3134 Background: Mucinous breast cancer (MuBC) is a rare subtype of invasive ductal carcinoma (IDC) that accounts for less than 2% of all breast cancers and is associated with a favorable prognosis. Since MuBCs are rare in clinical trials, current treatment guidelines are extrapolated from IDC-no special type (IDC-NST). To provide better understanding of MuBCs and factors contributing to their clinical behavior, we examined the transcriptomic profiles of MuBCs in our FLEX study. Methods: The prospective, observational FLEX Study (NCT03053193) includes stage I-III breast cancer patients who receive MammaPrint (MP)/BluePrint (BP) testing and consent to full transcriptome and clinical data collection. For this study, histologically confirmed MuBCs (n = 102) in the FLEX database were included. All patients examined were ER+/HER2- by immunohistochemistry and Luminal by BP. MuBC was compared with IDC matched for Age, MP, and BP index (n = 97). Differential gene expression analyses (DGEA) were performed with R package ‘limma’ and differentially expressed genes (DEGs) were considered significant if they had an adjusted p < 0.05 and fold change ≥ 2. Results: DGEA comparing MuBC (n = 102) with IDC (n = 97) revealed 60 DEGs, regardless of the genomic risk, of which 42 genes were upregulated and 18 were downregulated in MuBC relative to IDC. Genes associated with MuBC, such as MUC2, TFF1, CARTPT were among the upregulated genes. Of the 102 MuBC patients, 56 were Luminal A (MP Low Risk-LR) and 46 were Luminal B (MP High Risk-HR) by MammaPrint and BluePrint. Comparison of LR MuBC with LR IDC revealed 111 DEGs. Functional enrichment showed upregulation of pathways involved in estrogen response (early & late) and androgen response and a downregulation of the epithelial to mesenchymal transition (EMT) and E2F pathways in LR MuBC compared to LR IDC. DGEA between HR MuBC and HR IDC revealed only 22 DEGs with immune pathways being downregulated in HR MuBC. DGEA comparing LR MuBC with HR MuBC resulted in 63 DEGs, indicating LR and HR MuBC are biologically distinct types. Interestingly in LR MuBC, the tumor suppressor marker SCUBE2 is upregulated. Over expression of SCUBE2 is associated with better prognosis. Conclusions: Although MuBCs are often expected to have low clinical risk, MP revealed that half of the MuBCs examined in this study were MP High Risk (Luminal B). MP low risk MuBC is biologically different from MP low risk IDC, and downregulation of E2F and EMT pathways might lead to favorable prognoses in MP low risk MuBC. MP high risk MuBC showed limited DEGs compared to high-risk IDCs indicating these tumor types are highly genomically similar and likely to benefit from chemotherapy. The downregulation of immune pathways in MP high risk MuBC may lead to immune surveillance escape resulting in metastasis and further investigation is needed. Clinical trial information: NCT03053193.
9525 Background: Historically, patients with advanced malignant melanoma had a dismal prognosis with an estimated median overall survival of nine months. Therapy response rates and long-term survival have significantly improved with the advent of immunotherapies and targeted chemotherapies. First approved in 2011, there has been subsequent development of more advanced immunotherapeutic agents and targeted chemotherapies, with continued improvement in median overall survival. We examined patterns in the use of immunotherapy and other systemic therapies for metastatic melanoma, as well as the demographic and socioeconomic predictors for the use of these therapies, in order to identify and understand potential barriers to access in the United States. Methods: We used the NCDB for all patients aged 18-years and older who were diagnosed with metastatic melanoma of cutaneous origin from 2004-2014. Patients were included if they had distant metastases or American Joint Committee on Cancer (AJCC) Stage IV. Sociodemographic data, including race, age, insurance status, facility providing care, Charlson/Deyo comorbidity score11, and education by patient’s zip code, were collected. Results: In patients under age 65 with a Charlson-Deyo score of zero, immunotherapy utilization ranged between 8.5–13.4% during 2004 to 2010. In 2011, the usage increased to 16.5% and rose every subsequent year to 29.6% in 2014. Patients were less likely to receive immunotherapy if they had no insurance, were of older age, or received care at a community practice rather than an academic center. Those who received immunotherapy had greater overall survival compared with those who did not. Conclusions: Immunotherapy and targeted agents have become standard of care in those with metastatic melanoma. Adoption of immunotherapy use for metastatic melanoma has been relatively slow despite evidence showing an overall survival benefit; our analysis suggests this is explained in part by socioeconomic barriers.
