tbuckley/cabot-search huggingface dataset:
ERBB2 and PI3KCA mutations in endocrine resistant breast cancer (BC)
Authors: M. Venturelli, A. Toss, F. Piacentini, I. Bernardis, E. Tenedini, C. Omarini, L. Moscetti, S. Cascinu, E. Tagliafico, L. Cortesi
Journal: Annals of Oncology (2018)

Background: An increasing number of molecularly targeted drugs are now available and, for some of these therapies, predictive biomarkers have already been identified. In particular, mutations in ERBB2 might represent an alternative mechanism for HER2 activation. They occur more frequently in HER2-negative (HER2-) tumors and seem to be good target for HER2 therapy. Furthermore, PI3KCA mutations showed to predict sensitivity to Fulvestrant, Buparlisib, Taselisib and resistance to Lapatinib. We evaluated the incidence of ERBB2 and PI3KCA mutations in 14 hormone receptor (HR)-positive BC and in their matched endocrine-resistant recurrences. Methods: We evaluated a panel of genes including ERBB2 and PI3KCA, in FFPE tissues. We analysed 14 HR-positive BCs and their matched recurrences. All the relapses have been developed during an endocrine treatment. Results: 4/14 pts were diagnosed with HER2+ BC, while 10/14 pts developed HER2- BC. Overall, we found 8 different mutations of ERBB2 in 9 samples: A356D, Q1206X, Q396X, Q393X, P523L, I654V, G1220C, 135 + 3G>T. We found 6 different mutations of PI3KCA in 10 samples: N345K, V344M, E542K, E545K, A1035V, H1047R. ERBB2 mutations were found in the 28.6% of primary tumors and in the 35.7% of relapsed sites. PI3KCA mutations were found in the 35.7% of primary tumors and in the 35.7% of relapsed sites. mOS in PI3KCA mutated pts was 112,8 months, while mOS in PI3KCA wild-type pts was 99. mOS in HER2+ and/or ERBB2 mutated pts was 115.6 months, while mOS in HER2- ERBB2 wild type pts was 97.5. mDFS in PI3KCA mutated pts was 41.2 months, while mDFS in PI3KCA wild-type pts was 28. mDFS in HER2+ and/or ERBB2 mutated pts was 46.4 months, while mDFS in HER2- wild-type pts was 28.5. Conclusions: We found an overall detection rate of ERBB2 mutations higher than that described in literature, while PI3KCA mutations were in line with the literature. The identification of ERBB2 or PI3KCA mutation might justify a more targeted neo/adjuvant approach and might guide the subsequent treatment choices. According to the literature, pts with PI3KCA mutation showed better prognosis, while, contrary to the previous literature, in our study the majority of ERBB2 mutations occurred in HER2+ samples and HER2+ and/or ERBB2 mutated samples did not show worse outcomes. Legal entity responsible for the study: Marta Venturelli. Funding: Angela Serra Association. Disclosure: All authors have declared no conflicts of interest.
Correlation of circulating tumor cells (CTCs) with peripheral blood leukocytes to predict outcome in metastatic breast cancer (MBC).
