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Background: Breast cancer (BC) is the most commonly diagnosed cancer and one of the leading causes of cancer death in women. Despite significant therapeutic advances, the majority of patients with unresectable or recurrent/metastatic disease eventually develop resistance to available standard of care (SOC) therapies. B7-H4 is a poor prognostic factor and is overexpressed in several cancers including endometrial, ovarian, and breast. As a member of the CD28/B7 family of cell surface proteins, it promotes tumorigenesis by suppressing anti-tumor immunity. XMT-1660 is a B7-H4-targeted Dolasynthen antibody drug conjugate with a precise, optimized drug-to-antibody ratio and a DolaLock microtubule inhibitor payload with controlled bystander effect. In the preclinical setting, XMT-1660 has demonstrated anti-tumor activity in TNBC and ER+/HER2- patient-derived xenograft mouse models, which included tumors from heavily pre-treated patients (Collins et al, AACR 2022). Increased anti-tumor activity tended to be more frequent in models with higher B7-H4 expression, providing rationale for a Ph1 clinical trial. Methods: The Ph1 trial includes a first-in-human open-label dose escalation (DES) portion followed by dose expansion (EXP) evaluating XMT-1660 in patients with BC, EC, and OC following progression on SOC as applicable (i.e., CDK4/6i + ET; platinum-based chemotherapy). In the DES, Bayesian Optimal Interval (BOIN) design will be used to determine the MTD. Patients will receive XMT-1660 IV Q3 weeks. Primary endpoints in DES are to assess safety and determine a recommended phase 2 dose (RP2D) and assessment of preliminary efficacy as a secondary endpoint. In the EXP portion, cohorts enrolling TNBC, ER+/HER2- BC, EC/OC are planned and additional patients may be enrolled based on emerging data. The primary endpoint of EXP is to assess safety and tolerability, overall response rate, disease control rate, and duration of response. Secondary endpoints include pharmacokinetic analysis and antidrug antibodies. Patients are not selected by B7-H4 status, but baseline tumors samples are collected for retrospective tumor tissue evaluation. The trial is currently enrolling patients. NCT05377996 Citation Format: Erika Hamilton, Arvind Chaudhry, Alexander I. Spira, Sylvia Adams, Nour Abuhadra, Antonio Giordano, Ritesh Parajuli, Hyo S. Han, Amy Weise, Aubri Marchesani, Kate Josephs, Chu Ri Shin, Kevin Kalinsky. XMT-1660: A Phase 1b trial of a B7-H4 targeted Antibody Drug Conjugate (ADC) in Breast, Endometrial, and Ovarian Cancers [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-03-01.

High stromal tumor-infiltrating lymphocytes (sTILs) are associated with improved pathologic complete response (pCR) in triple-negative breast cancer (TNBC). We hypothesize that integrating high sTILs and additional clinicopathologic features associated with pCR could enhance our ability to predict the group of patients on whom treatment de-escalation strategies could be tested. In this prospective early-stage TNBC neoadjuvant chemotherapy study, pretreatment biopsies from 408 patients were evaluated for their clinical and demographic features, as well as biomarkers including sTILs, Ki-67, PD-L1 and androgen receptor. Multivariate logistic regression models were developed to generate a computed response score to predict pCR. The pCR rate for the entire cohort was 41%. Recursive partitioning analysis identified ≥20% as the optimal cutoff for sTILs to denote 35% (143/408) of patients as having high sTILs, with a pCR rate of 59%, and 65% (265/408) of patients as having low sTILs, with a pCR rate of 31%. High Ki-67 (cutoff > 35%) was identified as the only predictor of pCR in addition to sTILs in the training set. This finding was verified in the testing set, where the highest computed response score encompassing both high sTILa and high Ki-67 predicted a pCR rate of 65%. Integrating Ki67 and sTIL may refine the selection of early stage TNBC patients for neoadjuvant clinical trials evaluating de-escalation strategies.

Supplementary Figure from Molecular Characterization and Prospective Evaluation of Pathologic Response and Outcomes with Neoadjuvant Therapy in Metaplastic Triple-Negative Breast Cancer

Purpose:Metaplastic breast cancer (MpBC) is a rare subtype of breast cancer that is commonly triple-negative and poorly responsive to neoadjuvant therapy in retrospective studies.Experimental Design:To better define clinical outcomes and correlates of response, we analyzed the rate of pathologic complete response (pCR) to neoadjuvant therapy, survival outcomes, and genomic and transcriptomic profiles of the pretreatment tumors in a prospective clinical trial (NCT02276443). A total of 211 patients with triple-negative breast cancer (TNBC), including 39 with MpBC, received doxorubicin-cyclophosphamide–based neoadjuvant therapy.Results:Although not meeting the threshold for statistical significance, patients with MpBCs were less likely to experience a pCR (23% vs. 40%; P = 0.07), had shorter event-free survival (29.4 vs. 32.2 months, P = 0.15), metastasis-free survival (30.3 vs. 32.4 months, P = 0.22); and overall survival (32.6 vs. 34.3 months, P = 0.21). This heterogeneity is mirrored in the molecular profiling. Mutations in PI3KCA (23% vs. 9%, P = 0.07) and its pathway (41% vs. 18%, P = 0.02) were frequently observed and enriched in MpBCs. The gene expression profiles of each histologically defined subtype were distinguishable and characterized by distinctive gene signatures. Among nonmetaplastic (non-Mp) TNBCs, 10% possessed a metaplastic-like gene expression signature and had pCR rates and survival outcomes similar to MpBC.Conclusions:Further investigations will determine if metaplastic-like tumors should be treated more similarly to MpBC in the clinic. The 23% pCR rate in this study suggests that patients with MpBC should be considered for NAT. To improve this rate, a pathway analysis predicted enrichment of histone deacetylase (HDAC) and RTK/MAPK pathways in MpBC, which may serve as new targetable vulnerabilities.

