Citations

AbstractT‐lymphoblastic leukemia/lymphoma (T‐ALL/LBL) accounts for approximately 15% of pediatric and 25% of adult ALL. While the underlying frequency of KMT2A (MLL) gene rearrangements has been identified in approximately 4‐8% of T‐ALL/LBL cases, a paucity of literature is available to characterize further the KMT2A rearrangements in pediatric/young adult T‐ALL/LBL. A 10‐year retrospective review was performed to identify KMT2A rearrangements in specimens sent for T‐ALL/LBL fluorescence in situ hybridization studies in patients under the age of 30 years. Of 806 T‐ALL/LBL FISH studies performed on unique individuals, 27 (3.3%) harbored KMT2A rearrangements. Nineteen patients were male and eight were female (M:F ratio, 2.4:1) with ages ranging from 1 to 20 years (mean 12, median 12). Of the 27 cases, nine (33%) had KMT2A/MLLT1 fusions, eight (30%) had KMT2A/AFDN fusions, two (7%) had KMT2A/ELL fusions, and one (4%) had a KMT2A/MLLT10 fusion. In addition, five (19%) had KMT2A rearrangements with unidentified gene fusion partners and two (7%) had 3’KMT2A deletions. Our results indicate that MLLT1 and AFDN account for the majority (63%) of KMT2A gene partners in pediatric/young adult T‐ALL/LBL, while no KMT2A/AFF1 or KMT2A/MLLT3 fusions were observed despite their common identification in B‐ALL and acute myeloid leukemia, respectively. In addition to diagnostic and prognostic value, detecting specific KMT2A fusions may also be of clinical importance in the era of targeted therapies.

e15168 Background: 2-8% of all colorectal cancer (CRC) cases are in younger adults (YAs), patients (pts) less than age 50. However, current understanding of CRC in YAs is inadequate, especially that of sporadic onset. We conducted a study to describe the landscape of genomic alterations in YA CRC pts presenting to a large academic practice. Methods: Adult pts with CRC presenting to The Ohio State University Comprehensive Cancer Center oncology clinics were offered next generation sequencing (NGS) through a customized 22-gene Ion AmpliSeq Mutation Panel as part of clinical care. Commonly mutated areas of select genes (including AKT1, ALK, BRAF, EGFR, ERBB2/4, FBXW7, FGFR1/2/3, KRAS/NRAS, MET, NOTCH1, PIK3CA, PTEN, TP53) were sequenced from tumor sections. Institutional review board approval was obtained to retrospectively analyze this NGS testing between 1/2013-3/2016. Results: 258 CRC pts underwent genomic profiling. 57 pts (22.1%) were YAs at diagnosis (range 22-49 years); 20 pts (7.8%) were 40 years old or younger. 31 YA pts (54.4%) had metastatic disease. Of the YAs with CRC, 18 pts (31.6%) were diagnosed with R-sided colon, 16 pts (28.1%) with L-sided colon, and 22 pts (38.6%) with rectal cancer. 110 genomic alterations were found in YA pts, with a mean of 1.9 mutations per tumor (range 0-6); 35 (31.8%) of these in 32 (56.1%) YA pts were actionable. Of these 110 alterations, 41.8% were in TP53, 28.2% in KRAS/NRAS, 10.0% in PIK3CA, 3.6% in BRAF, 3.6% in FBXW7, and 2.73% in PTEN. 6 YA pts (10.5%) had microsatellite instability (MSI-H). Only 1 pt had concomitant MSI-H and a BRAF mutation; 4 pts with BRAF mutations were microsatellite stable. Comparing our YA pts to a separate cohort of pts age > 50 who had testing done, no significant difference was seen in mutation incidence in KRAS/NRAS (p = 1.0), TP53 (p = 0.3), PIK3CA (p = 0.128), or BRAF (p = 1.0). Conclusions: Genomic profiling through a targeted NGS panel is feasible as part of routine clinical practice. There is disagreement in the literature on genetic mutations in YA compared to older age CRC pts. Knowledge of the genomic landscape in YAs with CRC will lead to improved understanding of the underlying biology of CRC in YAs as it differs from CRC in older pts, and could impact future care of this cohort.