Authors: Ugo De Giorgi, Michal Mego, Emanuela Scarpi, Antonio Giordano, Mario Giuliano, Vicente Valero, Ricardo H. Alvarez, Naoto T. Ueno, Massimo Cristofanilli, James M. Reuben
Journal: Journal of Clinical Oncology (2016)

11532 Background: We retrospectively evaluated the correlation between a baseline measurement of CTCs and neutrophils, lymphocytes and platelets levels from peripheral blood along with the neutrophyl-lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR) and systemic immune-inflammation index (SII), as general measures of immune-inflammation status in MBC. Methods: CTCs detection (CTCs+ = ≥ 5CTCs), white blood cell (WBC) counts plus platelet levels, and tumor features of 516 women with MBC before starting a new treatment between July 2002 and June 2009 were recorded at the Department of Breast Medical Oncology, MD Anderson Cancer Center. Counts were log-transformed and effects on these by tumor features and epidemiologic variables assessed by generalized linear models, followed by Cox proportional hazards models to assess effects on overall survival (OS). The optimal predictive value of NLR, PLR and SII to predict survival was determined and compared with CTC < 5 or > 5 per 7.5 ml of blood (CellSeach, Janssen Diagnostics). Results: In the overall population (n = 516), CTCs+ correlated with monocytes (p = 0.008) and neutrophils (p = 0.038). CTCs+ correlated with monocyte count only in triple negative tumors (n = 125), p = 0.009, with neutrophil count in HER2+ tumors (n = 100), p = 0.009, with a trend versus monocyte count, p = 0.061, whereas no correlation was found in HER2- estrogen receptor+ tumors (n = 280). In the overall population, univariate logistic regression analyses of WBC, differential counts, NLR, PLR and SII as a function of CTC ( < 5, ≥ 5) correlated with WBC (OR 1.11, p = 0.006), neutrophils (OR 1.09, p = 0.045) and monocytes (OR 3.75, p = 0.001). In multivariate analysis only monocytes remained associated with CTCs+ (OR 2.72, 95% CI 1.09-6.80, p = 0.033). The following variables predicted OS: CTCs+ (HR 1.82; p < 0.0001), NLR (HR 1.47; p = 0.009), PLR (HR 1.46; p = 0.010), SII (HR 1.34.p = 0.047), respectively. Conclusions: CTC, NLR, PLR, and SII are predictors of OS in MBC. CTC directly correlates with monocytes, in particular in triple negative tumors. Links between CTC and monocytes may provide new clues about the pathogenesis and progression of MBC.
Efficacy of busulfan-melphalan high dose chemotherapy consolidation (BuMel) compared to conventional chemotherapy combined with lung irradiation in ewing sarcoma (ES) with primary lung metastases: Results of EURO-EWING 99-R2pulm randomized trial (EE99R2pul).
Authors: Uta Dirksen, Marie-Cecile Le Deley, Bernadette Brennan, Ian Robert Judson, Mark L. Bernstein, Richard Greg Gorlick, Neyssa Marina, Richard B. Womer, Nathalie Cozic, Nathalie Gaspar, Gwenael Le Teuff, Perrine Marec-Berard, Andreas Faldum, Michael Paulussen, Herbert Juergens, Lars Hjorth, Keith Wheatley, Mark D. Krailo, Jeremy Whelan, Douglas S. Hawkins
Journal: Journal of Clinical Oncology (2016)

11001 Background: EE99R2pul (ISRCTN61438620) was conducted in 16 countries, by 5 cooperative groups: COG, SFCE/GSF, GPOH, UK CCLG, EORTC. It evaluated the effect on event-free (EFS, main endpoint) and overall survival (OS) of BuMel without radiation to the lung, compared to standard chemotherapy with lung irradiation in ES presenting with metastases to the lung or pleura. Methods: Eligible pts had histological confirmation of ES, lung or pleural metastases, no other metastatic site, were aged <50, received chemotherapy with 6 VIDE (vincristine, ifosfamide, doxorubicin, etoposide) courses and 1 VAI (vincristine, actinomycin-D, ifosfamide) before randomization to BuMel with stem cell rescue or VAI x 7 courses and lung irradiation (VAI-RT). The analysis was conducted as intention-to-treat. The estimate of the hazard ratio, HR, and the p-value were corrected for the 3 previous interim analyses by the Inverse Normal Method. Results: Between 2000 and 2014, from 576 pts with lung or pleural metastases, 265 pts (median age, 14 yrs) were randomized to VAI-RT (132) or BuMel (133). Some pts requiring radiation therapy to the primary site were excluded from randomization to avoid excess organ toxicity from interaction between RT and Busulfan. Median follow up is 7.6 yrs. Overall, 3yr-EFS is 53.0% and OS, 68.4%. We did not observe any significant difference in survival outcomes between treatment groups: For BuMel pts, 3yr-EFS was 55.7% (95%CI, 47.0-64.0) vs. 50.3% (95CI%, 41.8-58.9) for VAI-RT pts, hazard ratio (HR) of 0.80 (0.57-1.14), p=0.21. OS is 55.9% for BuMel vs. 51.5% for VAI-RT, HR 0.97 (0.66-1.42), p=0.88. Results were consistent across subgroups, and in the sensitivity analyses. Three pts died of BuMel-related toxicity and none after standard chemotherapy. Significantly more pts in BuMel-arm experienced severe acute toxicities than in the VAI-RT arm. Conclusions: In ES with lung metastases, there is no clear benefit associated with BuMel high-dose chemotherapy without lung irradiation compared to conventional chemotherapy combined with lung irradiation. Clinical trial information: 61438620.
