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BACKGROUND: Abnormalities of the PI3kinase/AKT/mTOR signaling network are common in breast cancer (BC) and are associated with endocrine resistance. Everolimus, an mTOR-inhibitor increased PFS when combined with endocrine therapy (ET) in the metastatic setting and is thought to revert endocrine resistance. S1207 is a phase III randomized, placebo-controlled trial evaluating the role of everolimus in combination with ET in the adjuvant setting among patients with high-risk hormone receptor-positive, HER2-negative BC (NCT01674140). METHODS: Eligible patients were >18 years of age with histologically confirmed invasive hormone receptor-positive and HER2-negative high-risk BC. Four risk groups were defined as: 1) > 2cm node-negative disease (or pN1mi), and either an Oncotype DX® Recurrence Score (RS) > 25 or MammaPrint® high-risk category (MP high); 2) 1-3 positive nodes and either RS >25, MP high or a pathological grade 3 tumor; 3) >4 positive lymph nodes. Patients treated with neoadjuvant chemotherapy were eligible if: 4) after surgery had >1 lymph node involvement. Patients were randomized 1:1 to physician’s choice adjuvant ET in combination with one year of everolimus (10 mg PO daily) or ET plus placebo stratified by risk group. The primary endpoint was invasive disease-free survival (IDFS) evaluated by a stratified log-rank test. Secondary endpoints included overall survival (OS) and safety. The hazard ratio (HR) for treatment efficacy was estimated using Cox regression with stratification by risk groups. Subset analyses included preplanned evaluation within risk group and exploratory analyses of menopausal status and age. RESULTS: 1,939 patients were randomized between September 2013 and May 2019, of them 1,792 were eligible and included in the analysis (896 per arm). Primary reason for ineligibility was timing after chemotherapy/radiation or not high risk. Median age was 54 years (22-85) and 32% were premenopausal. With a median follow-up of 50.5 months, there were 389 IDFS events as of May 2022 (data cutoff). 5-year IDFS was 74.8% among patients treated with everolimus and 73.9% among patients treated with placebo, HR=0.93 (95% CI 0.76-1.14). However, the proportional hazards assumption was violated (p=0.02) suggesting differential treatment effect over time. The HR during the one year of treatment was 0.72 (95% CI 0.47-1.10) while after one year it was 1.00 (95% CI 0.80-1.26). The 5-year OS was 87.6% in the everolimus arm and 85.5% in the placebo arm, HR=0.98 (95% CI 0.75-1.28). Analysis by risk group did not show higher everolimus benefit as risk increased. No difference in IDFS or OS was seen among postmenopausal patients (IDFS HR=1.08 [95% CI 0.85-1.36], OS HR=1.19 [95% CI 0.87-1.61]). Among premenopausal patients, everolimus was associated with improved IDFS (HR=0.63 [95% CI 0.43-0.93]) and OS (HR=0.48 [95% CI 0.26-0.88]). Treatment completion of randomized therapy was lower in the everolimus arm compared to placebo (47.9% v 72.7%). Grade 3 and 4 toxicities were noted in 6.5% and 0.5% of patients in the placebo arm and in 31.2% and 3.7% in the everolimus arm respectively. CONCLUSIONS: Addition of one year of adjuvant everolimus to standard adjuvant ET did not improve IDFS or OS and was associated with low completion rate and increased AEs. Among premenopausal patients there was a benefit in IDFS and OS that is hypothesis generating. Future translational studies will evaluate potential predictors of everolimus benefit and drug toxicity. Citation Format: Marianna Chavez, Jieling Miao, Lajos Pusztai, Matthew P. Goetz, Priya Rastogi, Patricia A. Ganz, Eleftherios (Terry) Mamounas, Soonmyung Paik, Hanna Bandos, Wajeeha Razaq, Anne O’Dea, Virginia Kaklamani, Andrea L.M. Silber, Lisa E. Flaum, Eleni Andreopolu, Joseph Baar, Albert G. Wendt, Jennifer F. Carney, Priyanka Sharma, Julie R. Gralow, Danika L. Lew, William E. Barlow, Gabriel N. Hortobagyi. Results from a phase III randomized, placebo-controlled clinical trial evaluating adjuvant endocrine therapy +/- 1 year of everolimus in patients with high-risk hormone receptor-positive, HER2-negative breast cancer: SWOG S1207 [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 GS1-07. more...

Adjuvant therapy; Breast cancer; Olaparib Terapia adyuvante; Cáncer de mama; Olaparib Teràpia adjuvant; Càncer de mama; Olaparib Background The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI −0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals. Funding for this work, which was conducted as a collaborative partnership among the Breast International Group, NRG Oncology, Frontier Science, AstraZeneca, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A. (MSD), was provided by the National Institutes of Health (grant numbers: U10CA 180868, UG1CA 189867, and U10CA 180822) and by AstraZeneca as part of an alliance between AstraZeneca and MSD. Provision of olaparib and placebo was from AstraZeneca. more...

PURPOSE Distant metastases are present in 6% or more of patients with newly diagnosed breast cancer. In this context, locoregional therapy for the intact primary tumor has been hypothesized to improve overall survival (OS), but clinical trials have reported conflicting results. METHODS Women presenting with metastatic breast cancer and an intact primary tumor received systemic therapy for 4-8 months; if no disease progression occurred, they were randomly assigned to locoregional therapy for the primary site (surgery and radiotherapy per standards for nonmetastatic disease) or continuing sysmetic therapy. The primary end point was OS; locoregional control and quality of life were secondary end points. The trial design provided 85% power to detect a 19.3% absolute difference in the 3-year OS rate in randomly assigned patients. The stratified log-rank test and Cox proportional hazards model were used to compare OS between arms. Cumulative incidence of locoregional progression was compared using Gray's test. Quality-of-life assessment used standard instruments. RESULTS Of 390 participants enrolled, 256 were randomly assigned: 131 to continued systemic therapy and 125 to early locoregional therapy. The 3-year OS was 67.9% without and 68.4% with early locoregional therapy (hazard ratio = 1.11; 90% CI, 0.82 to 1.52; P = .57). The median OS was 53.1 months (95% CI, 47.9 to not estimable) in the systemic therapy arm and 54.9 months (95% CI, 46.7 to not estimable) in the locoregional therapy arm. Locoregional progression was less frequent in those randomly assigned to locoregional therapy (3-year rate: 16.3% v 39.8%; P < .001). Quality-of-life measures were largely similar between arms. CONCLUSION Early locoregional therapy for the primary site did not improve survival in patients presenting with metastatic breast cancer. Although it was associated with improved locoregional control, this had no overall impact on quality of life. more...