531 Background: The greatest age disparity in early stage breast cancer (BC) outcomes is in young women with hormone receptor positive (HR+) BC. While differences in biology may play a role, understanding the role of non-persistence (early discontinuation) with endocrine therapy (ET) is critical given the demonstrated efficacy of ET in this population. Methods: As part of a prospective cohort that enrolled women with BC diagnosed (dx) at age ≤40 between 2006-2016, we identified women with HR+, Stage I-III BC. Socio-demographic and treatment information, fertility concerns and confidence with the ET treatment decision were assessed by survey within 1 yr of dx. Medical record review was used to ascertain stage and HR status. Women who initiated ET but did not report taking tamoxifen or an aromatase inhibitor at 3 yrs post-diagnosis (or last follow-up if <3 yrs) were classified as non-persistent. Chi-square tests were used to compare categorical variables between persisters and non-persisters and stepwise multivariable regression to evaluate predictors of non-persistence. Results: In 538 women who initiated ET, median age at dx was 36; 10% were non-persistent. Discontinuation of ET was more likely in those who were less confident with their ET decision compared to those who were more confident (25/179, 14% vs 18/263, 7%, p=0.01). A greater proportion of women concerned about fertility discontinued vs. women not concerned (29/213,14% vs 25/319, 8%, p=0.03), and fertility concerns were associated with non-persistence in multi-variable analyses (OR: 1.85, 95% CI 1.05-3.26, p=0.03). Age at dx, race, education, employment, financial comfort, marital status, parity, stage, chemotherapy and local therapy were not associated with non-persistence. Conclusions: A significant minority of women with HR+ BC discontinued ET within 3 yrs. The association between fertility concerns expressed soon after dx and non-persistence underscores a need to address psychosocial issues that can impact treatment decisions in young women. Strategies to reduce decisional conflict and increasing confidence with the choice to take ET, may influence persistence. Future work will evaluate the contribution of other factors (eg symptom burden) to non-persistence.

526 Background: Young age at diagnosis (dx) is a predictor of worse prognosis in patients (pts) with luminal breast cancer (BC). Poorer adherence to endocrine therapy (ET) among younger women may contribute to this disparity. Aim: To assess non-adherent behaviors and associated factors among young women with stage 1-3 hormone receptor (HR)+ BC taking ET. Methods: This study is a part of a multi-center, prospective cohort of pts with dx of BC at or under age 40. On a survey 30 months after dx, among pts reporting taking ET, adherence was measured using a 3-item Likert-type scale (Do you ever forget to take your ET? If you feel worse when you take your ET, do you stop taking it? Did you take your ET exactly as directed by your doctor?). Pts reporting any non-adherent behavior during the last 3 months were classified as non-adherers. Variables with a p-value <0.20 were included in a multivariate logistic model. Results: Among361 pts eligible for this analysis, 174 (48%) reported some non-adherent behaviors in the last 3 months; 56 (16%) moderate or greater non-adherent behaviors. None of the studied variables was associated with non-adherent behaviors (table). Conclusions: Non-adherent behaviors to ET are present in almost half of the young women with HR+ BC. Further analyses of explanatory factors and impact of non-adherence are required to understand and potentially improve this problem. [Table: see text]

9517 Background: Although PD-1/L1 axis directed therapies induce durable responses in some mm patients (pts), biomarkers of response remain elusive. We hypothesized that quantifying key immune suppression mechanisms within the tumor microenvironment would provide superior predictors of response to anti-PD-1 compared with single marker assessment. Methods: Pre-treatment tumor biopsies from 124 mm pts treated with anti-PD-1 at 7 academic centers were fluorescently stained with multiple immune markers in discovery (n = 24) and validation (n = 100) cohorts. Selected biomarker signatures, PD-1/PD-L1 interaction score (proportion of PD-1+ cells co-localized with PD-L1) and IDO1/HLA-DR co-expression were evaluated for anti-PD-1 treatment response and survival. Slides were imaged using Vectra; biomarker positive cells and their co-localization were objectively quantified in pathologist-selected regions using novel Automated Quantitative Analysis (AQUA) algorithms. Results: In the discovery cohort, high levels of PD-1/PD-L1 interaction score and/or IDO1/HLA-DR coexpression was strongly positively associated with response to anti-PD-1 (p = 0.0005). In contrast, other individual biomarkers (PD-1, PD-L1, CD8) were not associated with response or survival (p > 0.10). This finding was replicated in the validation cohort: pts with high PD-1/PD-L1 and/or IDO1/HLA-DR were more likely to respond to treatment (p = 0.009). These pts also experienced a three-fold increase in progression free survival (hazards ratio (HR) = 0.33; p = 0.003) and overall survival (HR = 0.34; p = 0.004). Multivariate analyses revealed that these findings were independent of BRAF mutation, stage, LDH and prior therapy. In the combined cohort (n = 124), 80% of responding pts had higher levels of PD-1/PD-L1 interaction scores and/or IDO1/HLA-DR. In contrast, PD-L1 expression alone (≥1% or ≥50%) was not predictive of PFS or OS (p > 0.1). Conclusions: This novel multiplexed method profiling key tumor-immune suppression pathways identified mm pts likely to respond to anti-PD-1 therapy. This method could help stratify patients for PD-1 monotherapy and be useful in guiding future clinical trials.