A phase Ib, first-in-human, dose escalation and expansion study of XMT-1522, a novel antibody-drug conjugate (ADC) directed against HER2, in patients with advanced breast cancer and other advanced tumors expressing HER2.
Authors: Howard A. Burris, Minal A. Barve, Erika Paige Hamilton, Aditya Bardia, Hatem Hussein Soliman, Donna Jarlenski, Rebecca Mosher, Donald Alan Bergstrom
Journal: Journal of Clinical Oncology (2017)

TPS2606 Background: XMT-1522 is an ADC consisting of a novel human IgG1 anti-HER2 monoclonal antibody conjugated to an auristatin-based cytotoxic payload (AF-HPA). An average of 12 AF-HPA molecules is conjugated to each antibody via a biodegradable polymer. In pre-clinical xenograft experiments XMT-1522 achieved complete, durable tumor regressions in models of HER2-positive and HER2 1+/2+ breast cancer, HER2 2+/3+ NSCLC, and HER2-positive and HER2 1+ gastric cancer. Methods: This study (NCT02952729) is comprised of two parts: a dose escalation segment (DES) and an expansion segment (EXP). The primary objectives of the DES are determination of the maximum tolerated dose and recommended Phase 2 dose (RP2D) and assessment of safety and tolerability. The DES will enroll patients with advanced or metastatic breast cancer who have progressed following standard therapies and have HER2 protein at least 1+ by IHC. XMT-1522 will be administered intravenously every 3 weeks. DES uses a 3+3 design. Post-dose assessments include LVEF measurement at the end of cycles 1, 3, then every 3 cycles, ophthalmologic exams at the end of cycles 1, 2, then every 2 cycles, and re-staging CT scans every 2 cycles. Pharmacokinetics of antibody, AF-HPA payload and an AF-HPA metabolite will be measured. Two patients have completed dose level 1 without DLT. The EXP segment will open at the RP2D and will further assess safety and tolerability of XMT-1522 and assess efficacy in selected patient populations. EXP will enroll 4 cohorts (N = 20 each). Cohort 1: HER2 1+/2+ advanced breast cancer with 2-3 prior chemotherapy regimens Cohort 2: HER2-positive advanced breast cancer with prior pertuzumab and ado-trastuzumab emtansine (T-DM1) Cohort 3: HER2-positive advanced gastric cancer with prior trastuzumab Cohort 4: HER2 2+/3+ NSCLC with at least 1 prior platinum regimen The protocol requires archival tumor tissue for central confirmation of HER2 status, alternative HER2 measurements, and targeted gene expression and sequencing studies. Tumor biopsies will be requested at the time of progression from patients who responded to XMT-1522. Clinical trial information: NCT02952729.
Expression profile associated with CD274 (PD-L1) expression in cervical cancer.
