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  • 1
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 4_Supplement ( 2021-02-15), p. PS3-08-PS3-08
    Abstract: Introduction CEST MRI permits quantitation of macromolecules such as amide proteins that are of interest in cancer metabolism. However, optimal CEST acquisition and analysis methods remain undetermined. In this study, we investigated CEST MRI as an imaging biomarker for early treatment response in 51 TNBC patients receiving NAST and compared the performance with two different CEST saturation power levels and two analysis methods. Methods A total of 51 stage I-III TNBC patients enrolled in the prospective ARTEMIS trial (NCT02276443) had CEST imaging performed on a 3T MRI scanner at baseline before NAST (BL, N = 51), after 2 cycles (C2, N = 37), and 4 cycles (C4, N = 44) of NAST. 33 of the 51 patients had imaging at all 3 time points. 29 of the 33 patients had pathological findings, with N = 16 with pathological complete response (pCR) and N = 13 with non-pCR. Two sets of CEST images using 0.9 and 2.0 µT saturation power levels were acquired and analyzed using the magnetization transfer ratio asymmetry (MTRasym) and the Lorentzian line fitting (Mag3.5) methods, for a total of 4 acquisition/analysis combinations. The group averaged CEST signals, MTRasym at 0.9 and 2.0 µT and Mag3.5 at 0.9 and 2.0 µT, at BL, C2 and C4 were determined and evaluated using unpaired (51 patients) and paired (33 patients) Kruskal-Wallis tests. The Mag3.5 at 0.9 µT and the MTRasym at 2.0 µT were further compared between pCR and non-pCR. The group averaged CEST signals at BL, C2, and C4 were evaluated using the Friedman test for the pCR and the non-PCR groups. Separately, the change in the CEST signal from BL to C2 and C4 was determined for each patient and evaluated using the Mann-Whitney test for both groups. P & lt; 0.05 was considered statistically significant. Results The MTRasym at BL was higher at 2.0 µT than at 0.9 µT. In contrast, the Mag3.5 at BL was higher at 0.9 µT than at 2.0 µT. The MTRasym at 2.0 µT and the Mag3.5 at 0.9 µT decreased during treatment while the MTRasym at 0.9 µT and the Mag3.5 at 2.0 µT were similar. Both the unpaired and the paired Mag3.5 at 0.9 µT showed a significant decrease at C2 and C4 vs. BL (p & lt; 0.01). The unpaired and paired MTRasym at 2.0 µT showed a decrease, although the change was not significant except for the unpaired data at C4. The decrease in the group averaged Mag3.5 at 0.9 µT was significant at C2 vs. BL for the pCR group (p = 0.04), while it was not significant for the pCR group at C4 vs. BL and for the non-pCR group at either C2 or C4 vs. BL. The group averaged MTRasym at 2.0 µT changes were not significant for either the pCR or the non-pCR groups. None of the CEST signal changes on a per patient basis at C2-BL, C4-BL and C4-C2 were significantly different between the pCR and the non-pCR groups. Further, none of the group averaged CEST signals at BL, C2 and C4 were significantly different between the pCR and the non-pCR groups. Conclusion Our study demonstrates that the CEST quantitation in TNBC patients undergoing NAST depends on acquisition and analysis. For a maximum change in the CEST effect, Lorentzian line fitting is better paired with acquisition at a low saturation power (0.9 µT) and MTRasym is better paired with acquisition at a high saturation power (2.0 µT). Further, a significant CEST signal decrease was observed in TNBC patients with pCR after NAST when a 0.9 µT saturation power and the Lorentzian line fitting were used. In comparison, the decrease was not significant in non-pCR patients using the same saturation power and analysis method. The results suggest that the CEST signal acquired at 0.9 µT saturation power and analyzed using Lorentzian line fitting may be able to differentiate between pCR and non-pCR among TNBC patients undergoing NAST. Additional studies with a larger patient population are ongoing to further validate our findings and their potential for determining pCR. Citation Format: Shu Zhang, Gaiane M Rauch, Beatriz E Adrada, Medine Boge, Rania MM Mohamed, Abeer H Abdelhafez, Jong