Supplementary Table from Molecular Characterization and Prospective Evaluation of Pathologic Response and Outcomes with Neoadjuvant Therapy in Metaplastic Triple-Negative Breast Cancer

Purpose:Metaplastic breast cancer (MpBC) is a rare subtype of breast cancer that is commonly triple-negative and poorly responsive to neoadjuvant therapy in retrospective studies.Experimental Design:To better define clinical outcomes and correlates of response, we analyzed the rate of pathologic complete response (pCR) to neoadjuvant therapy, survival outcomes, and genomic and transcriptomic profiles of the pretreatment tumors in a prospective clinical trial (NCT02276443). A total of 211 patients with triple-negative breast cancer (TNBC), including 39 with MpBC, received doxorubicin-cyclophosphamide–based neoadjuvant therapy.Results:Although not meeting the threshold for statistical significance, patients with MpBCs were less likely to experience a pCR (23% vs. 40%; P = 0.07), had shorter event-free survival (29.4 vs. 32.2 months, P = 0.15), metastasis-free survival (30.3 vs. 32.4 months, P = 0.22); and overall survival (32.6 vs. 34.3 months, P = 0.21). This heterogeneity is mirrored in the molecular profiling. Mutations in PI3KCA (23% vs. 9%, P = 0.07) and its pathway (41% vs. 18%, P = 0.02) were frequently observed and enriched in MpBCs. The gene expression profiles of each histologically defined subtype were distinguishable and characterized by distinctive gene signatures. Among nonmetaplastic (non-Mp) TNBCs, 10% possessed a metaplastic-like gene expression signature and had pCR rates and survival outcomes similar to MpBC.Conclusions:Further investigations will determine if metaplastic-like tumors should be treated more similarly to MpBC in the clinic. The 23% pCR rate in this study suggests that patients with MpBC should be considered for NAT. To improve this rate, a pathway analysis predicted enrichment of histone deacetylase (HDAC) and RTK/MAPK pathways in MpBC, which may serve as new targetable vulnerabilities.

Targeting the HER2 oncogene represents one of the greatest advances in the treatment of breast cancer. HER2 is one member of the ERBB-receptor family, which includes EGFR (HER1), HER3 and HER4. In the presence or absence of underling genomic aberrations such as mutations or amplification events, intricate interactions between these proteins on the cell membrane lead to downstream signaling that encourages cancer growth and proliferation. In this Review, we contextualize efforts to pharmacologically target the ErbB receptor family beyond HER2, with a focus on EGFR and HER3. Preclinical and clinical efforts are synthesized. We discuss successes and failures of this approach to date, summarize lessons learned, and propose a way forward that invokes new therapeutic modalities such as antibody drug conjugates (ADCs), combination strategies, and patient selection through rational biomarkers.

Introduction High levels of TIL at baseline are associated with higher pCR rates and better overall survival in TNBC. Recent studies have also indicated that higher TIL in post-NACT residual disease in TNBC are an important independent predictor of improved survival. We evaluated the role of mid-treatment (post-AC; Adriamycin/Cyclophosphamide) TIL in predicting pCR rates in early-stage TNBC. Methods Of 242 patients with stage I-III TNBC enrolled in the ARTEMIS trial (NCT02276443), 156 patients had pre-AC TIL and pCR status available for this analysis. Both pre-and post-AC TIL counts were available in 29 patients. Post-AC TIL counts for the remaining patients were imputed using linear regression with age, race, stage III, vimentin >50% and post-AC tumor volume reduction. Using these imputed TIL counts we evaluated the association of post-AC TIL with pCR. We also evaluated the change in TIL before and after treatment with AC. Results At baseline the median TIL count was 10% (n=156). In the post-AC samples, the median TIL count was 5%. Using imputed TIL counts, we did not conclude that post-AC TIL was associated with pCR (p= 0.28). Using a cut-point of 15% TIL, our analysis showed that baseline TIL is more strongly correlated with pCR than post-AC TIL (Table 1). In our univariable logistic regression, both baseline TIL and the difference in TIL pre-and post- treatment were significantly associated with pCR (p= 0.0015 and p=0.0068, respectively), however in the multivariable analysis only baseline TIL was significant. Our analysis did show that a decrease in TIL from pre- to post-treatment was significantly associated with pCR (p=0.022). However, this measure was not significant in our logistic regression model when pre-TIL was also included. Conclusion Higher pre-treatment TIL correlated more strongly with pCR rate when compared to post-AC TIL. Pre-treatment high TIL was associated with pCR regardless of changes in TIL pre and post treatment. Table 1. Changes in TIL before and after treatmentBaseline TILPost-AC TILN#pCR (%)LowLow6217 (27%)LowHigh4012 (30%)HighLow2513 (52%)HighHigh2916 (55%)TIL; Low: 15 Citation Format: Nour Abuhadra, Kenneth Hess, Jennifer Litton, Gaiane Rauch, Alastair Thompson, Bora Lim, Beatriz Adrada, Elizabeth Mittendorf, Senthil Damodaran, Rosalind Candelaria, Banu Arun, Wei Tse Yang, Naoto Ueno, Lumarie Santiago, Rashmi Murthy, Nuhad Ibrahim, Sahin Aysegul, William Symmans, Lei Huo, Stacy Moulder. Serial TILs: Evaluating the role of mid-treatment tumor infiltrating lymphocytes (TIL) in predicting pathologic complete response (pCR) in 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 P1-10-20.

To the Editor,The myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic conditions characterized by dysplastic changes and ineffective hematopoiesis [1]. Almost all patients with...