3570 Background: Biological heterogeneity of HER2 positive breast cancers has been suggested by a modest benefit of HER2-targeted therapies reported in the APHINITY and ExteNET trials. This highlights the need for improved biomarkers that more precisely identify patients who benefit from HER2-directed agents. The 80-gene molecular subtyping signature (80GS) classifies breast tumors into Luminal, HER2 or Basal type based on the gene expression of downstream signaling pathways. Previous work showed a substantial proportion of tumors identified as HER2 equivocal or HER2 positive by 2013 ASCO/CAP guidelines may be reclassified as non-HER2 type by 80GS. In 2018, ASCO/CAP HER2 IHC/ISH classification guidelines were revised to reduce the frequency of HER2 equivocal cases, for which treatment recommendations have been ambiguous. Here we evaluated concordance between HER2 status by 2018 ASCO/CAP guideline classification and 80GS molecular subtyping. Methods: Pathology reports are provided by physicians for samples that are tested with the 70-gene risk of distant recurrence signature (70GS) and 80GS as part of routine diagnostic care. This analysis includes data sent to Agendia (Irvine, CA) from January 2019 to January 2020. HER2 IHC/ISH results based on ASCO/CAP 2018 guidelines were available for 1453 samples. Results: Of 1453 samples, 1336 (92%) were HER2 negative, 99 (7%) were HER2 positive, and 18 (1.2%) were HER2 equivocal under 2018 guidelines. 80GS reclassified 57 of 99 (58%) HER2 positive tumors as Luminal and 11 of 99 (11%) as Basal; the remaining 31% were confirmed HER2. Furthermore, 55 of 99 (55%) HER2 positive tumors were also ER and PR positive by IHC, with 48 (87%) of these reclassified as Luminal type. Of HER2 negative tumors, 80GS classified 94 of 1336 (7%) as Basal and 2 of 1336 (0.15%) as HER2. Of HER2 equivocal tumors, 16 of 18 (89%) reclassified as Luminal and 2 of 18 (11%) as Basal. Conclusions: In this real-world diagnostic dataset, 2018 ASCO/CAP guidelines resulted in few HER2 equivocal tumors overall, confirming the positive impact of the revised guidelines. However, 80GS reclassified 69% of HER2 positive tumors to non-HER2 molecular subtypes, suggesting these tumors may have suboptimal responses to HER2-directed therapy compared to HER2 enriched. All HER2 equivocal tumors reclassified to non-HER2 subtypes. Molecular classification by 80GS adds further precision in classifying HER2 positive patients and potential to predict responsiveness to HER2-targeted therapies. Further studies are warranted to validate the utility of HER2 status based on 80GS.