Bum Son, Jia Sun, Nabil A Elshafeey, Jason B White, Deanna L Lane, Jessica WT Leung, Marion E Scoggins, David A Spak, Elsa Arribas, Elizabeth Ravenberg, Lumarie Santiago, Tanya W Moseley, Gary J Whitman, Huong Le-Petross, Benjamin C Musall, Mitsuharu Miyoshi, Xinzeng Wang, Brandy Willis, Stacy Hash, Aikaterini Kotrotsou, Peng Wei, Ken-Pin Hwang, Alastair Thompson, Stacy L Moulder, Rosalind P Candelaria, Wei Yang, Jingfei Ma, Mark D Pagel. Assessment of early response to neoadjuvant systemic therapy (NAST) of triple-negative breast cancer (TNBC) using chemical exchange saturation transfer (CEST) MRI: A pilot study [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 PS3-08.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 2
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 1546-1546
    Abstract: 1546 Background: Previous studies have related germline BRCA mutations to pathologic complete response (pCR) in TNBC cohorts. However, prospective data is lacking on the frequency of non- BRCA germline mutations and pCR in TNBC patients who received neoadjuvant therapy (NAT). The aim of this study was to describe germline alterations in comparison with pCR in a prospective cohort of TNBC receiving NAT. Methods: Pre-NAT blood was drawn from patients enrolled in a clinical trial of genomically tailored NAT (ARTEMIS: NCT: 02276443, per eligibility patients had to have negative clinical BRCA tetsing). Germline DNA was extracted and sequenced on a HiSeq4000 sequencer (Illumina, coverage 60X). Reads were aligned to human reference hg19. Variants were filtered against public databases of normal cohorts: esp6500, 1000 genome, ExAC with a frequency cutoff at 1% in any ethnicity. Two integrative scores were used to evaluate the deleteriousness of the missense variants and the variants predicted to be damaging by both scores were included in the analyses. A 105 pan-cancer susceptibility gene panel was selected based on literature data and commercially available gene panels. NAT included anthracycline and taxane based chemotherapy +/- targeted therapy based on tumor genomic expression. Univariate logistic regression models were used to fit pCR for individual mutations, excluding genes mutated in fewer than three patients. All statistical analyses were performed using R version 3.6.1. with a significance of p=0.05. Results: Germline results and pCR were available for 152 patients. Median age was 55 yrs (range: 24-77). 7.9% were stage (st) I, 65.8% st II, 26.3% st III. 55 pts (36%) had pan-cancer associated germline mutations, whereas 33 (21%) had a breast-cancer associated mutation. Greater than 1% mutations were seen in seventeen genes (Table). There was no significant difference in pCR rate after NAT among pts with different germline mutations versus without mutation. Conclusions: Breast cancer related germline mutations other than BRCA in TNBC are relatively common supporting at least a breast panel (not only BRCA1/2) testing. Treatment implications of different germline mutations and their impact on pCR is ongoing on an extended series. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2005181-5
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  • 3
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 1105-1105
    Abstract: 1105 Background: Accumulating toxicities make indefinite chemotherapy unfeasible for many patients with metastatic/recurrent HER2-negative inflammatory breast cancer (IBC) or triple-negative breast cancer (TNBC). We conducted a single-arm phase II trial of pembrolizumab monotherapy to determine the efficacy of maintenance immunotherapy in patients with metastatic HER2-negative aggressive breast cancer and to identify biomarkers correlated with disease control. Methods: The study enrolled patients who had a complete response, partial response, or stable disease after a minimum of 3 cycles of chemotherapy for metastatic TNBC/IBC regardless of PD-L1 expression between 2015 and 2022. Pembrolizumab was administered at 200 mg every 3 weeks until disease progression, intolerable toxicity, or 2 years of exposure to the drug. The primary endpoint was the 4-month disease control rate (DCR), and