Background: NET is offered to postmenopausal patients (pts) with clinical stage 2/3 ER+/HER2- BC to promote breast-conserving surgery. Also limited surgical accessibility during the COVID19 pandemic has increased NET utility. Inability to identify ET-resistant disease at diagnosis risks disease progression (PD) and delays more effective treatments. Dowsett et al. recently demonstrated that baseline levels of ER, progesterone receptor (PR), Ki67 (>15% vs ≤15%), and Ki67 (>10% vs ≤10%) 2-4 weeks (wks) after starting NET may improve appropriate patient (pt) selection for NET (PMC7280290). The ER, PR and Ki67-based prediction model divides pts with primary ER+/HER2- BC into 3 groups for appropriateness for NET: (Group 1) NET is likely to be inappropriate (Allred ER 10% has been associated with worse outcome (PMC5455353), or (Group 3) NET is appropriate (ER 8 and PgR ≥6). The ALTERNATE trial (NCT01953588) randomized postmenopausal women with clinical stage II or III, ER+ (Allred score 6-8)/HER2- BC to receive anastrozole (ANA), fulvestrant (FUL), or ANA + FUL for 6 months, unless Ki67 was >10% on wk 4 or 12 biopsy, in which case pts were triaged to receive neoadjuvant chemotherapy (NCT) or surgery. As previously reported, the ET-sensitive disease (mPEPI 0 plus pCR) rates were similar across the treatment arms and overall 22% (286 of 1,299) pts had Ki67 >10% at wk 4 or 12. The ALTERNATE trial therefore provides a large independent data set to evaluate the NET appropriateness model. Results: Among 1,299 eligible pts randomized to receive 6 months of NET, 214 were excluded due to absent HR Allred score (n=41) or absence of pre-treatment and wk 4 Ki67 determinations (n=173). The proportions of the remaining 1,085 pts in Group 1, 2 and 3 were 1% (n=10), 43% (n= 468), and 56% (n=607), respectively. On-study Ki67 >10% prompting conversion from NET to NCT/Surgery occurred in: Group 1 90% (9 of 10), Group 2 30% (141 of 468), and Group 3 17% (104 of 607) (Table 1). Among the 1,075 pts in Groups 2 and 3, 260 (24%) pts had Ki67 ≤15% at baseline (BL), among whom only 14 (5.4%) had Ki67 >10% at wk 4, compared to 231 of the 815 (28.3%) who had BL Ki67 >15% and subsequent Ki67 >10% at wk 4. 2% of pts who remained on NET due to on-treatment Ki67 Conclusion: ALTERNATE trial data support a model whereby levels of ER, PR and Ki67 at diagnosis can be used for the identification of postmenopausal pts with primary ER+/HER2- BC who are appropriate for NET. When baseline ER Allred scores are >6 and Ki67 ≤15%, there is a low likelihood of ET-resistant disease. When BL Ki67 is >15%, ET sensitivity is variable, and on-treatment biopsy for Ki67 may assist in triaging regarding NET appropriateness, particularly given the extremely low local PD rates seen in ALTERNATE when on-treatment Ki67 was Table 1 Baseline levels of ER, PR, and Ki67 in Relation to Wk 4 Ki67 (N=1,085)BaselineWeek 4GroupNERAllred ScorePRAllred ScoreKi67Ki67 ≤10%N (%)Ki67 >10%N (%)1N=2615%1 (12.5%)7 (87.5%)2AN=647 or 815%148 (63%)87 (37%)2BN=466 or 7≥6≤15%42 (91.3%)4 (8.7%)51 (30.2)N=1236 or 7≥6>15%76 (61.8%)47 (38.2%)3N=1508≥6≤15%143 (95.3%)7 (4.7%)104 (17.1)N=4578≥6>15%360 (78.8%)97 (21.2%) Citation Format: Matthew J Ellis, Vera Suman, A. Marilyn Leitch, Souzan Sanati, Kiran Vij, Gary W Unzeitig, Jeremy Hoog, Mark Watson, Olwen Hahn, Joseph Guenther, Abigail Caudle, Erika Crouch, Horacio Maluf, Mitch Dowsett, Amy Tiersten, Monica Mita, Wajeeha Razaq, Tina J Hieken, Yang Wang, Travis Dockter, Jo Anne Zujewski, Anna Weiss, Clifford Hudis, Eric P Winer, Kelly Hunt, Ann H Partridge, Cynthia X Ma, Lisa A Carey. Validation of a predictive model for potential response to neoadjuvant endocrine therapy (NET) in postmenopausal women with clinical stage II or III estrogen receptor positive (ER+) and HER2 negative (HER2-) breast cancer (BC): An ALTERNATE trial analysis (Alliance A011106) [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 PD2-10. more...

Background: In patients with hormone receptor-positive metastatic breast cancer, palbociclib has been shown to improve overall survival and progression-free survival (PFS) when combined with endocrine therapy. Dose modification of palbociclib is effective in the management of adverse events. Despite variable clinical response, no predictive biomarkers of efficacy to palbociclib have been identified in metastatic breast cancer. In our study, we aimed to assess the PFS of metastatic breast cancer patients who received dose-reduced palbociclib and compare the results in the non-dose-reduced group. We also evaluated the clinical significance of progesterone receptor (PR) and Ki67 as predictive biomarkers of palbociclib. Methods: Seventy-six palbociclib-treated metastatic breast cancer patients were included in our study. PFS was compared between dose-reduced and non-dose-reduced groups. PR expression and Ki67 status were assessed by immunohistochemistry. Kaplan-Meier method and log-rank test were used to analyze PFS. Results: Of the 76 patients, 40 (52.6%) experienced dose reduction (DR). Statistical analysis of the results revealed that there were no statistically significant differences observed between dose-reduced (16.5 months) versus non-dose-reduced (17.7 months) patients in PFS (p = 0.5493). For patients with Ki67 ≥14%, PFS was 15.2 months (95% CI: 10.2–22.2 months; p = 0.3024). In patients with PR ≥20%, median PFS was 25.0 months (lower 95% CI: 16.8 months; p = 0.0069). Conclusion: Our study indicated that DR of palbociclib is frequently required but does not appear to affect PFS. PR expression was suggested to be a significant predictive factor for palbociclib responsiveness. more...

