tbuckley/cabot-search huggingface dataset:
Efficacy of palbociclib plus fulvestrant (P+F) in patients (pts) with metastatic breast cancer (MBC) and <i>ESR1</i> mutations (mus) in circulating tumor DNA (ctDNA).
Authors: Nicholas C. Turner, Yuqiu Jiang, Ben O'Leary, Sarah Hrebien, Massimo Cristofanilli, Fabrice Andre, Sibylle Loibl, Patricia A. English, Ke Zhang, Sophia Randolph, Cynthia Huang Bartlett, Maria Koehler, Sherene Loi
Journal: Journal of Clinical Oncology (2016)

512 Background: PALOMA-3 is a randomized, double-blind, phase III study comparing P+F with fulvestrant plus placebo (F+Pla) in pre- and postmenopausal women with HR+/HER2– MBC that progressed on prior endocrine therapy. Recent studies have implicated ESR1 mu as a mechanism for acquired endocrine resistance in MBC. ctDNA assessed in plasma is a potential surrogate for a tumor’s genetic profile. Here, we assess the relationship between ctDNA ESR1 mu status and palbociclib sensitivity, and the reproducibility of ESR1 ctDNA analysis. Methods: 396 baseline plasma samples from 521 pts enrolled in PALOMA-3 were collected and consented for use in this study. DNA was extracted from 2 mL aliquots using the QIAamp Circulating Nucleic Acid Kit and 12 ESR1 ligand-binding domain mus were analyzed in exons 5, 7, and 8 by Sysmex Inostics. To assess reproducibility of ESR1 mu analysis, separate samples were analysed by droplet digital PCR. Results: ESR1 mus were detected in 106 (26.8%) of the 395 plasma samples tested, most frequently D538G (14.1%), E380Q (8.1%), Y537S (7.3%), and Y537N (4.5%). Mus were poly-clonal in 10.1% of pts. All 106 pts with ESR1 mus were previously treated with an aromatase inhibitor; no ESR1 mus were identified in pts previously treated with tamoxifen only. Overall, median progression-free survival (PFS) was 5.7 months (mos) (95% confidence interval [CI]: 3.7–9.4) for pts with ESR1 mus versus 9.2 mos (95% CI: 7.5–10.9) for pts without ESR1 mus (hazard ratio [HR] = 1.33 [95% CI: 0.99–1.80]; 2-sided P= 0.0572). Median PFS was significantly longer in the P+F group compared with the F+Pla group both in pts without a detectable ESR1 mu (9.5 vs 3.8 mos; HR = 0.44 [95% CI: 0.31‒0.62], 1-sided P< 0.0001) and in pts with an ESR1 mu (9.4 vs 4.1 mos; HR = 0.52 [95% CI: 0.32‒0.87], 1-sided P= 0.0052). In samples independently tested by droplet digital PCR (353/395), the concordance between the two assays was 94.1% (Kappa = 0.84). Conclusions: ESR1 mus, detected in plasma ctDNA, were identified in a high percentage of pts with HR+ MBC confirming an important role in endocrine-resistance. P+F treatment provided significant benefit for MBC pts with and without ESR1 mus. Clinical trial information: NCT01942135.
Clinical significance of axillary lymph node count in axillary dissection following neoadjuvant chemotherapy for breast cancer.