1059 Background: Breast cancer brain metastases (BCBM) are associated with poor overall survival (OS) and no treatment guidelines exist. Localized treatments include neurosurgery (ns), stereotactic radiosurgery (SRS) and whole brain radiation therapy (WBRT). We studied the association of OS with tumor and patient (pt) characteristics, ns and radiation (rad). Methods: 196BCBM pts who received brain rad from 2009-2013 at three Mayo Clinic sites were retrospectively studied. Data included primary tumor histological subtype: ER+, HER2+, and triple negative (TN). ECOG status at BCBM diagnosis, number of brain lesions, ns and rad treatments were also studied. Results: In single variable analysis (Table), TN status had 1.8 fold (p = 0.004) increased hazard of death compared to ER+, while HER2+ had improved OS (HR 0.6, p = 0.008). Hazard of death in pts with leptomeningeal disease was 2.5 fold higher (p = 0.003) than pts with 1-3 brain lesions. Poor ECOG status was associated with poor OS. Pts who received WBRT and SRS had an improved OS (HR 0.37, p < 0.001) compared to WBRT alone. Combining ns, WBRT and SRS had better OS (HR 0.26, p < 0.001) than WBRT alone. Conclusions: In this large dataset,pts with the best OS had an ECOG score of 0, HER2+ disease, 1-3 brain lesions, and the combination of ns and rad. OS analysis. Variables Single variable analysis HR (95% CI) P-value ER+ 1.0 (Ref) HER2+ 0.61 (0.43, 0.88) 0.008 TN 1.76 (1.20, 2.58) 0.004 Number of BCBM 1- 3 1.0 (Ref) 0 (Leptomeningeal) 2.52 (1.38, 4.58) 0.003 ≥ 4 1.41 (1.03, 1.95) 0.034 ECOG 0 1.0 (Ref) 1 1.53 (1.05, 2.23) 0.028 2 2.93 (1.64, 5.26) < 0.001 3-4 6.79 (3.78, 12.19) < 0.001 NS 0.44 (0.30, 0.63) < 0.001 RAD WBRT 1.0 (Ref) SRS 0.78 (0.51, 1.19) 0.25 WBRT & SRS vs. WBRT as a ref 0.37 (0.26, 0.54) < 0.001 WBRT & SRS vs. SRS as ref 0.48 (0.30, 0.77) 0.002 NS status & RAD combinations No NS, WBRT only (n = 87) 1.0 (Ref) No NS, SRS only (n = 29) 0.67 (0.42, 1.05) 0.082 No NS, WBRT and SRS both (n = 28) 0.32 (0.20, 0.51) < 0.001 NS, WBRT only (n = 18) 0.29 (0.15, 0.57) < 0.001 NS, SRS only (n = 7) 0.48 (0.19, 1.18) 0.11 NS, WBRT and SRS both (n = 27) 0.26 (0.16, 0.42) < 0.001 Ref, reference; HR, hazard ratio; CI, confidence interval. Single variable Cox proportional hazard model was used for P-values.
Abstract Background: Triple negative breast cancers (TNBC) are more aggressive, have a worse prognosis, and few targeted therapies compared to other BC subtypes. TNBC is molecularly heterogeneous, with at least 4 distinct subtypes: basal-like immune-activated (BLIA), basal-like immunosuppressed (BLIS), luminal androgen receptor (LAR), and mesenchymal (MES). The molecular subtyping gene signature, BluePrint (BP), classifies breast tumors into Luminal, HER2, or Basal subtype based on the assessment of downstream signaling pathways and independently of IHC expression. Compared to IHC-defined TNBC, a higher frequency of BLIS or BLIA subtypes and fewer LAR or MES tumors were reported in BP-defined Basal tumors. To advance our understanding of TNBC heterogeneity, we evaluated the relationship between gene expression signatures, TNBC subtype and BluePrint, in IHC-defined TNBC. Methods: The FLEX registry (NCT03053193) is an ongoing, prospective study evaluating primary tumors from stage I-III BC patients who receive the risk of distant recurrence gene signature, MammaPrint (MP), and BP testing and consent to clinically annotated full transcriptome data collection. This analysis includes 204 IHC-defined TNBC patients. TNBC subtypes BLIA, BLIS, LAR, and MES were derived using an adjusted version of the Burstein centroid signature. BP classified patient samples into Luminal, HER2, and Basal subtypes. A proportion of tumors may exhibit a secondary but less pronounced activated pathway or BP subtype. Therefore, each BP subtype was divided into single activated or mixed subtype based on BP indices. Results: Of 204 TNBC tumors, 84% were classified as Basal by BP, most of which were BLIS (65%), followed by BLIA (22%), with a low frequency of MES (8%) and LAR (5%) subtypes (Table). Approximately 14% of TNBCs were reclassified as Luminal by BP, most of which were LAR (76%), whereas 24% were MES. Clustering analysis revealed similar gene expression profiles between Basal-BLIS and Basal-BLIA tumors. Interestingly, the transcriptional profile of Basal-MES and Basal-LAR tumors were similar to Luminal-MES and Luminal-LAR tumors. BP Basal indices distinguished between different TNBC subtypes. The Basal pathway was predominantly activated in 90% of BP Basals (single activated tumors), most