Introduction: The ALTERNATE trial randomized postmenopausal women with ER Allred 6-8 HER2- breast cancer to 6 months of NET with anastrozole (A), fulvestrant (F) or the combination (A+F). Biopsies were taken preNET and after 4-weeks(wks). Patients with Ki67 values >10% at 4-wks were offered triage to neoadjuvant chemotherapy. Patients with on-treatment Ki67 ≤ 10% who completed NET underwent surgery and Ki67 was reassessed. The primary endpoint was endocrine-sensitive disease rate (ESDR). ESD is defined as pCR or PEPI-0 residual disease (pT1-2, pN0, Ki67 ≤ 2.7%). We previously reported that the ESDR difference between the F-containing arms and the A arm was not >10% (ASCO 2020) and that baseline RNA-seq-based intrinsic subtypes predicted outcomes overall (SABCS 2021). Herein we describe relationships between PAM50 intrinsic subtype and Ki67 values by treatment arm because comparative drug effectiveness in adjuvant endocrine therapy studies in ER+ HER2- breast cancer can be predicted by the degree of Ki67 suppression (PMC3518447). Methods: 743 of the 1297 eligible patients (A: 264; F: 231; A+F: 248) had RNA extracted from preNET frozen tumor biopsies with >50% tumor content and subjected to RNA seq. Intrinsic subtypes were then assigned as LumA, LumB, and NonLum (Basal or HER2-E) using open-source PAM50-based informatics. Differences in the proportion with wk4 Ki67 > 10%, % change in wk4 ki67, and surgical CCCA (Ki67 ≤ 2.7%) rate (sxCCCA) between treatments and by intrinsic subtype was assessed using stratified logistic regression, Wilcoxon rank sum test, and Fisher’s exact test, respectively. Analysis of sxCCCA excluded those who failed to complete NET for reasons other than disease progression or early Ki67 >10%. Results: Amongst the 358 LumA cases there were no significant differences in Ki67-based endpoints between treatments. Among the 292 LumB cases, the wk4 ki67 > 10% rate was lower with A+F (19.4%) than A (43%) (P=0.0002) and was somewhat lower in F (31%) versus A (P=0.076). The % change in wk4 Ki67 in LumB cases, adjusted for baseline Ki67, showed markedly superior suppression for A+F versus A (-90% vs. -77%; P= Conclusion: The combination of A+F was significantly more effective than either drug alone for the control of LumB breast cancer cell proliferation. This suggests that A+F may be a more effective adjuvant endocrine therapy than A alone in LumB disease. The lower Ki67 suppression with A alone also suggests that poorer outcome in some LumB tumors may be due to insufficient ER targeting rather than ER-independent tumor growth Support: U10CA180821, U10CA180882, U24CA196171, UG1CA189856, U10CA180868 (NRG), NCI BIQSFP, BCRF, Genentech, AstraZeneca. https://acknowledgments.alliancefound.org. (MJE) CPRIT RR140033, P50-CA186784, P50-CA58223, U01-CA214125, U24-CA210954, Gift from Ralph and Lisa Eads, McNair Scholarship. ClinicalTrials.gov Identifier: NCT01953588 Citation Format: Matthew J. Ellis, Meenakshi Anurag, Jeremy Hoog, Aranzazu Fernandez-Martinez, Cheng Fan, Richard Gibbs, Souzan Sanati, Kiran Vij, Mark Watson, Travis Dockter, Olwen Hahn, Joseph Guenther, Abigail Caudle, Erica Crouch, Amy Tiersten, Monica Mita, Wajeeha Razaq, Tina J. Hieken, Yang Wang, A. Marilyn Leitch, Gary W. Unzeitig, Eric Winer, Anna Weiss, Kelly Hunt, Ann H. Partridge, Charles M. Perou, Vera Suman, Cynthia X. Ma, Lisa A. Carey. The effect of intrinsic subtype on inhibition of tumor growth by anastrozole vs. fulvestrant vs. the combination: Results from the Alliance neoadjuvant endocrine therapy (NET) ALTERNATE trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT026. more...

TPS1128 Background: Metastatic (met) TNBC remains a clinical challenge with limited treatment options and inevitable chemoresistance. Aberrant PI3K pathway signaling is frequently observed in TNBC. Increasing evidence shows PI3K pathway activation maintains the stemness and chemoresistance of BC stem cells (CSCs), and PI3K inhibition sensitizes CSCs to chemotherapy (chemo). Eribulin (E), a non-taxane microtubule dynamics inhibitor, showed survival benefit in met HER2 negative BC. Preclinically, E impacts tumor vascular remodeling, inhibits epithelial-to-mesenchymal transition and metastasis – key mechanisms implicated in PI3K inhibition resistance. Copanlisib (C), a potent pan-class I PI3K inhibitor ( i), improved anti-tumor effect in E-sensitive and resistant TNBC patient-derived xenograft models, irrespective of PIK3CA/PTEN mutation (mut) status, when combined with E. This phase I/II study is aimed to determine the safety and efficacy of E+C in pts with met TNBC. Methods: This trial includes a phase I portion with the primary objective to determine the dose limiting toxicity (DLT) and recommended phase 2 dose (RP2D) of E+C, followed by a phase II randomized portion of E+C (at RP2D) versus ( vs) E with the primary objective of progression-free survival (PFS). Key secondary objectives include objective response rate (ORR) and clinical benefit rate (CBR) [phase I]; and ORR and CBR, by arm and by PIK3CA/PTEN mut status and assessment of treatment induced target engagement [phase II]. Key exploratory objectives include analysis of genomic, proteomic and metabolomic changes as potential response biomarkers in tumor tissue and blood. Key eligibility criteria include pts with: met TNBC who progressed on ≤5 chemo lines, including anthracycline/taxane (unless contraindicated), ECOG 0-1, adequate organ function and known archival tumor PIK3CA/PTEN mut status. Key exclusions: prior E or PI3K/mTOR/AKT i, grade ≥2 neuropathy, tumor AKT mut, congenital QT prolongation, and uncontrolled diabetes or hypertension. Phase I portion will follow a 3+3 design for E+C dose escalation to enroll 18 max pts, starting at E 1.1 mg/m2 IV and C 45 mg IV on days (D) 1/8 of 21-D cycle (C) (to E 1.4 mg/m2 and C 60 mg max). RP2D will be defined as the highest dose level at which at most 1 of 6 pts experience DLT during C1. 88 pts will be randomized (1:1) in the phase II portion to E+C vs E (1.4 mg/m2 D 1/8), stratified by PTEN/PIK3CA mut status. Response assessment by Response Evaluation Criteria in solid tumors (RECIST) v1.1 will occur every 9 weeks (+/-7 D). Tumor biopsy is required at baseline and C2D1-2, and optional at progression. A sample size of 88 achieves 80% power to detect PFS difference of median PFS 6.95 vs 4 months (corresponding to a hazard ratio of 0.5755) between the 2 arms, based on 1-sided two-sample log rank test at 0.1 α level. The phase I study is actively enrolling pts. Clinical trial information: NCT04345913. more...