Authors: Tae-Kyung Yoo, Han-Byoel Lee, Young-Joon Kang, Jaihong Han, Yumi Kim, Eunshin Lee, Hee-Chul Shin, Hyeong-Gon Moon, Dong Young Noh, Wonshik Han
Journal: Journal of Clinical Oncology (2016)

e12508 Background: Axillary lymph node (ALN) count is known to be lower after neoadjuvant chemotherapy (NAC) compared to primary surgery patients. In this study, we have investigated the clinical significance of ALN count after ALN node dissection in breast cancer patients treated with NAC. Methods: A total of 427 patients who were treated with NAC between 2006 and 2011 were retrospectively reviewed. All patients were treated with anthracycline and/or taxane-based chemotherapy regimens with a median of 3 cycles and underwent breast surgery along with ALN dissection. The association between ALN count and treatment outcome was analyzed. Results: The median follow-up duration was 62 months. The median of dissected ALN count was 15 (range 0-52). Patient survival did not differ when dichotomized by median of ALN count. However an ALN count of 5 or lower was significantly associated with a lower disease-free survival (hazard ratio 2.316, p = 0.008). This extremely low ALN count ( ≤ 5) was also an independent prognostic factor when adjusted for clinical stage, grade, subtype, Ki67, yp stage and response to NAC (hazard ratio 2.761, p = 0.003). Conclusions: An extremely low ALN count of 5 or lower is an independent prognostic factor in breast cancer patients treated with NAC, despite of number of involved ALNs and response to NAC. Aggressive adjuvant treatment can be considered in this small group of patients.
A phase Ib dose escalation trial of SAR650984 (Anti-CD-38 mAb) in combination with lenalidomide and dexamethasone in relapsed/refractory multiple myeloma.
Authors: Thomas G. Martin, Karl Hsu, Eric Charpentier, Ravi Vij, Rachid C. Baz, Don M. Benson, Nikoletta Lendvai
Journal: Journal of Clinical Oncology (2014)

8512 Background: SAR650984 (SAR) is a humanized IgG1 monoclonal antibody that binds selectively to a unique epitope on human CD38 receptor. SAR kills tumor cells via antibody-dependent cellular-mediated cytotoxicity, complement-dependent cytotoxicity, direct apoptosis induction without secondary crosslinking and allosteric inhibition on CD38 enzymatic activity. We present data on the dose escalation phase of the study (NCT01749969). Methods: Three dose levels (DL) of SAR 3, 5 and 10 mg/kg were evaluated in combination with lenalidomide (LEN) and dexamethasone (Dex). LEN 25 mg was given on days (d) 1 – 21 and D 40 mg on d 1, 8, 15 and 22 every 28 d's. SAR was given IV on d 1 and 15 and escalated using the classic 3+3 design. Results: 13 patients (pts) with RRMM were treated; median age 61 yrs (48 - 73); median prior treatment regimens 6 (2 - 12), 100% had received prior LEN (23% prior pomalidomide) and 92.3% previously received bortezomib (38.5% prior carfilzomib). The median time from diagnosis to first SAR dosing was 4.5 yrs (3 - 11). The maximum tolerated dose was not reached. The most frequent adverse events included nausea, cough (n = 6 each); fatigue, muscle spasm, infection (n = 5 each); vomiting, diarrhea, dehydration and insomnia (n = 4 each). Grade (G) ≥ 3 hematologic abnormalities were neutropenia (n = 4) and thrombocytopenia (n = 3). One pt discontinued therapy (cycle 1, d 1) due to an infusion reaction (bronchospasm G 3). The ORR (≥ PR), according to IMWG criteria, among 12 evaluable pts was 58 %. Responses occurred at each DL of 3mg/kg (1PR), 5mg/kg (1PR, 1 VGPR) and 10 mg/kg (1PR, 3 VGPR). Clinical benefit response (≥ MR) was 67 % with 1 MR at 3 mg/kg. Median time on treatment was 20.6 weeks (0 - 35) and 7 pts remain on therapy. PK showed non linearity at select dose levels, SAR plasma trough levels were above target for tumor eradication from preclinical data. Conclusions: The combination of SAR with LEN/Dex was tolerated and no DLT's were reported at any DL. SAR + LEN/Dex demonstrated encouraging efficacy in pts with heavily pretreated RRMM. An expansion cohort of 18 pts recently enrolled on the trial and the results will be reported at the meeting. Clinical trial information: NCT01749969.