Authors: Edgar Roman Bassaure, Jaime Berumen Campos, Ingrid Yasbeth Medina
Journal: Journal of Clinical Oncology (2017)

e17005 Background: In Mexico, cervical cancer (CaCU) is the second leading cause of death in women. New treatment strategies are now emerging specifically the pathway of PD-1. We evaluated the frequency of PD-L1 expression at mRNA level and analyzed the expression profiles associated with different levels of CD274 expression. Methods: We analyzed the mRNA of 17 controls and 59 cervical cancer tumors by an expression microarray that allows the analysis of 22,607 human genes. Tumors were classified based on the mRNA expression of CD274. The deregulated genes in each group of tumors were compared against the control group using a T-test and Fold Change value. Functional analysis was using the DAVID tool. Correlation gene analysis was performed using the Pearson test. Results: The 59 cervical cancer tumors were classified in 3 groups: CD274-, CD274 low expression and CD274 high expression. The 71.2% of the tumors of CaCU have CD274 expression, 20 tumors with low expression and 22 tumors with high expression. 786 altered genes in the CD274- group, 1759 in the group of low expression and 2465 in the group of high expression were found. We found 19 altered biological processes in the CD274- group, being the most significant, cell cycle, DNA replication and DNA repair. In the tumors CD274 low were found 20 biological processes altered and were similar to those identified in the CD274- tumors. In the group CD274 high, 28 altered biological processes were found, interestingly 5 biological processes associated with innate immune response and antigenic processing. We found 24 genes correlated with the CD274 expression related to the immune response. Conclusions: The frequency of CD274 expression in cervical cancer is similar to that found in other tumors, it would be interesting explore the correlation between mRNA and protein. The number of altered genes is higher in the group of high expression of CD274. In the CD274 high group genes associated with processes related to the immune response are altered. The genes that correlate with the expression of CD274 are mostly associated with the immune system, these results suggest that overexpression of CD274 is accompanied by other immune processes.
Cytokeratin 19 expression as a risk factor for metastasis in cutaneous squamous cell carcinoma.
Authors: Hisashi Uhara, Junji Kato, Tokimasa Hida
Journal: Journal of Clinical Oncology (2018)

e21603 Background: Cytokeratin 19 (CK19) expression has been reported to be a risk factor for metastasis in some malignancies including oral squamous cell carcinoma. However, the significance of CK19 expression in cutaneous squamous cell carcinoma (cSCC) is unclear. The aim of this study is to clarify the relationship between CK19 expression in cSCC and metastasis. Methods: We retrospectively evaluated 42 cases of cSCC obtained from 2010 to 2016 in our hospital. Immunohistochemically, the population of CK19-expressing tumour cells was classified as < 1%, 1–49%, and ≥ 50%. Results: The rates of metastasis and poor histopathological differentiation were higher in the ≥ 50% group than in the < 50% group in univariate analysis. A multivariate analysis also showed significant correlation between CK19 expression and metastasis. By contrast, no association between CK19 expression and clinicopathological factors was found when a 1% cut-off value was used. Conclusions: High CK19 expression was more frequent in metastatic cSCC than that without metastasis. CK19 expression may be an indicator for metastasis in cSCC.
A phase I/II study of the oncolytic peptide LTX-315 combined with checkpoint inhibition generates <i>de novo</i> T-cell responses and clinical benefit in patients with advanced solid tumors.
Authors: James F. Spicer, Aurelien Marabelle, Jean-Francois Baurain, Ahmad Awada, Rebecca Sophie Kristeleit, Dag Erik Jossang, Nina Jebsen, Delphine Loirat, Anne Caroline Armstrong, Giuseppe Curigliano, Berit Nicolaisen, Oystein Rekdal, Baldur Sveinbjornsson, Vibeke Sundvold Gjerstad, Paal Brunsvig
Journal: Journal of Clinical Oncology (2018)

3094 Background: LTX-315 disintegrates cytoplasmic organelles and induces immunogenic cell death and systemic immune responses preclinically. Systemic efficacy can be enhanced in vivo by combination with immune checkpoint inhibitors (ICI). Clinical safety has been demonstrated as a single agent administered intratumorally in a phase I study Methods: Patients with heavily pretreated advanced solid tumors were treated twice weekly with intratumoral LTX-315 over 3 weeks; as monotherapy, or in combination with ipilimumab or pembrolizumab. Primary endpoint was safety of LTX-315 combined with ICI. Anti-tumor activity was assessed by using immune-related response criteria (irRC). Immunohistochemistry and gene expression analysis were performed on tumor biopsies pre and post treatment. T-cell receptor (TCR) repertoire in peripheral blood and biopsies was assessed by TCRb-gene sequencing. Results: Fifty-nine patients were treated. Eleven experienced LTX-315-related grade 3/4 adverse events, mainly allergic/anaphylaxis, all resolving without sequelae. Out of 36 patients treated with LTX-315 monotherapy, best overall response of SD at 2 months was seen in 28%. Out of 17 TNBC patients treated with LTX-315 plus pembrolizumab, 12 were evaluable, of which 17% had PR, and 25% SD. Six melanoma patients received LTX-315 plus ipilimumab, of those SD was observed in 33%. LTX-315 monotherapy resulted in increased number of CD8+ T-cells in treated lesions in 89% of evaluable biopsied patients. TCR sequencing revealed clonal expansion of T-cells in blood after LTX-315 monotherapy, and 50% of these clones were detected in post-treatment biopsied tumors. Conclusions: Intratumoral LTX-315 is generally safe and tolerable when combined with ICI. The combination has anti-tumor activity. LTX-315 monotherapy enhances TIL population and induces polyclonal T-cell responses, demonstrating the potential of LTX-315 as a T-cell primer combined with other immunotherapies. Clinical trial information: NCT01986426.