Background: Neoadjuvant ET (NET) offers an opportunity to assess ET sensitivity for ER+ HER2- BC and potentially to tailor therapy. Ki67 >10% on biopsy after 2-4 weeks (wks) of NET identifies patients (pts) with intrinsic ET resistance; while pathologic complete response (pCR) and modified preoperative endocrine prognostic index of 0 (mPEPI 0: pT1-2N0, Ki67 ≤2.7%) at surgery indicates sensitivity to ET. However, on-NET biopsy is not always acceptable or feasible and delays the ET sensitivity determination. PAM50 ROR score and intrinsic subtypes by tumor RNA profiling are prognostic in pts with early stage ER+ HER2- BC, and predict pCR rates to neoadjuvant chemotherapy (NCT) (PMC2667820). We therefore hypothesized that PAM50 analysis on pre-NET biopsies could predict the likelihood of a) a high on-NET Ki67, b) mPEPI-0 or pCR at surgery and, c) pCR for pts triaged to NCT. Methods: The ALTERNATE trial is a phase III study that randomized postmenopausal pts with clinical stage II/III ER+ (Allred score 6-8) HER2- BC to receive neoadjuvant anastrozole, fulvestrant, or both for 6 months before surgery. Research biopsy was required at pre-NET and wk 4, then optional at wk 12. Pts with Ki67 >10% on biopsy at wk 4 or 12 discontinued NET and were offered NCT. PAM50 intrinsic subtype and ROR-P values were generated from mRNA sequencing (RNASeq) analysis on pre-NET biopsies using open-source informatics (PMC7723687) and evaluated for prediction of on-NET Ki67 >10% at wk 4 or 12, pCR or mPEPI-0 post NET, and pCR post NCT. Results: 749 of 1,297 eligible trial pts were included in the analyses, after excluding 548 pts due to insufficient pre-NET tumor for RNASeq (n=511) or PAM50 normal subtype (n=37). Similar to the entire ALTERNATE population, the rate of Ki67 >10% at wk 4 or 12 was 24.4% (95% CI: 21.4-27.7%) and the rate of mPEPI-0/pCR post NET was 19.8% (95% CI: 17.0-22.8%). There were 393 (52.5%) Lum A, 302 (40.3%) Lum B, and 54 (7.2%) non-Lum (9 Basal, 45 HER2-E) BCs. These included 196 (26.2%) ROR-P low, 354 (47.3%) ROR-P medium and 199 (26.6%) ROR-P high BCs. Both the rates of Ki67 >10% at wk 4 or 12 and mPEPI-0/pCR differed significantly with respect to PAM50 subtype or ROR-P category, such that Lum A or ROR-P low BCs were least likely to have a Ki67 >10% at wk 4 or 12 and most likely to achieve mPEPI-0/pCR (Table). 93 of 168 (55.4%) pts triaged to NCT had RNA-seq results, yielding 26 Lum A, 49 Lum B, 4 Basal and 14 HER2-E, with the pCR rates of 0%, 6.1%, 0%, and 21.4%, respectively. There were 10 ROR-P low, 39 medium, and 44 high tumors, with a pCR rate of 0%, 5.1% and 9.1%, respectively. Conclusion: These data indicate that both baseline ROR-P and intrinsic subtype are predictive of early on-NET Ki67 > 10% and mPEPI 0/pCR at surgery after NET. For pts triaged to NCT based on an early on-NET Ki67 >10%, the HER2-E group had the highest pCR rate (20%) and no pCRs were observed in Lum A. These data may be useful for directing neoadjuvant therapy in postmenopausal pts with ER+ HER2- BC. Support: U10CA180821, U10CA180882, U24CA196171, UG1CA189856, U10CA180868 (NRG), NCI BIQSFP, BCRF, Genentech, AstraZeneca. https://acknowledgments.alliancefound.org. (MJE) CPRIT RR140033, P50CA186784, P50-CA58223, U01 CA214125, U24CA210954, Gift from Ralph and Lisa Eads, McNair Scholarship. Trials.gov Identifier: NCT01953588. Table 1.Rates of Ki67 >10% and mPEPI-0/pCR post NET by PAM50 subtype and ROR-P categoryKi67 >10% at wk 4 or 12mPEPI 0/pCR post NETPAM50 SubtypenYes, n (%)PnNo, n (%)PLum A37251 (13.7%) 95% CI: 10.4-17.6% Citation Format: Cynthia X Ma, Meenakshi Anurag, Travis Dockter, Jeremy Hoog, Aranzazu Fernandez-Martinez, Cheng Fan, Richard Gibbs, Souzan Sanati, Kiran Vij, Mark Watson, Olwen Hahn, Joseph Guenther, Abigail Caudle, Erika Crouch, Amy Tiersten, Monica Mita, Wajeeha Razaq, Tina J Hieken, Yang Wang, A. Marilyn Leitch, Gary W Unzeitig, Anna Weiss, Eric P Winer, Kelly Hunt, Ann H Partridge, Lisa A Carey, Charles M Perou, Matthew J Ellis, Vera Suman. Pam50 intrinsic subtype and risk of recurrence score (ROR) for the prediction of endocrine (ET) sensitivity and pathologic response to chemotherapy in postmenopausal women with clinical stage II/III estrogen receptor positive (ER+) and HER2 negative (HER2-) breast cancer (BC) in the alternate trial (Alliance A011106) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD9-03. more...

Background: Ki67 values >10% 2-4 weeks (wks) after starting neoadjuvant ET (NET) indicates persistent cell proliferation, resistance to ET, and is associated with increased risk of recurrence. The ACOSOG Z1031 trial suggested that these tumors are also relatively chemotherapy (chemo) resistant with a low pathologic complete response (pCR) rate to NCT. The ALTERNATE trial (NCT01953588) is a randomized study of neoadjuvant anastrozole (ANA), fulvestrant (FUL), or ANA + FUL in postmenopausal patients (pt) with newly diagnosed clinical stage II or III ER+ (Allred score 6-8)/HER2- BC. Ki67 >10% at wk 4 or 12 after starting NET triggered triage to NCT of physician choice or weekly paclitaxel. Pts who refused protocol-directed therapy, were not candidates for NCT, or decided to undergo immediate surgery are being followed per protocol. Here we report the rates of pCR and residual cancer burden (RCB) following NCT for pts triaged to NCT due to Ki67 >10% at wk 4 or 12. Results: Of the 1,299 eligible pts randomized to receive ANA, FUL, or ANA + FUL, 286 (22%) had Ki67 >10% at wk 4 or 12. 168 of these 286 pts (58.7%) chose to switch to NCT, 32 went to surgery (11.2%), and 86 discontinued further protocol-directed therapy (30.1%). Among the 168 pts who underwent NCT, the presenting clinical T stages were cT2 (n=113; 67.26%), cT3 (n=47; 27.98%) and cT4 (n=8; 4.76%) and N stages were cN0 (n=82; 48.8%), cN1 (n=75; 44.6%), cN2/3 (n=9; 5.4%) and cNx (n=2; 1.2%). Central ER testing was performed on pre-treatment biopsies and confirmed ER Allred score 6-8 in 155 of 168 (92.2%) pts, with the rest being ER Allred score 4-5 (n=5; 3%), ER- (Allred score 0) (n=2; 1.2%), or not tested (n=6; 3.6%). Most (n=139; 82.7%) were ER+/PR+, while 17.3% (n=29) were ER+/PR-, and tumor grades were G1 (n=10; 6%), G2 (n=99; 58.9%), G3 (n=54; 32.1%), not reported (n=5; 3%). Baseline Ki67 levels prior to NET were >10% in 94% (n=158), ≤10% in 3% (n=5), and not done in 3% (n=5). NCT regimens administered included doxorubicin/cyclophosphamide (AC) followed by paclitaxel (T) (n=60; 35.71%); weekly paclitaxel (n=56; 33.33%), docetaxel/cyclophosphamide (TC) (n=33; 19.65%), other doxorubicin and/or taxane containing regimen (n=17; 10.12%), and cyclophosphamide/methotrexate/fluorouracil (CMF) (n=2; 1.19%). 35 (20.8%) pts did not complete planned course of NCT due to toxicity (n=27) or refusal (n=8). 154 NCT pts underwent surgery (mastectomy in 40.3%, and breast conserving surgery in 59.7%). The path ypT stages were Tis/0 (n=10; 6.5%), T1 (n=62; 40.3%), T2 (n=61; 39.6%), and T3/4 (n=21; 13.6%), and the ypN stages were N0 (n=66; 42.9%), N1 (n=57; 37%), N2/3 (n=30; 19.5%), and Nx (n=1; 0.6%). Among the 168 pts who started on NCT (intent to treat population), there were 8 pCRs (no invasive disease in the breast or lymph nodes) (4.8%; 95% CI: 2.1% to 9.2%). Residual Cancer Burden (RCB) categories include RCB 0 (n=8; 4.8%), RCB 1 (n=15; 8.9%), RCB 2 (n=82; 48.8%), RCB 3 (n=42; 25.0%), and not determined (n=21; 12.5%). Correlations of baseline pt and tumor characteristics with pathology response to NCT will also be presented. Conclusion: In pts with NET-resistant ER+/HER2- BC, salvage NCT is not likely to induce a complete or near complete response. More effective treatments are needed for this high-risk ER+/HER2- pt population. Support: U10CA180821, U10CA180882, U24CA196171, UG1CA189856, U10CA180868 (NRG); NCI BIQSFP, BCRF, Genentech, AstraZeneca. https://acknowledgments.alliancefound.org. Clinical Trials.gov Identifier: NCT01953588 Citation Format: Cynthia X Ma, Vera Suman, A. Marilyn Leitch, Souzan Sanati, Kiran Vij, Gary W Unzeitig, Jeremy Hoog, Mark Watson, Olwen Hahn, Joseph Guenther, Abigail Caudle, Erika Crouch, Horacio Maluf, Amy Tiersten, Monica Mita, Wajeeha Razaq, Tina J Hieken, Yang Wang, Travis Dockter, Jo Anne Zujewski, Anna Weiss, Kelly Hunt, Clifford Hudis, Eric P Winer, Matthew J Ellis, Lisa A Carey, Ann H Partridge. Neoadjuvant chemotherapy (NCT) response in postmenopausal women with clinical stage II or III estrogen receptor positive (ER+) and HER2 negative (HER2-) breast cancer (BC) resistant to endocrine therapy (ET) in the ALTERNATE trial (Alliance A011106) [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 GS4-05. more...