Propensity-Matched Comparisons of Clinical Outcomes After Transapical or Transfemoral Transcatheter Aortic Valve Replacement
Authors: Eugene H. Blackstone, Rakesh M. Suri, Jeevanantham Rajeswaran, Vasilis Babaliaros, Pamela S. Douglas, William F. Fearon, D. Craig Miller, Rebecca T. Hahn, Samir Kapadia, Ajay J. Kirtane, Susheel K. Kodali, Michael Mack, Wilson Y. Szeto, Vinod H. Thourani, E. Murat Tuzcu, Mathew R. Williams, Jodi J. Akin, Martin B. Leon, Lars G. Svensson
Journal: Circulation (2015)

Background— The higher risk of adverse outcomes after transapical (TA) versus transfemoral (TF) transcatheter aortic valve replacement (TAVR) could be attributable to TA-TAVR being an open surgical procedure or to clinical differences between TA- and TF-TAVR patients. We compared outcomes after neutralizing patient differences using propensity score matching. Methods and Results— From April 2007 to February 2012, 1100 Placement of Aortic Transcatheter Valves (PARTNER)-I patients underwent TA-TAVR and 1521 underwent TF-TAVR with Edwards SAPIEN balloon-expandable bioprostheses. Propensity matching based on 111 preprocedural variables, exclusive of femoral access morphology, identified 501 well-matched patient pairs (46% of possible matches), 95% of whom had peripheral arterial disease. Matched TA-TAVR patients experienced more adverse procedural events, longer length of stay (5 versus 8 days; P &lt;0.0001), and slower recovery (New York Heart Association class I, 31% versus 38% at 30 days, equalizing by 6 months at 51% versus 47%); stroke risk was similar (3.4% versus 3.3% at 30 days and 6.0% versus 6.7% at 3 years); mortality was elevated for the first 6 postprocedural months (19% versus 12%; P =0.01); but aortic regurgitation was less (34% versus 52% mild and 8.9% versus 12% moderate to severe at discharge, P =0.001; 36% versus 50% mild and 10% versus 15% moderate to severe at 6 months, P &lt;0.0001). Conclusions— The likelihood of adverse periprocedural events and prolonged recovery is greater after TA-TAVR than TF-TAVR in vasculopathic patients after accounting for differences in cardiovascular risk factors, although stroke risk is equivalent and aortic regurgitation is less. As smaller delivery systems permit TF-TAVR in many of these patients, we recommend a TF-first access strategy for TAVR when anatomically feasible. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00530894.
Circulating miR-200c-3p as a marker of metastatic disease at diagnosis in breast cancer patients.
Authors: Esther Navarro Manzano, Gines Luengo-Gil, Elisa Garcia-Garre, Maria Piedad Fernandez Perez, Ana Fernandez Sanchez, Alejandra Ivars Rubio, Pilar de la Morena, Gema Marin Zafra, Elena Garcia Martinez, Alberto Martínez, Enrique Gonzalez-Billalabeitia, Francisco Ayala
Journal: Journal of Clinical Oncology (2017)

e12559 Background: MicroRNAs are involved in cancer biology through their role in regulation of protein expression. The miR-200 family plays a dual role in breast cancer (BC), both regulating epithelial to mesenchymal transition and promoting metastatic colonization. Plasma levels of miR-200 have been previously evaluated as prognostic factors in early and metastatic BC (MBC) but its role as a potential diagnostic marker is less well established. The aim of this study was to determine the potential diagnostic value of miR-200c-3p plasmatic levels in women with locally advanced and metastatic BC. Methods: We included 73 BC patients and 14 controls. Plasma samples were obtained at diagnosis, before treatment. RNA from plasma samples was extracted with NucleoSpin miRNA plasma (Macherey-Nagel). We analyzed expression levels of miR-200c-3p, which were relativized (2-ΔΔCT method) to miR-16. Non-parametric statistical tests were used to determine the association of miR-200c levels with clinical variables. Receiver-operating curves (ROC) were constructed and diagnostic ability evaluated. Kaplan-Meier curves and Cox models were used for survival analyses. Results: 73 BC patients were included: 36 locally advanced BC (LABC) and 37 MBC (7 recurrences and 30 MBC at initial diagnosis [MBCID]). Plasma miR-200c levels were significantly higher in MBC than in controls (p = 0.001) and in LABC (p = 0.001). We found differences neither for age nor for estrogen receptors, HER2, tumor subtype or histology. Overall and disease free survival did not differ by miR-200c levels in any of the groups. Among MBC patients, higher levels were observed in MBCID (p = 0.023). In the group of women with an initial diagnosis of BC (n = 65), high miR-200c levels (over 1st tertile) identified metastatic disease with a sensitivity of 90.0% (95%CI: 72.3-97.4%) and a specificity of 51.4% (95%CI: 34.3-68.3%); negative predictive value: 85.7%; positive predictive value: 61.4%; ROC AUC: 0.79. Conclusions: MiR-200c plasma levels are higher in BC patients with metastatic disease at diagnosis, and might be clinically useful to identify them. Further research on miR200c biological role in MBC and validation in larger populations with sequential samples are warranted.