High stromal tumor-infiltrating lymphocytes (sTILs) are associated with an improved pathologic complete response (pCR) and survival in triple-negative breast cancer (TNBC). We hypothesized that high baseline sTILs would have a favorable prognostic impact in TNBC patients without a pCR after neoadjuvant chemotherapy (NACT). In this prospective NACT study, pretreatment biopsies from 318 patients with early-stage TNBC were evaluated for sTILs. Recursive partitioning analysis (RPA) was applied to search for the sTIL cutoff best associated with a pCR. With ≥20% sTILs identified as the optimal cutoff, 33% patients had high sTILs (pCR rate 64%) and 67% had low sTILs (pCR rate 29%). Patients were stratified according to the sTIL cutoff (low vs. high) and response to NACT (pCR vs. residual disease (RD)). The primary endpoint was event-free survival (EFS), with hazard ratios calculated using the Cox proportional hazards regression model and the 3-year restricted mean survival time (RMST) as primary measures. Within the high-sTIL group, EFS was better in patients with a pCR compared with those with RD (HR 0.05; 95% CI 0.01–0.39; p = 0.004). The difference in the 3-year RMST for EFS between the two groups was 5.6 months (95% CI 2.3–8.8; p = 0.001). However, among patients with RD, EFS was not significantly different between those with high sTILs and those with low sTILs (p = 0.7). RNA-seq analysis predicted more CD8+ T cells in the high-sTIL group with favorable EFS compared with the high-sTIL group with unfavorable EFS. This study did not demonstrate that high baseline sTILs confer a benefit in EFS in the absence of a pCR.

The number of online resources for patients with MDS is exponentially increasing; this is in large part due to the advent of social media which has introduced multiple avenues for information exchange and communication. Whether this information is targeted towards the patient population or not, the wealth of information online represents a new era of patient engagement in their health care. This review aims to highlight the different online resources being used in the field of MDS. Patients with MDS have access to the opinions of thought leaders in the field, advances in research and clinical trials, and the latest updates at national conferences and leading journals through social media. Social media is a powerful educational resource for patients with MDS when used conscientiously.

Introduction: Emerging data suggest that the gut microbial composition influences responses to chemotherapy and immunotherapy. However, similar data in patients with TNBC receiving NAT remains limited. Thus, we investigated the association between the gut microbial composition in patients with newly-diagnosed, early-stage TNBC and response to NAT in a cohort of patients enrolled in the ARTEMIS trial (NCT02276443). Methods: We performed 16S sequencing on bacterial genomic DNA extracted from pre-NAT fecal samples using the 2x250 bp paired-end read protocol. Quality-filtered sequences were clustered into Operational Taxonomic Units and classified using Mothur method with the Silva database version 128. Associations between abundance and pathologic response to NAT were assessed using the Mann Whitney U Test. A cohort of 32 patients had longitudinal samples collected. Mann-Whitney U Test and Fishers exact were used to compare clinical variables as appropriate between the pCR and non-pCR groups. Results: There was no significant difference in age, race or stage between the pCR and non-pCR groups (Table 1). As expected, the pCR group was enriched for high TIL (p=0.026). There was no difference in alpha-diversity of the gut microbiome between patients with NAT-sensitive (pCR) and NAT-resistant disease (non-pCR) (p=0.5). Relative to patients with NAT-sensitive disease (pCR), the gut microbiome in patients with NAT-resistant disease was enriched for Fusobacterium (p=0.009), Intestinimonas (p=0.01) and Lachnospiraceae (p=0.003) at the genus level; the median abundances between pCR and non-pCR are provided in Table 1. Longitudinal samples collected during NAT demonstrated no substantial impact of NAT on the gut microbiome. Conclusions: Taken together, these data suggest that response to NAT may be influenced by the gut microbial composition, which remains unaltered during NAT. Research efforts to modulate the gut microbiome should be further explored as a potential therapeutic strategy in TNBC. Table 1: Median Microbial Abundance and Clinicopathological Variables (N=43)pCR (n=18)Non-pCR (n=25)p- valueMicrobial AbundanceFusobacterium1 x 10-61.02 x 10-50.009Intestinimonas6.4 x 10-54.8 x 10-40.01Lachnospiraceae6.2 x 10-31.0 x 10-20.003Age median, interquartile range (n=44)45 (38-59)53 (46-58)0.61n (%)Race/EthnicityWhite, non-Hispanic11 (61.1)14 (56.0)0.53White, Hispanic4 (22.2)3 (12.0)Black2 (11.1)7 (28.0)Asian1 (5.6)1 (4.0)T categoryT15 (27.8)4 (16.0)0.15T213 (72.2)17 (68.0)T304 (16.0)T400Nodal statusNegative12 (66.7)14 (56.0)0.54Positive6 (33.3)11 (44.0)StageI3 (16.7)3 (12.0)0.91II11 (61.1)15 (60.0)III4 (22.2)7 (28.0)TIL20%11 (61.1)6 (24.0) Citation Format: Nour Abuhadra, Chia-Chi Chang, Clinton Yam, Ryan Sun, Lei Huo, Jason White, Elizabeth E Ravenberg, Jennifer Litton, Bora Lim, Naoto T Ueno, Banu Arun, Debu Tripathy, Senthil Damodaran, Rashmi Murthy, Vicente Valero, Gabriel Hortobagyi, Nuhad Ibrahim, Alastair Thompson, Elizabeth Mittendorf, Stacy Moulder, Robert Jenq. Prospective evaluation of the gut microbiome and response to neoadjuvant therapy (NAT) in early-stage triple negative breast cancer (TNBC) [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 PS4-05.