Background: Cognitive complaints (“chemo brain”) are reported frequently after breast cancer treatment but little is known about its incidence and causes. Before we can intervene we need to be able to diagnose it properly. Mini Mental state examination (MMSE) can detect advanced Alzheimer's but won't help in detecting mild cognitive disturbances. We used Montreal Cognitive Assessment for Telephone (MoCA-T) and full scale Montreal Cognitive Assessment for Telephone (MoCA) to diagnose mild cognitive impairments in patients having normal MMSE. Methods: 20 breast cancer survivors aged 50 years or older completed MoCA-T and MoCA, a year after they completed their treatment for breast cancer, describing the impact of their treatment regimen on their short term memory and ability to think and concentrate. On Day 5, they underwent a standardized laboratory protocol that assessed both behavioral and electroencephalographic (EEG) indicators of memory consolidation. Results: Patient characteristics: 20 postmenopausal breast cancer survivors aged 50 or above participated in the study a year after they completed their therapy. We are reporting preliminary results of 10 patients. Patients had stage I-III disease (stage I – One patient, Stage II – five patients, and stage III- four patients). All of them received various chemo regimens e.g. Cytoxan, methotrexate, 5-FU (CMF), Taxol, Trastuzumab (TH), Adriamycin (AC), taxotere, carboplatin (TCH). 8/10 patients received adjuvant radiation. 1/10 patient underwent reconstruction later. 7/10 patients received hormonal therapy with aromatase inhibitors. Results of MoCA –T and MoCA: MoCA-T, tests attention and concentration, executive functions, memory, language, conceptual thinking, calculations, and orientation. Possible scores range from 0-22 and scores 26 is normal but 5/10 patients had abnormal MoCA and 3/10 patients had impaired MoCA-T signifying that almost 50%patients develop mild cognitive impairment after breast cancer treatment. During memory consolidation, EEG contained less theta and frequent bursts of alpha waves which is commonly seen in patients with neuropathic pain and insomnia. MoCA-T and MoCA results for the patientsPatient no.MoCA-TMoCAPtient 00817*23*Patient 0102126Patient 0111923*Patient 01216*27Patient 0132027Patient 01517*21*Patient 0161824*Patient 0172025*Patient 0191926Patient 0202129*presents affected patient Conclusions: The study signifies that mild cognitive impairment from breast cancer treatment (or “chemo brain”) was frequently reported and MoCA-T and MoCA tests were able to show even mild cognitive impairment in these patients. We are compiling our full data for EEG but the early results show that the patients had less theta but had frequent bursts of alpha waves, a pattern seen commonly in patients with insomnia and neuropathic pain. They retain fewer items and take more time responding to items as compared to normal people. We need more studies to diagnose and treat mild cognitive impairment (“chemo brain”) in breast survivors as most of these patients are still working and can be a valuable part of the community. Citation Format: Razaq WA, Tanaka T, Carlson B, Wenger M, Friedman J, Benbrook D, Craft M. Diagnosing cognitive impairment (“chemo brain”) in breast cancer survivors [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-20-09. more...

LBA2 Background: About 6% of newly diagnosed breast cancer patients present with Stage IV disease and an intact primary tumor (IPT). Locoregional treatment (LRT) for the IPT is hypothesized to improve survival based on retrospective analyses, but randomized trials have provided conflicting data. We now report the results of E2108, a Phase 3 trial that examined the worth of LRT for the IPT following initial systemic therapy. Methods: Stage IV patients with IPT were registered, treated with optimal systemic therapy (OST) based on patient and tumor characteristics; those who did not progress during 4-8 months of OST were randomized to LRT for the IPT, or no LRT. The primary endpoint was overall survival (OS), with locoregional disease control as a secondary endpoint. Stratified log rank test and Cox proportional hazard model were used to compare OS between treatment groups. Cumulative incidence of locoregional recurrence/progression was estimated and Gray test was used for treatment group comparisons. The trial was designed to detect an improvement in 3 year OS rate from 30% with OST alone to 49.3% for OST+LRT (power 95%, 1-sided alpha 0.05) with full information expected after 152 deaths; the data monitoring committee recommended data release after 80% of full information. Results: 390 patients were enrolled between 2/8/11 and 7/23/15, and received OST. Of these, 256 eligible patients were randomized to either continued OST alone (N = 131) or OST+LRT (N = 125).There were 121 deaths and 43 locoregional progression events after a median follow up 59 months (range: 0-91). There was no significant difference in OS (3-year OS rate 68.4% in OST+LRT vs. 67.9% OST alone arm, stratified log-rank p = 0.63, HR = 1.09, 90% CI: 0.80, 1.49) or in progression-free survival (p = 0.40). The locoregional recurrence/progression was significantly higher in the OST alone arm (3-year rate 25.6% vs 10.2%, Gray test p = 0.003). Health-related quality of life (HRQOL) measured by FACT-B Trial Outcome Index was significantly worse in the OST+LRT arm than OST alone arm at 18 months post randomization (60% completion, Wilcoxon rank sum test p = 0.01), but no difference was observed at time points 6 months (74% completion) or 30 months (56% completion). Conclusions: Early local therapy does not improve survival in patients with de novo metastatic breast cancer and an IPT. Although there was a 2.5-fold higher risk of local disease progression without LRT, LRT of the IPT did not lead to improved HRQOL. Clinical trial information: NCT01242800 . more...