The association between proton pump inhibitors (PPI) use for gastro-esophageal reflux disease (GERD) and lung cancer (LC): A nested case-control study.
Authors: Hadas Dresler, Daniel Keizman, Ronac Mamtani, Maya Gottfried, Natalie Maimon, Moshe Mishaeli, Kevin Haynes, Yu-Xiao Yang, Ben Boursi
Journal: Journal of Clinical Oncology (2017)

1562 Background: Data suggests that GERD with recurrent reflux and microaspiration of stomach contents, may be associated with lung injury, inflammation, activation of proliferative signals, and eventually DNA damage and malignant transformation. Recently, a large population based cohort study found that GERD may increase the risk of lung cancer in Asians. In the present nested case control study, we aimed to evaluate the association between PPI use as a surrogate for GERD and lung cancer in a large western population. Methods: We conducted a matched case-control study within a population-representative database from the United Kingdom. Study cases were defined as individuals with any diagnostic code of lung cancer. For every case, four eligible controls were matched on age, gender, practice site, time and duration of follow-up. Exposure of interest was PPI use prior to cancer diagnosis. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer were estimated using conditional logistic regression. Adjustment was performed for smoking. Results: The study population included 19143 lung cancer cases and 74473 matched controls. PPI use was associated with a significantly increased lung cancer risk (adjusted OR 1.70, 95%CI 1.64-1.77, p &lt; 0.001). In a sensitivity analyses we observed similar associations when PPI use was initiated more than one year prior to cancer diagnosis (adjusted OR 1.18, 95%CI 1.13-1.23, p &lt; 0.001) and more than two years prior to cancer diagnosis (adjusted OR 1.15, 95%CI 1.10-1.20, p &lt; 0.001) Conclusions: ChronicPPI use, as a surrogate for symptomatic GERD, may be associated with a higher lung cancer risk.
Erratum: Semi-quantitative X-ray microanalysis of bronchoalveolar lavage samples from silica-exposed and nonexposed subjects (Eur Respir J, 1992, 5, 798-803)
Authors: M. Lusuardi, A. Capelli, C. F. Donner, O. Capelli, G. Velluti
Journal: European Respiratory Journal (1992)
Clonality of PIK3CA mutations (mut) and efficacy of PI3K/AKT/mTOR inhibitors (PAMi) in patients (pts) with metastatic breast cancer (MBC).