590 Background: The impact of gut microbiome on tumor biology, progression and response to immunotherapy has been shown across cancer types. However, there is little known about the impact of gut microbial composition on response to chemotherapy. We have previously shown that the gut microbiome remains unaltered during NACT in a cohort of 32 patients. Here we investigate the association between gut microbiome and response to NACT in a larger cohort of early-stage TNBC. Methods: Longitudinal fecal samples were collected from 85 patients with newly-diagnosed, early-stage TNBC patients enrolled in the ARTEMIS trial (NCT02276443). Patients all received standard NACT with adriamycin/cyclophosphamide (AC); volumetric change was assessed using ultrasound and patients with < 70% volumetric reduction (VR) after 4 cycles of AC were recommended to receive targeted therapy in addition to standard NACT to improve response rates. We performed 16S sequencing on bacterial genomic DNA extracted from 85 pre-AC fecal samples using the 2x250 bp paired-end read protocol. Quality-filtered sequences were clustered into Operational Taxonomic Units and classified using Mothur method with the Silva database version 138. For differential taxa-based univariate analysis, abundant microbiome taxa at species, genus, family, class, and order levels were analyzed using DESeq2 after logit transformation. Alpha-diversity indices within group categories were calculated using phyloseq. Microbial alpha diversity (within-sample diversity) was measured by Simpson's reciprocal index. β-diversity was measured using weighted UniFrac distances between the groups. The association between microbiota abundance and pathologic complete response (pCR) or residual disease (RD) was assessed using DESeq2 analysis. Results: Pre-AC fecal samples from 85 patients were available for analysis. Amongst them, there were 46 patients with pCR and 39 patients with RD. There was no significant difference in alpha diversity (p = 0.8) or beta-diversity (p = 0.7) between the pCR and RD groups. However, relative to patients with RD, the gut microbiome in patients with pCR was enriched for the Bifidobacterium longum species (p = 0.03). The gut microbiome in patients with RD was enriched for Lachnospiraceae (p = 0.03) at the genus level and the Bacteroides thetaiotaomicron species (p = 0.02). Conclusions: We have demonstrated significant differences in the gut microbial composition in patients with pCR as compared to patients with RD. Further investigation in larger studies is needed to support therapeutic exploration of gut microbiome modulation in TNBC patients receiving chemotherapy such as probiotic supplementation or fecal microbiota transplant.

Background: Germline TP53 mutations predispose to early onset breast cancer (BC) and are associated with Li-Fraumeni syndrome (LFS) Published data on the clinical and pathological characteristics and screening outcome for secondary cancers among women with BC and TP53 mutations is limited. The UTMD Anderson's Li-Fraumeni Education and Early Detection (LEAD) program conducts comprehensive cancer screening for patients with LFS. Here we report characteristics and screening outcome of patients with BC and LFS who were referred to the LEAD program. Methods: Patients with BC and LFS were identified from a prospective BC database between 2001 to 2018. Patients had genetic testing at The University of Texas MD Anderson Cancer Center (MDACC) Clinical Cancer Genetics (CCG) program and confirmed to have germline TP53 mutations. Data reviewed included clinical and pathological characteristics of their BC, the pattern of referral to the LEAD program, adherence to screening recommendation and rate of secondary cancer detection in the LEAD program. Results: A total of 78 female patients with positive germline TP53 mutation and BC diagnosis were identified. The clinical and pathological characteristics of these patients are provided in table 1. Out of the 78 patients, 62 patients were referred and followed at the LEAD clinic. 50 were referred after BC diagnosis and 12 were referred to LEAD clinic before BC diagnosis. A total of 137 cancers were diagnosed in the total population. The cancers were further grouped into diagnosed before or after BC diagnosis. (table 2). 24 cancers were diagnosed in LEAD clinic including 12 breast cancers, 2 soft tissue tumors, 2 thyroid cancers, 2 acute myeloid leukemia, 1 brain tumor, 1 lung cancer, 1 pancreatic cancer, 1 melanoma, 1 parotid cancer and 1 Merkel cell cancer. Adherence to follow up and recommended screening in the first year was 77%, second year 75% and third year 65%. 6 patients, who were diagnosed with leukemia, had received adjuvant chemotherapy with anthracycline and/or cyclophosphamide-based therapy for breast cancer with median time from chemotherapy to leukemia diagnosis of 9 years (5-10yrs). 8 patients developed chest wall sarcoma in the same location of prior radiation therapy for breast cancer with median time from radiation therapy to chest wall sarcoma diagnosis of 7 years (3-11yrs). Conclusion: Patients with LFS associated breast cancer are at significant increased risk to develop secondary cancers. Increased surveillance for secondary cancers in a dedicated program can increase adherence to screening, lead to early detection that could potentially lead to improved outcomes. Patient outcome of this cohort will be presented at the meeting. Table 1: Clinical and Pathological Characteristics of Women with Breast cancer and LFSN(%)N(%)Median Age (Range)33 (20, 63)——Hormonal receptor/HER-2 status+/+22(31.4%)RaceAsian/Pacific islander7(9%)+/-27(38.6%)Black8(10.3%)-/+14(20%)Hispanic12(15.4%)-/-7(10%)White51(65.4%)Menopausal status at the time of BC diagnosis.Pre-menopausal(72%)Stage013(16.9%)Post-menopausal(28%)I21(27.3%)HistologyDCIS12(15.6%)II31(40.3%)IDC49(63.6%)III9(11.7%)ILC3(3.9%)IV3(3.9%)LCIS1(1.3%)Breast cancer diagnosisMRI4(5.2%)Mixed8(10.4%)Palpated lesion51(66.2%)Mucinous2(2.6%)Screening mammogram22(28.6%)Phyllodes2(2.6%) Table 2: Cancer diagnosed in the total population N=78 grouped into before and after to BC diagnosisCancer diagnosed before BC diagnosisNCancer diagnosed after BC diagnosisNSoft tissue sarcoma13Soft tissue sarcoma18CNS1Lung2Thyroid3Thyroid3leukemia2Merkel cell1Adrenal2Leukemia6Uterus1CNS3Renal1pancreas1Melanoma1Parotid1 Citation Format: Aydah Al-Awadhi, Nour Abuhadra, Diane D Liu, Angelica M Gutierrez Barrera, Jessica Corredor, Louise C Strong, Banu K Arun. Clinical and pathological characteristics and screening outcome for secondary cancers in breast cancer patients with li-fraumeni syndrome attending the MD anderson li-fraumeni education and early detection program clinic [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 PS8-04.

