifying a significant proportion of patients who could safely forgo chemotherapy within a cohort of patients with high risk clinical characteristics. Nearly half of all patients (46%) who would have been advised chemotherapy according to clinical guidelines were identified genomically by MammaPrint as being low risk and found to have equivalent rates of freedom from metastasis at 5 years with or without chemotherapy. Based upon the MINDACT trial, the ASCO Biomarker Guidelines now approve the use of MammaPrint to inform decisions regarding chemotherapy for women with clinically high-risk ER+ breast cancer, and as the only approved assay for use in women with 1-3 involved lymph nodes. Recent studies suggest information obtained from the 70-gene assay may also help inform decisions regarding endocrine therapy, as well as chemotherapy, targeted therapy and immunotherapy. CONCLUSION: The power of gene expression analysis in breast cancer, effectively illustrated with MammaPrint in the MINDACT trial, is now being explored through examination of the full transcriptome in breast cancer.