Authors: Mafalda Oliveira, Rodrigo Dienstmann, Meritxell Bellet, Jose Manuel Perez-Garcia, Patricia Gómez-Pardo, Eva Muñoz-Couselo, Maria Vidal, Vanessa Ortega, Jesus Soberino, Esther Zamora, Cinta Hierro, Fiorella Ruiz, Paolo Nuciforo, Ana Vivancos, Javier Cortes, Cristina Saura
Journal: Journal of Clinical Oncology (2016)

528 Background: PAMi are being developed in unselected populations with MBC, but not all pts derive equal benefit. Aim: to assess predictive factors influencing PAMi efficacy in MBC pts enrolled in phaseI/II clinical trials, with exploratory analysis according to PIK3CAmut allele fractions (MAF). Methods: MBC pts treated with PAMi and with genomic information were identified. MAF was corrected for tumor purity and categorized as clonal (cl; > 0.3) or subclonal (scl; ≤ 0.3). Efficacy of PAMi measured as clinical benefit rate [CBR: CR+PR+SD@4 months (m)] and time to treatment failure (TTF: time from PAMi start until discontinuation for any reason). Results: From Oct10-Sep15, 105 pts received 112 PAMi. Median (med) age 56; HR+/HER2- 74.3%; med number (N) of prior lines and MBC sites 2; visceral metastasis in 66%. Mut: PIK3CA 31%, AKT1 7%, NF2 4%. PIK3CA med MAF (N = 28) 0.5 (interquartile range 0.4-0.6), cl in 80% of samples. PAMi: AKTi 12%, pan-PI3Ki 12%, PI3K/mTORi 17%, mTORi 21%, PI3Kαi 38%. Type of treatment: single agent 15%, +anti-HER2 19%, +endocrine therapy (ET) 52%, +chemotherapy (CT) 14%. Efficay of PAMi: CBR 56%, TTF 4.9m (95%CI 3.9-5.8). Overall, PIK3CAmut increased the likelihood of efficacy of PAMi (CBR 78% vs 45%, P = .001; TTF 7.4 vs 4.0m, HR 0.5 P = .006). In PI3Kαi treated pts, having PIK3CAmut increased the likelihood of benefit (CBR 86.7% vs 46.4%, P = .02), with a trend for improved TTF (7.4 vs 4.9m, HR 1.7, P = .14). In PIK3CAmut pts treated with PI3Kαi and with MAF counts available (N = 13), PIK3CA cl MAF associated with a trend for higher TTF (11.4 vs 5.6m, HR 2.3, P = .22). In multivariate models, PIK3CAmut, ET/CT combo, and receiving PAMi ≤ 2nd line associated with better TTF (all P < .005), but not tumor subtype, N/metastatic sites, type of PAMi, or PIK3CA clonality. Conclusions: PIK3CAmut associated with increased efficacy of PAMi, mainly with combos given in 1st/2nd line. The high proportion of PIK3CA cl MAF may suggest that PIK3CAmut is a truncal event in those tumors. Despite small numbers, pts with cl events had longer TTF while on matched targeted drugs. This association, described in EGFRmut lung cancer with selective inhibitors, needs confirmation in larger homogenous clinical trial cohorts.
Abstract 314: Allogeneic Cortical Bone Stem Cells Preserve Cardiac Structure and Function by Inhibition of Cell Death and Enhancing Angiogenesis in the Swine Heart After Myocardial Infarction
Authors: Thomas E Sharp, Remus M Berretta, Timothy Starosta, Sadia Mohsin, Jon C George, Jason M Duran, Hajime Kubo, Steven R Houser
Journal: Circulation Research (2015)

Introduction: Novel therapies are needed to improve cardiac function after MI; one strategy is to replace lost myocardium. Despite the success of bone marrow- and cardiac- stem cell clinical trials, we’re still searching for the optimal stem cell type most suitable for cardiac regeneration. Previously, we described a novel cell population derived from the cortical bone (CBSCs) which repaired the heart post MI via transdifferentiation and paracrine signaling mechanisms in a mouse model. In the present study, we evaluate the translational potential of allogeneic CBSCs in swine MI model. Hypothesis: Intramyocardial injection of CBSCs into the MI border zone immediately after reperfusion will preserve cardiac structure and pump function by enhancing endogenous repair through secretion of paracrine factors. Methods &amp; Results: Female Göttingen minipigs received MI via occlusion of the