Accountable care organizations and the use of prostate cancer screening and breast cancer screening.
Authors: Quoc-Dien Trinh, Christian Meyer, Anna Krasnova, Jesse Sammon, Stuart R. Lipsitz, Joel S. Weissman, Maxine Sun
Journal: Journal of Clinical Oncology (2017)

e18308 Background: Accountable Care Organizations (ACOs) were established under the Affordable Care Act as a new payment model intended to impose greater responsibility on all stakeholders for cost control and quality improvement. Preventive services are an ideal target to monitor the effectiveness of new health care delivery models. We sought to examine and compare the prevalence of breast cancer screening (BCa-S), and prostate cancer screening (PCa-S) between ACO and traditional Medicare beneficiaries. We hypothesized that the use of BCa-S is higher among beneficiaries attributed to an ACO, whereas the use of PCa-S, a non-recommended test, would be unaffected by ACO assignment. Methods: Using a random 20% sample of Medicare beneficiaries, we assessed BCa-S in women aged &lt; 75, (evidence-based cancer screening), and PCa-S in men &lt; 75 (non-recommended cancer screening) between January 1, 2013 and December 31, 2013 with appropriate exclusion criteria following the review of guideline recommendations. ACO coverage was ascertained from the quarterly assignment in the Shared Savings Program ACO Beneficiary-level file. Propensity-score weighting was performed to balance out patient and sociodemographic covariates. Results: Following propensity-score weighting, our final cohorts of ACO and traditional Medicare beneficiaries included 52,987 and 526,063 women for BCa-S; 86,936 and 814,221 men for PCa-S, respectively. The prevalence of screening in ACO vs. traditional Medicare were 35.0% vs. 25.2% for BCa-S, and 54.6% vs. 41.7% for PCa-S (all p &lt; 0.001) Conclusions: The ACO model appears to have a salutary effect on preventive service utilization. Our findings vis-à-vis PCa-S among ACOs are likely a reflection of improved health care access rather than vetted screening practices. There is hope that such nonrecommended screening will decrease if more ACOs are required to move towards a “two-sided” risk shared savings and loss model.
Effect of premorbid body mass index on mortality in patients with lung cancer: A systematic review and meta-analysis.