Chemotherapy destroys cells indiscriminantly and releases proinflammatory factors into the bloodstream that can adhere to endothelial cells (ECs); resulting in phenotypical changes consistent with “accelerated vascular aging”. This pilot study examined associations between markers of EC integrity, vascular aging, and cognition in 15 female breast cancer survivors 12–18 months after chemotherapy (median age: 57 years) and 2 non-cancer controls (58/59 years). EC integrity was evaluated using frequency-dependent electrical impedance (Z4000Hz) and levels of apoptosis (caspase-3/7), inflammation (NFkB activation), and oxidative stress (NRF2 activation) in cultured human endothelial cells (EC) exposed to the subject’s serum. Vascular aging was characterized by low serum insulin growth factor ([IGF1a] more...

Advances in breast cancer treatment have markedly increased survivorship over the past three decades, with over 3.1 million survivors expected to live into their 70s and 80s. Without symptom relief interventions, nearly 35% of these survivors will have life-altering and distressing cognitive symptoms. This pilot study explored associations between serum markers of vascular aging, laterality in cerebral oxygenation, and severity of cognitive impairment in women, 12-18 months after chemotherapy for stage 2/3 invasive ductal breast cancer. Fifteen women (52-84 years) underwent a brief cognitive assessment (Montreal Cognitive Assessment [MOCA]) and blood draws to assess markers of vascular aging (interleukin-6 [IL-6], tumor necrosis factor alpha [TNF-α], C-reactive protein [CRP], and insulin growth factor-1 [IGF-1]). All underwent a computer-based test protocol that is known to increase blood flow within the frontal lobes. Percent cerebral oxyhemoglobin saturation (rcSO2) was recorded during and after testing. Laterality in rcSO2 was defined by ≥ 3% difference between left and right rcSO2 (|rcSO2 meanRIGHT - meanLEFT|). Eight participants had MOCA scores between 21 and 25 points, suggestive of mild cognitive impairment. Neither CRP (r = -.24) nor IL-6 (r = .34) nor TNF-α (r = .002) were associated with MOCA scores. Higher IL-6 was associated with greater laterality (r = .41). MOCA scores were significantly lower in subjects with laterality in rcSO2 than in those without laterality (F(1,14) = 13.5, p = 003). Lower IGF-1 was significantly associated with greater laterality (r = - .66, p = .007) and lower cognitive function (r = .58). These findings suggest that persistent cognitive impairment is associated with phenotypical changes consistent with accelerated vascular aging. more...

Background Despite adjuvant radiotherapy, survival outcomes remain poor in patients with salivary gland malignancies who have multiple poor prognostic factors. This study aimed to determine which patients may benefit from treatment intensification. Patients and methods Patients who underwent curative resection with or without adjuvant radiotherapy between 2002 and 2014 were identified and a retrospective chart review was performed. Overall survival (OS) and disease-free survival (DFS) were the main outcomes measured. Results A total of 95 patients met the inclusion criteria. The median follow-up was 46.8 months. The median age was 60 years. Radiotherapy was given to 78 patients. Multivariate analysis revealed that male sex and perineural invasion significantly reduced overall and disease-free survival. Distant metastases comprised of 67% of recurrences and 33% were locoregional. Conclusion Adjuvant chemoradiotherapy should be considered for patients with tumors with perineural invasion, especially in males with high-risk histopathology or high-grade, late-stage disease. To our knowledge, this is the first study to assess the impact of pack-year smoking history on survival outcomes. more...

Cancer metastasis to the bone develops commonly in patients with various malignancies, and is a major cause of morbidity and diminished quality of life in many affected patients. Emerging treatments for metastatic bone disease have arisen from advances in our understanding of the unique cellular and molecular mechanisms that contribute to the bone metastasis. The tendency of cancer cells to metastasize to bone is probably the end result of many factors including vascular pathways, the highly vascular nature of the bone marrow (which increases the probability that cancer cells will be deposited in bone marrow capillaries), and molecular characteristics of the cancer cells that allow them to adapt to the bone marrow microenvironment. The goals of treating osseous metastases are manifold. Proper treatment can lead to significant improvements in pain control and function, and maintain skeletal integrity. The treatment plan requires a multidisciplinary approach. Widespread metastatic disease necessitates systemic therapy, while a localized problem is best managed with surgery, external beam radiotherapy, or both. Patients with bone metastasis can have prolonged survival, and proper management can have a significant impact on their quality of life. We will review the factors in this article that are promising molecular bone-targeted therapies or will be likely targets for future therapeutic intervention to restore bone remodeling and suppress tumor growth. more...

E-selectin is an adhesion molecule expressed on the luminal surface of inflamed blood vessels that mediates hematogenous metastasis by assisting shear-resistant adhesion of circulating tumor cells to the vessel surface under dynamic blood flow. Previously, we developed an E-selectin antagonistic thioaptamer (ESTA) for the prevention of hematogenous metastasis through the blockade of CD44high breast cancer cells (BCa) adhesion to E-selectin-expressing premetastatic endothelial niche. The current study focuses on developing a PEGylated E-selectin targeting thioaptamer with improved pharmaceutical properties. A serial deletion of stem-loops reveled that loop-1 and -2 (ESTA7) are the minimally effective backbone structure necessary to obtain inhibition of the E-selectin/CD44 interaction and shear resistant adhesion of CD44high BCa to E-selectin-expressing human endothelial cells (HMVECs) at a level equal to ESTA. Chemical conjugation of methoxy-polyethylene-glycol (PEG) at the sizes of 5 and 10 kDa did not interfere with ESTA7-mediated shear-resistant adhesion. However, in vivo study demonstrated that only 10 kDa PEG-conjugated ESTA7 (ESTA7-p10) retains the activity to inhibit metastases at a level equal to parental ESTA. Additionally, a single intravenous injection of ESTA7-p10 inhibited the development of lung, brain, and bone metastases of MDA-MB-231, through the blockade of E-selectin. Moreover, PEGylation led to an extension of elimination half-life and increase of AUC, resulting in superior inhibition of metastasis development compared to parental ESTA with a longer interval between dosing in a spontaneous metastasis model. Lastly, repeated intravenous administration of ESTA7-p10 was tolerated in mice, highlighting the potential prophylactic application of ESTA7-p10 for metastasis prevention. more...