of which were either BLIS or BLIA (96%), whereas 10% of BP Basals were mixed subtype and more likely to classify as LAR (53%) or MES (35%). Approximately 25% of the BP Basal gene signature overlapped with the TNBC subtype gene signature. Expression of 18 and 12 genes out of 28 genes that make up the BP basal signature were significantly different in Basal-BLIA/BLIS compared to LAR or MES, respectively (P < 0.05). PRR15 and CAPN13 were significantly differentially expressed between LAR and MES within Basals. Conclusion: BP reclassified a subgroup of TNBC tumors to Luminal, explaining the discrepancy in the distribution of TNBC subtypes between IHC-defined TNBC and BP Basal tumors. Furthermore, BP indices distinguished between single activated and mixed subtypes, which correlated with different TNBC subtypes. These data suggest that molecular classification by BP adds further precision in classifying TNBC patients and sheds new light on the heterogeneity of these tumors. These findings have clinical implications in stratifying patients and identifying successful targeted treatment options. Future studies are warranted to investigate treatment response and prognosis in these molecular subgroups. BasalLuminalHER2TotalBLIA370037BLIS11100111LAR1022335MES147021Total172 (84.3%)29 (14.2%)3 (1.5%)204 (100%) Citation Format: Virginia G. Kaklamani, Cathy Graham, Karen L. Tedesco, Abirami Sivapiragasam, Jennifer A. Crozier, Apurva N. Shah, Yuan Yuan, Josien Haan, Andrea Menicucci, Michelle L. Bolner, Shiyu Wang, Lorenza Mittempergher, Erin Yoder, William Audeh, FLEX Investigators' Group. Using blueprint to elucidate the molecular heterogeneity of triple negative breast cancers [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 PS18-05.
Abstract Background: Genomic expression profiles have enabled the classification of breast cancers into molecular subtypes and provide prognostic information about the metastatic potential of the tumor, both of which have implications for the personalized treatment of breast cancer beyond clinical and pathological features. However, to precisely stratify tumors into actionable subgroups, full genome expression data should be combined with comprehensive clinical information. The FLEX Registry aims to aggregate a large, real-world dataset, which will enable the discovery of novel genomic profiles, particularly for patient subsets that are poorly represented in traditional clinical trials and will contribute to improved precision in the management of breast cancer. Trial Design: The FLEX Registry (NCT03053193) is a multicenter, prospective, observational trial for patients with Stage I, II, and III breast cancer. Patients with stage I-III breast cancer who receive MammaPrint, with or without BluePrint, on a primary tumor are eligible for enrollment. The primary objective of FLEX is to create a large scale, population-based registry that links complete clinical data with full genome expression data to elucidate new prognostic and/or predictive gene associations in a real-world setting. The FLEX Registry employs a shared study infrastructure to develop and investigate hypotheses for targeted subset analyses and/or clinical trials based on full genome expression data. The adaptable protocol is designed to be amended with the inclusion of targeted sub-studies. Patients enrolled in the initial study are eligible for inclusion in sub-studies for which they meet all eligibility criteria and additional consent is not required. Data will be collected on patients from diagnosis through 10 years of follow-up and any necessary additional clinical data will be collected as specified in the appendix protocols. Target enrollment is a minimum of 10,000 patients; >4,000 patients have enrolled since April 2017 at more than 80 sites, including seven National Cancer Institute-designated comprehensive cancer centers. The FLEX collaborative platform enables participating investigators the opportunity to author their own sub-study protocols, as approved by the FLEX Steering Committee. Fifteen sub-studies have been approved for investigation within the FLEX Registry. Citation Format: Jennifer Crozier, Adam Brufsky, Ian Grady, Sami Diab, Blanche Mavromatis, Nina D'Abreo, Carrie Dul, Rakhshanda Layeequr Rahman, Sarah Untch, Erin Yoder, Heather M. Kling, Amy M. Truitt, William Audeh, Bastiaan van der Baan, FLEX Investigators Group. The FLEX real world data platform explores new gene expression profiles and investigator-initiated protocols in early stage breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-320.