Background: MpBC is a rare breast cancer subtype that is commonly triple-negative and associated with a diminished response to NAT in published retrospective data sets, prompting some clinicians to recommend surgical resection followed by adjuvant therapy. Methods: The ARTEMIS trial (NCT02276443) uses imaging response and molecular profiling to personalize NAT in early stage TNBC. Patients with sensitive disease after 4 cycles of AC receive standard taxane-based NAT as the second phase of NAT, while those with resistant disease are offered biomarker-guided therapeutic trials. Pathologic response is assessed at surgical resection. Prospective data from 195 patients with early-stage TNBC (MpTNBC: N=37; Non-MpTNBC: N=158) enrolled on the ARTEMIS trial were evaluated. Due to short duration of follow-up, restricted mean survival time up to four years of follow-up was used to evaluate event-free survival (RM-EFS), metastasis-free survival (RM-MFS) and overall survival (RM-OS). RNAseq and whole exome sequencing (WES) were performed on pre-NAT core biopsies (155 and 158 non-MpTNBC respectively; 20 MpTNBC). Stromal tumor infiltrating lymphocytes (sTIL) and PD-L1 staining were also compared. Results: Pathologic complete response (pCR) rates were significantly lower in MpTNBC vs non-MpTNBC (18.9% vs. 41.4%, p=0.013). Among MpTNBC without pCR (n=30, 81%), 21 were detected early to have progression (PD) or suboptimal response to standard therapy with ultrasound and clinical exam and were offered the opportunity to participate in clinical trial. Notably, 6 patients (16.2%) had PD after 2 cycles of AC. There was a non-statistically significant trend of lower RM-EFS, RM-MFS, and RM-OS in MpTNBC; however, MpTNBCs with pCR had similar RM-OS compared to non-MpTNBCs with pCR. MpTNBCs had lower rates of high TIL (>20%) compared to non-MpTNBCs (16% vs. 36%, p=0.02) but similar rates of PD-L1+ disease. Compared to non-MpTNBCs, using Vanderbilt classification methods, MpTNBCs were more frequently M/MSL subtype (50% vs 22%, p=0.011) and less frequently BL-1 subtype (p=0.028). By RNAseq, MpTNBC tumors had significantly lower gene expression of epithelial markers CDH1, EPCAM, ESRP1, and increased expression of EMT inducer TWIST1. WES identified PIK3CA missense mutations in 15% of MpTNBCs. Unsupervised clustering based on expression profiles revealed that 85% of MpTNBCs had a Mp-like expression signature. Interestingly, the Mp-like expression signature was identified in 12% of histologically defined non-MpTNBC. The pCR rate was lowest in the MpTNBC (18.9%) but similar between Mp-like TNBC (36.8%) and non-MpTNBC (42.2%). Conclusion: Early-stage MpTNBC has lower rates of pCR with NAT however those with pCR appear to have similar survival rates to non-MpTNBC with pCR. Notably, 16.2% of MpTNBC had PD after 2 cycles of AC NAT suggesting that a neoadjuvant approach with frequent imaging would reduce unnecessary exposure to inactive chemotherapy. 81% of MpTNBCs had either PD or suboptimal response to AC chemotherapy, thus novel treatment strategies need to be developed for this chemorefractory subtype of TNBC. PAM (PI3K/mTOR/AKT) pathway alterations were frequently detected in MpTNBCs and novel inhibitors should be further tested. Citation Format: Nour Abuhadra, Clinton Yam, Ryan Sun, Lei Huo, Jason White, Elizabeth Ravenberg, Beatriz Adrada, Aysegul Sahin, Jennifer Litton, Bora Lim, Naoto T Ueno, Banu Arun, Debu Tripathy, Senthil Damodaran, Rashmi Murthy, Vicente Valero, Gabriel Hortobagyi, Nuhad Ibrahim, Alastair Thompson, Anthony Lucci, Elizabeth Mittendorf, Stacy Moulder, Jeffrey Chang. Prospective evaluation of patients with metaplastic (Mp) triple negative breast cancer (TNBC): Molecular characteristics and outcomes with neoadjuvant therapy (NAT) [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 PS18-04.

ObjectiveQatar is a small country on the Eastern coast of the Arabian Peninsula. Its population is a unique mixture of native citizens and immigrants. We aimed to describe the features of epilepsy in Qatar as such information is virtually lacking from the current literature.MethodsWe summarized information retrospectively collected from 468 patients with epilepsy seen through the national health system adult neurology clinic.ResultsEpilepsy was classified as focal in 65.5% of the cases and generalized in 23%. Common causes of epilepsy were as follows: stroke (9%), hippocampal sclerosis (7%), infections (6%), and trauma (6%). Sixty-six percent of patients were receiving a single antiepileptic drug, with levetiracetam being the most frequently prescribed drug (41% of subjects). When the patients were divided by geographical background, remote infections caused the epilepsy in 15% of Asian patients (with neurocysticercosis accounting for 10%) but only in 1% of Qatari and 3% of Middle East/North African subjects (with no reported neurocysticercosis) (p

Adding molecular data to prognostic models can improve predictive power in treated patients with myelodysplastic syndromes