left anterior descending coronary artery (LAD) for 90 minutes, followed by reperfusion. Animals received either 20 million CBSCs (via 10 intramyocardial injections) or saline injections. Cardiac structure and function was evaluated using echocardiography at baseline and 4 weeks post-MI. During the 4 weeks after MI there was depression if pump function in saline treated group (EF: 69.27% ± 1.92 [baseline] to 46.305% ± 3.53 [4 weeks post MI] p&lt;0.0001 ) and dilation of the LV (EDV: 39.01 ml ± 3.47 [baseline] to 51.5 ml ± 5.67 [4 weeks post MI] and ESV was 13.71 ml ± 2.47 to 27.72 ml ± 3.86 ( p= 0.0136 ). The MI + CBSC group had no significant change in ventricular pump function from baseline to 4 weeks post-MI; while demonstrating preservation of cardiac structure indicating a decrease in ventricular remodeling/scar formation. A decrease in TUNEL+ cells and an increase in angiogenesis was also observed in CBSC’s treated animals. Conclusion: CBSC’s appear to reduce infarct expansion by reducing post MI myocyte death and by increasing angiogenesis. These data show that administration of CBSCs immediately after reperfusion of an infarcted region of the heart can reduce adverse cardiac remodeling and improve cardiac function.
Multi-institutional study of triple negative breast cancer stratification by a metric that quantifies cell cycling kinetics.
Authors: Sergey Klimov, Guanhao Wei, Andrew R. Green, Mohammed Aleskandarany, Emad Rakha, Ian O. Ellis, Guilherme Henrique Cantuaria, Ayodeji Agboola, Michelle D. Reid, Xiaoxian Li, Padmashree C.G. Rida, Remus Osan, Ritu Aneja
Journal: Journal of Clinical Oncology (2016)

1091 Background: Ki67 Index (KI) and Mitotic Index (MI) are proliferation markers with established prognostic value in breast cancer. These indices are evaluated individually and on disparate measurement scales; they therefore fail to capture information about cell cycling kinetics of proliferating cells. Methods: Pathology reports of breast cancer patients (n = 10,504 from Northside Hospital, Atlanta and n = 1560 from Nottingham Hospital, UK) were retrospectively analyzed for mitotic scores, KI and clinical outcomes. Mitotic counts in 267 H&E-stained breast carcinoma samples were evaluated by two pathologists to transform mitotic scores into %MI based on cellularity. %MI: %KI ratio was defined as the Ki67 Adjusted Mitotic Score (KAMS), which reflects cycling kinetics of proliferative cells. Ability of KAMS to stratify triple negative breast cancers (TNBCs) was tested in three cohorts who received only adjuvant chemotherapy (n = 478 from Northside Hospital, USA; n = 322 from Nottingham Hospital, UK, and n = 108 from Olabisi Onabanjo University, Nigeria). Stratification of KAMS, KI and MI were performed on the thresholds that produced the lowest AIC (best model fit). Slow cycling and fast cycling TNBC subgroups from Nottingham Hospital were analyzed for biomarker expression. Results: Kaplan-Meier survival analyses, AIC and c2values showed that KAMS based stratification of TNBCs into two subgroups was superior to that by either KI or MI, regardless of hospital, and KAMS retained its significance in multivariate analyses. Fast-cycling TNBCs have poorer prognosis than slow-cycling TNBCs, perhaps due to higher intratumoral heterogeneity in fast cycling tumors. Fast-cycling TNBCs showed high expression of proteins implicated in DNA damage response, sumoylation, EGFR signaling and metastasis. By contrast, slow-cycling TNBCs showed extensive chromatin modification. Conclusions: KAMS quantifies cell cycling kinetics, stratifies TNBCs and yields new risk-predictive information that is not revealed by either KI or MI. KAMS reveals the underlying heterogeneity in cycling kinetics among TNBCs and helps identify TNBCs who might benefit from treatments that target the cell cycle machinery.