the secondary endpoint was progression-free survival (PFS). Correlative studies were performed to determine associations between clinical response, and immune profiling consisting of T-cell clonality, immunophenotyping, and dendritic cell (DC) function with blood collected at baseline and after 2 cycles of pembrolizumab treatment. Results: Of 43 treated patients, 11 had metastatic IBC and 32 had TNBC. The median number of prior lines of chemotherapy for metastatic disease was 1. During a median follow-up of 11.4 months, 33 patients had progressive disease and 25 were deceased. The 4-month DCR was 58.1% (95% CI: 43.4%-72.9%) and the median PFS was 4.8 months (95% CI: 3.0-7.1 months). The median PFS of the metastatic IBC group (2.2 months) and TNBC group (4.8 months) did not differ significantly ( p = .12). Thirty-one patients discontinued treatment due to progressive disease rather than toxicity. Observed toxicities were consistent with the known profile of pembrolizumab. Correlative blood studies showed availability of PD-1 on CD8 T cells decreased on therapy. T-cell exhaustion markers 2B4, CTLA4, and TIM3 decreased in patients who had therapeutic benefit, while LAG3 increased in patients without benefit. During therapy, ex vivo cytokine synthesis (IL-6/IL-12/TNFα) by DCs was superior in patients who benefited from therapy and increased from pretreatment samples. High T-cell clonality at baseline predicted response to immunotherapy (10.4 vs 3.6 months, p = .04). Additionally, patients exhibiting the greatest clinical benefit also had a significant increase in T-cell clonality over the course of therapy (20% vs 5.9% mean increase, p = .04). Conclusions: Increased T-cell clonality and DC activity, along with reductions in T-cell exhaustion, were associated with prolonged disease control following pembrolizumab maintenance therapy, achieving acceptable disease control with manageable toxicity. Clinical trial information: NCT02411656 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
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  • 4
    Online Resource
    Online Resource
    American Society of Clinical Oncology (ASCO) ; 2015
    In:  Journal of Clinical Oncology Vol. 33, No. 15_suppl ( 2015-05-20), p. 612-612
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 33, No. 15_suppl ( 2015-05-20), p. 612-612
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2015
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  • 5
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. 1016-1016
    Abstract: 1016 Background: The combination of CDK4/6 inhibitor (CDK4/6i) + endocrine therapy (ET) provides consistent improvement in PFS and response rates compared with single-agent ET as first- or subsequent-line therapy in HR+, HER2− advanced breast cancer (ABC), but the optimal regimen postCDK4/6i progression, including the role of continued CDK 4/6 blockade, is unclear. Methods: TRINITI-1 is a Phase I/II, open-label trial (NCT02732119) of triplet therapy: ribociclib (RIB; CDK4/6i) + everolimus (EVE; mTORi) + exemestane (EXE; ET) in men or postmenopausal women with HR+, HER2− ABC that progressed on prior CDK4/6i and up to 3 lines of therapy (≥ 1 ET and ≤ 1 chemotherapy regimen). Phase I determined RP2D; Phase II assessed efficacy/safety of RIB 300 or 200 mg + EVE 2.5 or 5 mg + EXE 25 mg/day. Here we present the first results in the entire patient population who received this triplet regimen and the correlation of biomarkers with outcomes. Results: As of October 24, 2018, 95 patients were evaluable (ET refractory and postCDK4/6i) in Phases I (n = 17) and II (n = 78). Continuous RIB + EVE + EXE demonstrated clinical benefit at week 24 in 39 patients (41.1%), exceeding the predefined primary end point threshold ( 〉 10%). ORR was 8.4% by investigator assessment, median PFS was 5.7 months, and 1-year PFS was 33%. AEs were consistent with known safety profile of RIB, EVE, and EXE. Most common AEs were neutropenia (all grades, 41.7%; grade 3/4, 31.3%), stomatitis (41.7%; 3.1%), and fatigue (35.4%; 1.0%). No grade 3/4 QTc prolongation was noted. ctDNA genotyping revealed patients with certain tumor alterations, eg ESR1, had shorter median PFS vs wild-type: 3.5 vs 6.9 mo (HR 1.76, 95% CI 1.01–3.05). Additional genomic results, including PIK3CA, will be presented. Conclusions: TRINITI-1 met its primary efficacy end point and is the first trial to demonstrate clinical benefit and tolerability of continuous triplet therapy with ET + mTORi + CDK4/6i in patients with ET-refractory HR+, HER2− ABC postCDK4/6i progression. Tumor genomic profile might impact the clinical outcome with triplet therapy and warrants additional research to guide rational therapy selection. Clinical trial information: NCT02732119.