583 Background: Pathologic complete response is an excellent surrogate for disease-free survival (DFS) and overall survival (OS) in TNBC. High sTIL is associated with improved pCR rates in TNBC. Recent data suggest that high sTIL is also associated with improved outcomes in patients who received no chemotherapy for early stage TNBC (Park, Annals of Oncology, 2019). Thus, we hypothesized that high sTIL may have prognostic impact in patients who do not achieve pCR to NAT. Methods: Pretreatment core biopsies from 182 patients with early-stage TNBC enrolled on the ARTEMIS trial (NCT02276443) were evaluated for sTIL by H&E. Patients were stratified according to sTIL (low < 30%, and high > 30%) and pCR (patients with pCR vs. no pCR). The primary outcome measure was DFS, defined from the date of diagnosis to the first local recurrence, distant metastases or death. Cox proportional hazards regression model was used. During follow-up 33 events for DFS were observed. Results: Among subjects who achieve pCR, DFS was excellent regardless of sTIL status and significantly better than those without pCR (p < 0.05). However, patients with high sTIL and no pCR demonstrated significantly worse DFS compared to all subjects having pCR (HR 0.18, 95% CI 0.04-0.76, p = 0.02). Additionally, we did not find a significant difference between high and low sTIL patients who did not achieve pCR. Conclusions: In early TNBC receiving NAT, for patients failing to achieve pCR, high sTIL was not associated with improved DFS; outcomes were comparable to those with low sTIL without pCR. Thus, high sTIL at baseline does not appear to confer an intrinsic prognostic benefit in the absence of pCR.

Background Children with Langerhans cell histiocytosis (LCH) and single-bone CNS-risk lesions have been reported to be at increased risk of diabetes insipidus (DI), central nervous system neurodegeneration (CNS-ND), and recurrence of disease. However, it is unknown whether the addition of chemotherapy or radiotherapy changes outcomes in these patients. Methods Ten pediatric institutions across North America and Europe contributed data of their patients with LCH and single-bone CNS-risk lesions. Clinical information on age, sex, specific craniofacial site involvement, and intracranial extension at diagnosis, therapy, and disease course was collected for all eligible patients. Results The final analysis included 93 eligible children who were either treated with systemic therapy (chemotherapy, chemo-radiotherapy, or radiotherapy) or local therapy (biopsy, curettage, and/or intralesional steroids). Fifty-nine patients had systemic and 34 had local therapy. The 5-year event-free survival (EFS) and overall survival (OS) were 80 ± 5% and 98 ± 2% in the systemic therapy group versus 85 ± 6% and 95 ± 5% in the local therapy group. There was no statistically significant difference between either group with regard to EFS (P = 0.26) and OS (P = 0.78). On multivariable analysis, there was no significant difference among the two treatment groups after adjusting for site and intracranial soft tissue extension, nor any trend favoring systemic therapy (HR = 2.26, 95% CI = 0.77-6.70; P = 0.14). Conclusion Systemic therapy may not reduce the risk of recurrence or late sequelae in children with LCH and single-bone CNS-risk lesions as compared to local treatment.

In the era of modern communication, the physician and patient relationship has evolved to include an entirely new dimension-social media. This new dimension offers several opportunities for patient education, research and its dissemination, and professional development for health care providers; it can also serve as a platform for addressing important public health issues. However, these advantages come with challenges such as threats to patient and professional privacy. In this article, we dissect the benefits and drawbacks of this social evolution on the practicing hematologist-oncologist. We also perform a review of the current literature on the integration of social media in the practice of hematology/oncology; examine available guidelines for information exchange between health care professionals, industry, pharmaceutical companies, advocacy groups, and patients; and offer ways to create its seamless integration into clinical hematology-oncology practice.

572 Background: Increased TIL in TNBC is associated with higher rates of pCR. High TIL is also associated with improved disease free survival and overall survival. The aim of this study is to identify data cut-points of pre-treatment low, moderate and high TIL count based on pCR and to identify clinical and pathological predictors of pCR in patients with moderate TIL. Methods: We evaluated the relationship between pCR and TIL in 180 patients with stage I-III TNBC enrolled in the ARTEMIS trial (NCT02276443). Recursive portioning was used to identify cut-points. Clinical and pathological variables such as age at diagnosis, stage, race, histology as well as Ki-67, vimentin, and androgen receptor (AR) by immunohistochemistry, were evaluated in pts with moderate TIL. A multivariable logistic regression model identified variables independently, significantly associated with pCR. Results: Four TIL groups were identified with pCR rates of 23%, 31%, 48% and 78% respectively (p < 0.0001) (Table A). In the two combined moderate TIL groups, 90 (97%) pts were evaluable for the multivariate model. Stage I-II disease, high Ki-67 and low AR were associated with increased probability of pCR (Table B). The multivariable logistic regression model area under the ROC curve was 0.78 (95% CI=0.68-0.88; p

RationaleEpilepsy is one of the most prevalent neurologic conditions. It is estimated to affect 70 million people worldwide. Epilepsy is an important cause of disability and mortality. It is associated with social stigma and significant economic costs. Although epilepsy is a disease with a worldwide distribution, its prevalence varies between different countries. Very little is known about the epidemiology of epilepsy in Qatar. Qatar's population is a mixture of native citizens and immigrants. We aim at describing the features of epilepsy in Qatar as such information is virtually lacking from the current literature.MethodsA database was created in 2014 to summarize information retrospectively collected on patients with epilepsy seen through the national health system (HMC) adult neurology clinic. For each subject, in addition to the typical demographic variables, we identified the age at onset, seizure types, epilepsy syndrome, etiology, treatment and outcome. Brain imaging and EEG results were also tabulated. All these variables were analyzed using the statistical package for social science (IBM-SPSS, version 20).ResultsOf 504 patients included in the database, 467 with sufficient information were analyzed. Sixty percent were men. The mean age at the last clinic visit was 35. Native Qataris represented 38.5%, Asian subjects 33%, and Middle Eastern/North African (MENA) origin accounted for 25% of the studied population. Generalized tonic-clonic seizures were the most common seizure type, noted in 89% of subjects. Epilepsy was classified as focal in 65.5% of the cases, and generalized in 23%. EEGs were abnormal in 55.5 %, showing epileptiform discharges in 49% of subjects. Imaging studies revealed epileptogenic pathologies in 40% of reports. Common causes of epilepsy were: vascular (11%), hippocampal sclerosis (8%), infectious (6%) and trauma (6%). Sixty six percent of patients were receiving a single antiepileptic drug, and 53% were seizure free at the last follow-up. Overall, the most commonly prescribed drug was Leviteracetam (41%) followed by Valproic Acid (25%) and Carbamazepine (22%). On current therapy, 54% of patients were seizure-free, 41% had a partial response and five percent were refractory. When the patients were divided by geographical background, some differences were noted. Remote infections caused the epilepsy in 15% of Asian patients (with neurocysticercosis accounting for 10%), but only in 1% of Qatari and 3% of MENA subjects (with no reported neurocysticercosis) (p