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 .
Post-transplant lymphoproliferative disorders (PTLD) are a serious complication of transplantation with a high mortality. Most PTLD present within the first year of transplantation and are associated with Epstein-Barr virus (EBV) infection. Plasmablastic lymphoma (PBL) is a rare but aggressive disease originally described in patients with HIV, presenting most commonly in the jaw and oral mucosa. To our knowledge, this is the first case of PBL presenting as PTLD of the lung in a HIV and EBV negative patient. Given the increasing number of transplants performed, we would like to share this uncommon presentation of PTLD as PBL.
Abstract Background: Genomic expression profiles have implications for the personalized treatment of breast cancer beyond clinical and pathological features by enabling the classification of breast cancers into molecular subtypes and providing prognostic information about the metastatic potential of tumors. However, full genome expression data should be combined with comprehensive clinical information to precisely stratify tumors into clinically actionable subgroups. The FLEX Registry aims to aggregate a large, real-world dataset, which will enable the discovery of novel genomic profiles to improve precision in the management of breast cancer, particularly in underrepresented patient subsets in traditional clinical trials. Trial Design: The FLEX Registry (NCT03053193) is a multi-center, prospective, observational trial for patients with stage I-III breast cancer whose primary tumor is analyzed by MammaPrint, with or without BluePrint.The primary objective of FLEX is to create a large scale, population-based registry that links comprehensive clinical data with full genome expression data to elucidate new prognostic and/or predictive gene associations in a real-world setting. The FLEX Registry employs a shared study infrastructure to develop and investigate hypotheses for targeted subset analyses and/or clinical trials based on full genome expression data. The adaptable protocol is designed to be amended with the inclusion of additional targeted sub-studies. Patients enrolled in the initial study are eligible for inclusion in sub-studies for which they meet all eligibility criteria and additional consent is not required. Data will be collected on patients from diagnosis through10 years of follow-up and any necessary additional clinical data will be collected as specified in the appendix protocols. The target enrollment of FLEX is a minimum of 10,000 patients; over 5,000 patients have enrolled sinceApril 2017 at more than 85 sites, including eight National Cancer Institute-designated comprehensive cancer centers. The FLEX collaborative platform allows participating investigators the opportunity to author their own sub-study protocols, as approved by the FLEX Review Committee. Sub-study research categories include: Age and Breast Cancer, Optimizing Therapy Strategies, Breast Cancer and MetabolicSyndrome, ctDNA and Liquid Biopsy, Genomics and Subtypes, Social and Ancestry, and Neoadjuvant Therapy and Surgery. To date, twenty-five investigator-initiated sub-studies have been approved.Trial contact information: NCT03053193FLEX@agendia.com Citation Format: Laura Lee, Sami Diab, Julie Barone, Jennifer A Crozier, Margret Chen, Rakshanda L Rahman, Robert Maganini, Douglas Marks, Amy M Truitt, Lisa Blumencranz, Erin Yoder, Sarah Untch, William Audeh, Bastiaan van der Baan, FLEX Investigators Group. The FLEX real-world data platform explores new gene expression profiles and investigator-initiated protocols in early stage breast cancer [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 OT-12-01.