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
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  • 6
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 10613-10613
    Abstract: 10613 Background: Bone is the preferred site for metastasis of breast cancer, affecting approximately 70% of women with advanced disease. N-terminal of procollagen type 1 (P1NP), c-terminal peptide crosslinks (CTX), Osteocalcin (OC) and interleukin-6 (IL-6) are markers of bone turnover that may have clinical utility as predictors of breast cancer recurrence in the bone. Methods: Serum was collected from 168 patients with stage I/II/III breast cancer prior to treatment from 09/2001 to 12/2008 and stored at -80 C. Serum levels of P1NP, CTX, OC and IL-6 were determined using the Roche’s Elecsys 2010 automated immunoassay system. Correlations of biomarker levels with time to bone metastasis (BM) development were assessed with Cox proportional hazards regression analysis and the Kaplan-Meier method. Results: Among the 168 patients analyzed, 60 patients subsequently developed BM. The biomarkers all had skewed distributions with long right tails and thus were all analyzed on the log scale. Residual analysis suggested non-linear relationships between each biomarker and risk of developing BM during follow-up. Thus, we fit Cox proportional hazards regression models for each biomarker with quadratic polynomials (on the log scale). On univariate analysis, these analyses generated p = 0.33 for IL-6, 0.26 for osteocalcin, 0.40 for CTX, and 0.032 for P1NP. Adjusting for clinical factors (stage, age, race, post menopausal, ER/PR status, HER2 status, nuclear grade) yielded p = 0.0035 for the quadratic polynomial for log P1NP. A cut-point of 75 ng/mL identified patients with a short time to development of BM. The 1, 3, and 5-year freedom-from-BM probabilities were 96%, 77% and 66% for the 150 patients with P1NP values ≤ 75 ng/mL and 88%, 45%, and 36% for the 16 patients with P1NP values 〉 75 ng/mL. The hazard ratio comparing patients with P1NP values ≤ 75 ng/mL to patients with P1NP values 〉 75 ng/mL was 3.0 (95% CI, 1.5 - 6.2) and p = 0.0075 ng/mL. After adjustment for clinical factors, the hazard ratio was 3.4 (1.5, 7.6) with p = 0.0026. Conclusions: Serum P1NP levels 〉 75 ng/mL correlate with a shorter time to development of BM in patients with stage I-III breast cancer.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
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  • 7
    Online Resource
    Online Resource
    American Society of Clinical Oncology (ASCO) ; 2013
    In:  Journal of Clinical Oncology Vol. 31, No. 15_suppl ( 2013-05-20), p. 601-601
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. 601-601
    Abstract: 601 Background: Breast cancer (BC) is one of the most common tumors to involve the leptomeninges. Outcome of leptomeningeal disease (LMD) across BC subtypes is not well documented. We aimed to characterize clinical features and outcomes of LMD based on BC subtypes. Methods: We retrospectively reviewed medical records of patients diagnosed with LMD from BC (1997 to 2012). All patients had BC. Cases of LMD were based on the presence of neoplastic cells on cerebrospinal fluid examination and/or evidence of LMD by imaging studies. Survival was estimated by the Kaplan-Meier method and significant differences in survival were determined by Cox proportional hazards or log-rank tests. Results: 232 patients were included, 189 of them had available tumor subtype classified as: hormone receptor positive (HR+) BC N=67 (35.5%), human