Background Distant metastasis resulting from vascular dissemination of cancer cells is the primary cause of mortality from breast cancer. We have previously reported that E-selectin expression on the endothelial cell surface mediates shear-resistant adhesion and migration of circulating cancer cells via interaction with CD44. As a result of shedding, soluble E-selectin (sE-selectin) from the activated endothelium is present in the serum. In this study, we aimed to understand the role of sE-selectin in tumor progression and metastasis. Methods We investigated the effect of sE-selectin on shear-resistant adhesion and migration of metastatic breast cancer cells and leukocytes in vitro and in vivo. Results We found that sE-selectin promoted migration and shear-resistant adhesion of CD44+/high breast cancer cell lines (MDA-MB-231 and MDA-MB-468) to non-activated human microvessel endothelial cells (ES-HMVECs), but not of CD44-/low breast cancer cell lines (MCF-7 and T-47D). This endothelial E-selectin independent, sE-selectin-mediated shear-resistant adhesion was also observed in a leukocyte cell line (HL-60) as well as human peripheral blood mononuclear cells (PBMCs). Additionally, the incubation of MDA-MB-231 cells with sE-selectin triggered FAK phosphorylation and shear-resistant adhesion of sE-selectin-treated cells resulted in increased endothelial permeabilization. However, CD44 knockdown in MDA-MB-231 and HL-60 cells resulted in a significant reduction of sE-selectin-mediated shear-resistant adhesion to non-activated HMVECs, suggesting the involvement of CD44/FAK. Moreover, functional blockade of ICAM-1 in non-activated HMVECs resulted in a marked reduction of sE-selectin-mediated shear-resistant adhesion. Finally, the pre-incubation of CD44+ 4 T1 murine breast cancer cells with sE-selectin augmented infiltration into the lung in E-selectin K/O mice and infusion of human PBMCs pre-incubated with sE-selectin stimulated MDA-MB-231 xenografted breast tumor growth in NSG mice. Conclusions Our data suggest that circulating sE-selectin stimulates a broad range of circulating cells via CD44 and mediates pleiotropic effects that promote migration and shear-resistant adhesion in an endothelial E-selectin independent fashion, in turn accelerating tissue infiltration of leukocytes and cancer cells. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2366-2) contains supplementary material, which is available to authorized users. more...

1027Background: T-DM1 is an antibody-drug conjugate composed of trastuzumab and the maytansinoid antimicrotubule, DM1. T-DM1 was granted FDA approval in 2nd-line MBC after prior trastuzumab (T) and... more...

Breast cancer is the most common cancer diagnosed and second leading cause of death among women in United States. Surgical resection with or without radiation remains the cornerstone of treatment for early stage breast cancer. Systemic adjuvant therapy with Tamoxifen or Aromatase Inhibitors (AIs) is indicated for Estrogen/Progesterone receptor (ER/PR) positive non metastatic breast cancer, depending upon their menopausal status. AIs are the drug of choice in postmenopausal women. They block or prevent estrogens from stimulating the growth of cancer by inhibiting aromatase from converting androgen into estrogen. According to an updated 2004 assessment from the American Society of Clinical Oncology, AIs are recommended to be used in adjuvant therapy initially or after Tamoxifen use for postmenopausal women with ER/PR positive breast cancer. more...

e17587 Background: Survival outcomes remain poor in salivary gland malignancies (SGMs) with multiple poor prognostic factors despite adjuvant radiotherapy. We examined prognostic factors that portended poor survival in resected SGMs to determine possible indications for adjuvant chemoradiotherapy. Methods:Patients who underwent curative resection with or without adjuvant radiotherapy between 2002 and 2014 were identified and retrospective chart review was performed. Bivariate analysis was performed on continuous variables using Analysis of Variance. Chi-Square analysis and Fishers Exact Tests were performed on categorical variables. To evaluate the overall survival (OS) and disease-free survival (DFS), Kaplan-Meier curves and log-rank tests of homogeneity were used. Results: Overall, 99 patients met inclusion criteria. Median follow-up time was 46.8 months. Univariate analysis revealed male sex, smoking history ≥ 10 pack-years, high grade, stage III-IVB, squamous cell histology, and perineural invasion significantly impacted OS and DFS. High-risk histopathology significantly impacted DFS and trended towards poor OS. Positive resection margins trended towards significantly impacting DFS. Multivariate analysis revealed only male sex and perineural invasion significantly impacted OS and DFS. Conclusions: Survival outcomes remain poor for patients with high-grade, late-stage tumors with perineural invasion. Specifically, perineural invasion is a poor prognostic factor regardless of age, histology, stage, and grade. Males and patients with a smoking history ≥ 10 pack-years have worse survival outcomes with male sex being a more influential prognostic factor. Notably, this is the first study to quantify patient’s smoking history in malignant salivary gland tumors and assess the impact of pack-year smoking history on survival outcomes. Given our observed trend, positive resection margins would likely become significant influencer of DFS with larger sample size and longer follow up. Adjuvant chemoradiotherapy should be evaluated in patients with the above-mentioned characteristics. more...

Idiopathic hypereosinophilic syndrome represents a heterogenous group of leukoproliferative disorders with hypereosinophilia of an unknown etiology resulting in multiorgan dysfunction. The disease can involve any organ but commonly involves heart, nervous system, skin, and gastrointestinal system. Steroids and chemotherapy agents remain the mainstay of the treatment to suppress organ damage and eradicate eosinophilia. We are presenting an interesting patient of idiopathic hypereosinophilic syndrome with cardiac involvement who was refractory to many chemotherapeutic drugs including imatinib but had an excellent response to etoposide. Although the mechanism by which etoposide works in this disease is not well understood, it has been tried in the past with success. The patient is off therapy for the past 24 months with stable eosinophil count. more...