Authors: Arjun Gupta, Kaustav Majumder, Nivedita Arora, Helen G Mayo, Preet Paul Singh, Siddharth Singh, Ethan Halm, David H. Johnson
Journal: Journal of Clinical Oncology (2016)

8523 Background: Obesity is associated with reduced risk of developing lung cancer (LC), but its effect on LC mortality remains unclear. We performed a systematic review and meta-analysis to assess the association between premorbid body mass index (BMI) and LC mortality. Methods: Conducting a systematic search of MEDLINE and the Cochrane library through December 2015, we identified observational studies reporting the association between premorbid BMI, and mortality in LC patients. We estimated summary adjusted hazard ratio (aHR) with 95% confidence intervals (CI), comparing highest vs. lowest BMI category, and obese (BMI > 30 kg/m2) and overweight (BMI 25-29.9 kg/m2) categories with reference category in each study, using random effects model; heterogeneity was measured using the inconsistency index (I2). Results: 16 studies were initially identified of which 5 were excluded since data did not allow for estimation of aHR using predefined obesity categories. 11 studies (including 1 pooled cohort study) comprising 2,953,278 individuals at inception, in whom 27,282 LC deaths occurred were analysed. On meta-analysis, highest vs lowest BMI category was associated with 33% reduction in LC mortality (11 studies, aHR, 0.67; 95% CI, 0.54-0.82; I2= 90%). After exclusion of one study which was contributing to considerable heterogeneity, a significant 21% reduction in LC mortality was a more conservative, consistent estimate (aHR, 0.79; 95% CI, 0.73-0.85; I2= 26%). Compared with LC patients with normal BMI, a reduction in mortality in both overweight [9 studies, aHR, 0.83; 95% CI, 0.78-0.89; I2= 68%] and obese [9 studies, aHR 0.80, 95% CI; 0.74-0.87; I2= 45%] individuals was seen, p-value between obese and overweight vs normal, 0.30). On subgroup analysis by sex and smoking status, no difference was noted between men vs women, and never smokers vs ever-smokers. Conclusions: Based on meta-analysis, obese and overweight LC patients have reduced mortality compared to leaner individuals. There was no clear dose response relationship between BMI and LC mortality in our study. The protective effect was seen across sexes and smoking status. Ideal body weight in LC patients should be reconsidered.
Combination of dabrafenib (DAB) and lapatinib (LAP) for the treatment of <i>BRAF</i>-mutant thyroid cancer.
Authors: Eric Jeffrey Sherman, Alan Loh Ho, James A. Fagin, Sofia Haque, Crystal Robinson, Ronald A. Ghossein, Helen X. Chen, David G. Pfister
Journal: Journal of Clinical Oncology (2018)

6087 Background: mutations (BRAFm) are the most common mutations in thyroid cancer. BRAF inhibitors (DAB) are active in BRAFm melanoma, but there is less activity noted in BRAFm thyroid cancer. Preclinically, BRAF inhibitors inhibit BRAFm thyroid cancers only transiently due to activation of HER2/HER3, driven by a neuregulin-dependent autocrine loop. The addition of LAP, a HER2/HER3 kinase inhibitor, sensitizes the cell to growth suppression by BRAF inhibitors (Cancer Discov 5(3):520, 2013). This study evaluates the safety and efficacy of the combination of DAB and LAP. Methods: Eligibility included thyroid cancers with the presence of a BRAFV600E mutation. Any prior treatment was allowed. All patients received DAB 150 mg bid starting 2 weeks prior to LAP. Doses of daily lapatinib were escalated in a standard 3+3 design at (1) 750 mg; (2) 1250 mg; (3) 1500 mg. Patients removed before the start of LAP were not included in the analysis. An additional 6 patients were added at the MTD. Responses were defined using RECIST 1.1. Results: 21 evaluable patients were enrolled on the phase I portion of the study. Gender – 14/21 (67%) male; median age – 63 years; histology – differentiated thyroid cancer (DTC) 19 (90%), anaplastic thyroid cancer (ATC) 2 (10%); brain metastases – 5 (24%); prior BRAF inhibitor – 5 (24%); prior BRAF or tyrosine kinase inhibitor – 13 (62%). There was one DLT - Grade 5 event unlikely related to drugs in a patient with ATC. Grade 4 toxicities – 0. Grade 3 toxicities –lymphocytes (1); uveitis (1). Median progression-free survival (PFS) and overall response rate (RR) of the subsets in the DTC only group are listed in the table. Clinical trial information: NCT01947023. Conclusions: The combination of DAB 150 mg bid and LAP 1500 mg daily was safe and well-tolerated. Despite the number of subjects with prior treatment (including with BRAF inhibitors) and brain metastases, excellent activity was found with this combination in DTC. Further investigation with this regimen is warranted. # RR PFS (months) DTC 19 58% 18 Dose Level 1 (LAP 750 mg) 5 60% 11 Dose Level 2 (LAP 1250 mg) 2 50% 16 Dose Level 3 (LAP 1500 mg) 12 58% 18 No prior BRAF inhibitor 14 64% 20 No brain metastases 14 57% 20 No prior BRAF inhibitor or brain metastases 11 64% 29