Approximately 25% of MDS patients (pts) progress to AML; 15% of those with lower-risk, and up to 40-50% of those with higher-risk disease. Predicting those who are likely to progress to AML early in their disease course could directly impact treatment decisions: lower-risk pts with higher risk of AML transformation may be offered transplant, while higher-risk pts may be considered for AML-like therapy. In this study, we developed a genomic model that evaluates mutational patterns and their association with AML progression. Development of this model mimics Netflix or Amazon9s recommender system in which customers who bought products A and B, are likely to buy C: pts who have a mutation in genes A and B, are then likely to progress to AML. Clinical and genomic data ofMDS pts diagnosed between 1/1996 and 9/2016 were analyzed. A panel of 60 gene mutations obtained by next generation targeted deep sequencing was included. Association rules using Apriori algorithm was used to study the relationship between multiple genes/cytogenetic abnormalities and AML progression in an unbiased approach. Association rules are a machine learning method that uncovers relationships between variables in a given dataset. Rules with highest confidence (>90% that an association exists) and highest lift (strength of the association) were chosen. Univariate and multivariate analyses were used to evaluate the impact of mutations on AML progression, adjusting for covariates (age, IPSS-R). A total of 527 pts with lower-/higher-risk MDS were analyzed, of those 105 (20%) progressed to AML, with a median time to progression (TTP) of 13 months (interquartile range, 6.3-29.8). Median age at diagnosis was 67 years (range, 19-99) and 38% were female. Risk categories by IPSS-R included: 78 (15%) very low, 200 (38%) low, 95 (18%) intermediate, 98 (18.5%) high, and 56 (10.5%) very high; IPSS-R cytogenetic risk groups were 15 (3%) very good, 331 (63%) good, 87 (16%) intermediate, 37 (7%) poor, and 57 (11%) very poor. The most commonly mutated genes were SF3B1 (14%), ASXL1 (13%), TET2 (12%), SRSF2 (11%), DNMT3A (10%), STAG2 (9%), and TP53 (8%). Per IPSS-R, 14% of pts with very low/low, 21% with intermediate and 30% with high/very high categories progressed to AML. Univariate analyses identified the following cytogenetic and mutational abnormalities to be associated with AML progression: complex karyotype (CK, P =.019), ASXL1 ( P =.023), DNMT3A ( P =.011), FLT3 ( P =.031), PHF6 ( P =.018), PTPN11 ( P =.037) , RUNX1 ( P =.001) , STAG2 ( P =.023) , TET2 ( P =.047) , U2AF1 ( P =.038), and ≥3 gene mutations( P =.002), whereas SF3B1 was associated with lower risk of AML progression ( P =.025). In multivariate Cox regression analyses, including significant mutations, age ( P =.5) and IPSS-R scores ( P RUNX1 (HR2.8 ; 95% CI 1.6-5.3; P= .001), and ≥3 gene mutations (HR=1.65; 95% CI 1.1-2.5; P= .021) were independent factors that associated with AML progression, while SF3B1 (HR=.417; 95% CI .205-.851, P =.016) was associated with lower risk of progression. Association rules identified the following combinations of cytogenetic/genomic abnormalities for AML progression: (ASXL1, RUNX1, STAG2/BCOR), (ASXL1, STAG2, ZRSR2/SRSF2), (ASXL1, TET2, Trisomy8 ), (RUNX1, STAG2, Trisomy 8 ), ( CK , TP53, TET2) . These combinations were associated with a 5 month reduction in time to AML progression.[Figure 1] Using genomic data to reliably identify patients at highest risk for progression to AML early in their disease course can dramatically alter treatment recommendations. Independent factors such as RUNX1 and ≥3 gene mutations predicted for AML progression, while SF3B1 was associated with a reduced risk. Certain cytogenetic/genomic abnormalities were associated with shorter time to AML progression. This data suggests that MDS pts with ≥3 genomic abnormalities or certain genomic combinations could be offered more aggressive therapy early in their disease course including those with lower risk disease. Disclosures Sekeres: Celgene: Membership on an entity9s Board of Directors or advisory committees. Gerds: Incyte: Consultancy; CTI BioPharma: Consultancy. Advani: Takeda/ Millenium: Research Funding; Pfizer: Consultancy. Maciejewski: Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Other: Speaker Fees; Apellis Pharmaceuticals: Consultancy; Ra Pharma: Consultancy.