Introduction: Circulating Tumor Cells (CTCs) have attracted significant attention as a new class of "liquid biopsy", enabling longitudinal and non-invasive disease monitoring to capture an overall snapshot of individual disease. Primary breast tumors are highly heterogeneous due to their genetic instability. Thus, the presence of heterogeneous populations of CTCs is expected. A number of attempts have been made to address CTC's phenotypic heterogeneity using different methods and approaches. For comprehensive understanding of distinct CTC phenotypes, transcriptomic and cell surface marker studies using single cell analysis separated CTCs into different subgroups with epithelial-, mesenchymal-, and stem-like signatures. These studies concluded that the prevalence of stem-like CTCs is associated with poor prognosis. Immunofluorescence is an ideal approach to understand the heterogeneity of 3 - 4 markers in a large number of distinct CTCs; however, such approach does not address the presence of overlapping phenotypic signatures. The collection method of CTCs adds another layer of complexity since the most commonly adopted CTC enumeration strategy relies on affinity-based selection using antibody against EpCAM, which, although abundantly expressed on epithelial cancer cells, automatically eliminates a large fraction of non-epithelial CTCs. To better understand the whole landscape of this heterogeneous disease, the use of marker-independent unbiased methods to collect CTCs is critical to obtain the overall landscape of phenotypic heterogeneity. Aim: We aimed to investigate the heterogeneity of breast CTCs on a single cell level using size exclusion- based enrichment principal. Methods: Whole blood was collected from metastatic breast cancer patients under IRB approved protocol. CTCs were isolated on porous membrane (8 µm) under negative pressure (ISET®) from 10 mL of blood. CTCs were fixed on the porous membrane and used for multiplexed immunofluorescence to investigate the expression of epithelial (CK and EPCAM), mesenchymal (Vimentin, Snail and TWIST), and stem-like markers (CD44, ALDH1, and CD133) on CTCs. Results: CTCs were isolated on ISET filter from all subtypes, Stage IV patients. CTCs were identified based on their morphological and phenotypical characteristics with our CTC criteria of size of nucleus ≥16 µm, triple negative for α-smooth muscle actin, fibroblast associated protein, and CD45. The CTCs were further characterized based on their mesenchymal and stem-like signatures to understand their heterogeneity. Conclusions: Multiplex immunofluorescence staining of CTCs collected using the size-based enrichment approach enabled us to identify the heterogeneity of CTCs. The phenotypic heterogeneity represents a corner stone for future studies to identify a subset of CTCs that may be associated with breast cancer patient prognosis. Citation Format: Kamal M, Zhang R, Walker M, Squires R, Talbert B, Dooley W, Razaq W, Tanaka T. A multiplexed immunofluorescence identifies phenotypic heterogeneity of circulating tumor cells in breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-01-18. more...

Primary presentation of intradural non-Hodgkin lymphoma is rare. Recently, B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) have been recognized as an important pathologic subtype. When MALT lymphomas present in the central nervous system (CNS), they are distinguishable from primary high-grade CNS lymphomas. We present the clinicopathologic features of 5 patients with primary CNS MALT lymphoma treated at our institution from 1999 to 2006. Four out of 5 patients were women, and all patients presented with headaches, focal motor deficits, or cranial nerve palsy. Radiologic studies demonstrated ill-defined dural masses in 3 and well-defined masses in 2 patients. Pathology revealed small to medium-sized cells with a moderate amount of cytoplasm and irregular nuclear borders, expressing pan B-cell markers (CD19, CD20, and CD79a) but lacking CD10, CD23, and cyclin D1, confirming low-grade MALT lymphoma. Plasma cells were encountered in all the biopsies with variable reactive T-cell infiltration. δ chain restriction was seen in 3 patients. Therapy consisted of either surgical resection, whole-brain radiation, or systemic or intrathecal chemotherapy. There was no evidence of recurrence or systemic relapse in 4 patients at 4 years of follow-up. One patient died in 2 months, unrelated to CNS lymphoma. This case series illustrates the rare occurrence of low-grade dural B-cell lymphoma and the need to consider this entity in the differential diagnosis of CNS lesions. more...

e17067 Background: Preclinical and recent randomized trials have shown benefit of NSAIDs in inhibition of carcinogenesis mainly in gastrointestinal cancers. Salivary gland tumors comprise a group o... more...

Peripartum cardiomyopathy creates complications for 1 in 3000 to 4000 pregnant women in the US. As this rare condition is associated with a high mortality rate (50% to 85%), it has been investigated to define the possible associated causes. Several factors including hypertension, nutritional and dietary discrepancies, and, recently, myocarditis are being implicated, but the mechanism of cardiac injury is yet to be discovered. Here we present an interesting case of possible interferon-induced reversible peripartum cardiomyopathy. The patient, with a diagnosis of chronic myelogenous leukemia, had been given interferon for 6 years. The therapy was discontinued when she became pregnant, and later she presented with symptoms of heart failure 6 weeks after her c-section. Interferon is an immunomodulating agent and used as an antiviral and an anticancer agent. Interferon-related dilated cardiomyopathy has been described as a rare side effect of the drug, the mechanism of which is unknown. There is compelling data supporting the fact that both peripartum cardiomyopathy and interferon-related cardiomyopathy are autoimmune disorders; so it is suggested that interferon therapy given in the past can have an additive effect in causing dilated cardiomyopathy. It is therefore advisable to follow closely those pregnant patients; who received interferon therapy in the past, for symptoms of cardiac failure, as there can be synergistic action between interferon and pregnancy causing dilated cardiomyopathy. more...

e11588 Background: Docetaxel, cyclophosphamide has less cardiotoxicity and improved disease-free and overall survival (OS) compared to doxorubicin, cyclophosphamide (AC) in EBC. However, dose-dense... more...

Distant metastasis resulting from vascular dissemination of cancer cells is the primary cause of mortality from breast cancer. We have previously reported that E-selectin expression on the endothelial cell surface mediates shear-resistant adhesion and migration of circulating cancer cells via interaction with CD44. As a result of shedding, soluble E-selectin (sE-selectin) from the activated endothelium is present in the serum. In this study, we aimed to understand the role of sE-selectin in tumor progression and metastasis.We investigated the effect of sE-selectin on shear-resistant adhesion and migration of metastatic breast cancer cells and leukocytes in vitro and in vivo.We found that sE-selectin promoted migration and shear-resistant adhesion of CD44(+) (/high) breast cancer cell lines (MDA-MB-231 and MDA-MB-468) to non-activated human microvessel endothelial cells (ES-HMVECs), but not of CD44(-/low) breast cancer cell lines (MCF-7 and T-47D). This endothelial E-selectin independent, sE-selectin-mediated shear-resistant adhesion was also observed in a leukocyte cell line (HL-60) as well as human peripheral blood mononuclear cells (PBMCs). Additionally, the incubation of MDA-MB-231 cells with sE-selectin triggered FAK phosphorylation and shear-resistant adhesion of sE-selectin-treated cells resulted in increased endothelial permeabilization. However, CD44 knockdown in MDA-MB-231 and HL-60 cells resulted in a significant reduction of sE-selectin-mediated shear-resistant adhesion to non-activated HMVECs, suggesting the involvement of CD44/FAK. Moreover, functional blockade of ICAM-1 in non-activated HMVECs resulted in a marked reduction of sE-selectin-mediated shear-resistant adhesion. Finally, the pre-incubation of CD44(+) 4 T1 murine breast cancer cells with sE-selectin augmented infiltration into the lung in E-selectin K/O mice and infusion of human PBMCs pre-incubated with sE-selectin stimulated MDA-MB-231 xenografted breast tumor growth in NSG mice.Our data suggest that circulating sE-selectin stimulates a broad range of circulating cells via CD44 and mediates pleiotropic effects that promote migration and shear-resistant adhesion in an endothelial E-selectin independent fashion, in turn accelerating tissue infiltration of leukocytes and cancer cells. more...