epidermal growth factor receptor 2 positive (HER2+) N=55 (29%), and 67 (35.5%) triple-negative BC (TNBC). Median age at diagnosis of LMD was 49.7 years. (Range 24-89). Median overall survival (OS) from LMD diagnosis across all subtypes was 3.1 months (95% CI, 2.5 to 3.7). Median OS correlated with BC subtype: 3.7 months (95% CI: 2.4, 6.0) in HR+, 4.0 months (95% CI: 2.6, 6.9) in HER2+, and 2.2 months (95% CI: 1.5, 3.0) in TNBC, (p=0.0002). There was an 11.4% chance a patient diagnosed with LMD would survive 1 year and the chance of surviving at least 3 years was 1.3%. When age was used as a continuous variable, older age was associated with worse outcome (p 〈 0.0001). Patients with HER2+ BC and LMD were more likely to have received systemic therapy (ST) (70%), compared to HR+ (41%) and TNBC (41%) (p=0.002). 38% of patients with HER2+ BC received HER2 directed therapy. There was no difference in the use of intrathecal therapy (IT) (52%) across subtypes (p=0.3). Use of IT therapy (p 〈 0.0001) and ST (p 〈 0.0001) were both associated with improved age-adjusted OS. After adjusting for age, ST, there was no difference in OS between patients with HR+ and HER2+ BC (p =0.14), but a significant difference remained between TNBC and HER2+ BC (p 〈 0.0001). Conclusions: LMD carries a dismal prognosis. Our data shows that OS correlates with tumor subtype. Patients with TNBC had a significantly shorter OS compared to patients with HER2+ BC. New treatment strategies are needed.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
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  • 8
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 15_suppl ( 2017-05-20), p. 1090-1090
    Abstract: 1090 Background: Metaplastic Breast Cancer (MpBC) is considered a chemo-refractory, aggressive subtype that is characterized by squamous and/or mesenchymal differentiation and associated with a high rate of molecular aberrations that activate the PI3K pathway. The goal of this study was to correlate outcomes data with underlying genomic aberrations in MpBC. Methods: A cohort of 52 archived samples of MpBC collected from 1986 and 2016 that had clinical outcomes data available for central review underwent hybrid capture sequencing of 202 cancer-related genes (n = 52) and, when sufficient material was available, whole exome sequencing (n = 21). Relapse free (RFS) and overall (OS) survival analyses at 5 years were compared between patients having mutation vs. wild-type (WT) in the whole genome using Kaplan-Meier statistics. Results: The variant allele frequency (VAF) was relatively low with most mutations having a VAF of 〈 50%. TP53 mutation was found in 33 tumors (63%) and was associated with improved RFS (HR = 2.4; p = 0.03) and OS (HR = 3.7; p = 0.006) compared to WT. Aberrations in the PI3K/AKT/mTOR pathway were present in 29% of tumors and associated with diminished OS (HR = 0.27; p = 0.02) but not RFS (HR = 0.67; p = 0.32). Though uncommon, the presence of an AKT1 (6%) mutation was associated with worse RFS (HR = 0.006; p = 0.006) and OS (HR = 0.0005; p 〈 0.0001). Conclusions: Surprisingly, TP53 mutation was associated with better prognosis in MpBC with increased RFS and OS. Mutations in AKT1 were uncommon but associated with a significantly worse RFS and OS. Notably, all patients harboring an AKT1 mutation died within a year of diagnosis. Mutations activating the PI3K/AKT/mTOR pathway were associated with worse OS.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2017
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  • 9
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 34, No. 15_suppl ( 2016-05-20), p. 507-507
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2016
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  • 10
    Online Resource
    Online Resource
    American Society of Clinical Oncology (ASCO) ; 2014
    In:  Journal of Clinical Oncology Vol. 32, No. 15_suppl ( 2014-05-20), p. TPS663-TPS663
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 32, No. 15_suppl ( 2014-05-20), p. TPS663-TPS663
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2014
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