Children with Langerhans cell histiocytosis (LCH) and single-bone CNS-risk lesions have been reported to be at increased risk of diabetes insipidus (DI), central nervous system neurodegeneration (CNS-ND), and recurrence of disease. However, it is unknown whether the addition of chemotherapy or radiotherapy changes outcomes in these patients.Ten pediatric institutions across North America and Europe contributed data of their patients with LCH and single-bone CNS-risk lesions. Clinical information on age, sex, specific craniofacial site involvement, and intracranial extension at diagnosis, therapy, and disease course was collected for all eligible patients.The final analysis included 93 eligible children who were either treated with systemic therapy (chemotherapy, chemo-radiotherapy, or radiotherapy) or local therapy (biopsy, curettage, and/or intralesional steroids). Fifty-nine patients had systemic and 34 had local therapy. The 5-year event-free survival (EFS) and overall survival (OS) were 80 ± 5% and 98 ± 2% in the systemic therapy group versus 85 ± 6% and 95 ± 5% in the local therapy group. There was no statistically significant difference between either group with regard to EFS (P = 0.26) and OS (P = 0.78). On multivariable analysis, there was no significant difference among the two treatment groups after adjusting for site and intracranial soft tissue extension, nor any trend favoring systemic therapy (HR = 2.26, 95% CI = 0.77-6.70; P = 0.14).Systemic therapy may not reduce the risk of recurrence or late sequelae in children with LCH and single-bone CNS-risk lesions as compared to local treatment.

African-American (AA) patients have a younger age at diagnosis and worse outcomes compared to Whites (WTs) across many cancers, including acute myeloid and acute lymphoblastic leukemias.1, 2, 3 Although inferior outcomes for AAs compared to WTs may be related to differential access to medical care or socioeconomic status, disease biology and genetic fingerprint may have a role. A recent study from the Cancer Genome Atlas has shown that WT and AA women with stage I to III breast cancer have differences in the genomic landscape that is correlated with a higher incidence of TP53 mutations, fewer PIK3CA mutations and greater intratumor genetic heterogeneity for AA compared to WTs. This finding suggests that the poor outcome of AA women with breast cancer is not only driven by the disease characteristics such as younger age at diagnosis and a higher incidence of triple-negative disease, but also related to differences in the genomic landscape of their disease.

Background Several recurrent somatic mutations have been identified in MDS and these mutations play an important role in disease pathophysiology and outcome. BCOR and BCORL1 are located on chromosome X and interact with histone deacetylases and other cell functions. The BCOR gene is mutated (BCORMUT) in 4-6% of MDS patients (pts) and is associated with poor outcome. BCORL1 mutations (BCORL1MUT ) are present in Methods We sequenced DNA samples from pts with MDS and related myeloid malignancies (MDS/myeloproliferative neoplasms (MPN) and secondary AML) for the presence of BCOR and BCORL1 mutations and 58 other genes that have been described as recurrently mutated in myeloid malignancies. The Revised International Prognostic Scoring System (IPSS-R) was calculated as descried previously. Overall survival (OS) was measured from the time of diagnosis to time of death or last follow up. Variant allele frequencies (VAFs) adjusted by zygosity were used to define architecture of driver clones. Results Of 621 included MDS pts, 29 (5%) had BCOR mutations and 13 (2%) had BCORL1 mutations. Patients with BCOR mutations were younger (median age 63 vs. 68 years, p= .04), and had a lower platelet counts at diagnosis (63 vs. 93 109/L, p = .01) compared to BCORWT pts. Cytogenetic risk categories per IPSS-R for BCORMUT was similar to BCORWT: very good 3% vs. 2%, good 65% vs. 62%, intermediate 10% vs. 17%, poor 13% vs. 7% and very poor 6% vs. 9%, respectively, p = .62). Risk categories per IPSS-R were also similar for BCORMUTcompared toBCORWT:very low 10 vs. 16%, low 31 vs. 40%, intermediate 24 vs. 18%, high 17 vs. 14%, and very high 13 vs. 10%, respectively, p = .69). BCOR mutations were missense in 9 pts (31%), frameshift insertion/deletion in 10 (34%), stopgain in 8 (28%), and nonsense in 2 (6%). BCOR is commonly co-mutated with ASXL1 (p=.008), RUNX1 (p= .0001), NF1 (p =.002), ETV6 (p =.026), BCORL1 (p =.0001), MECOM (p =.021), RAD21 (p =.021), and CEBPA (p = .0001). Clonal architecture analysis identified BCOR mutations as ancestral, subclonal, and mosaic in 41%, 21% and 38% of cases respectively. The median OS for BCORMUT pts was 24.5 months compared to 17.9 months for BCORWT, p = .23). The impact of BCOR mutations on OS was neutral even after adjustment for age and IPSS-R risk categories. Pts with BCORL1MUT had lower WBC counts (median 2.7 vs. 4 109/L p = .02), and lower platelets counts at diagnosis (72 vs. 91 109/L, p = .02) compared to BCORL1WT pts. In cytogenetic analyses, BCORL1MUT was associated with a higher incidence of very good cytogenetics per IPSS-R (15% vs. 2%, p =.001). Further, BCORL1MUT were more likely to be classified in the intermediate risk group per IPSS-R (46 vs. 18%, p = .01) and less likely to be classified in the low risk group (7 vs. 40%, p = .01) compared to BCORL1WT. BCORL1 mutations were missense in 7 patients (53%), frameshift insertion/deletion in 3 (23%), stopgain in 1 (7%), and nonsense in 2 (15%). BCORL1 is commonly co-mutated with TET2 (p =.001), BCOR (p Conclusion BCOR and BCORL1 mutations occur with low frequency in MDS. These mutations can be ancestral or subclonal. The impact of BCOR mutations on OS was neutral even after adjustment for age and IPSS-R risk scores. Although the median OS for pts with BCORL1MUT was longer compared to BCORL1WT,it was not statistically significant. A larger pt population with BCOL1 may show a positive impact of these mutations on OS. Disclosures Mukherjee: Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding. Advani:Blinatumomab: Research Funding; Pfizer Inc.: Consultancy, Research Funding. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.