bluuebunny/crossref_metadata_2025 huggingface dataset:
A randomized phase III study to determine the efficacy of capecitabine in addition to a taxane and bevacizumab as first-line therapy in patients with metastatic breast cancer.
Authors: Lueck Hans-Joachim , Luebbe Kristina , Bischoff Joachim , Maass Nicolai , Feisel Gabriele , Tome Oliver , Janni Wolfgang , Aydogdu Mustafa , Neuhoeffer Tanja , Ober Angelika , Aktas Bahriye , Park-Simon Tjoung-Won , Schumacher Claudia , Hoeffkes Heinz-Gert , Illmer Thomas , Wagner Harald , Mehta Keyur , Nekljudova Valentina , Loibl Sibylle , Von Minckwitz Gunter ,   German Breast Group
Published: March 2020

1082

Background: Conventional chemotherapy combined with novel molecular targeted agents has been proven effective and tolerable in metastatic breast cancer (MBC). Taxanes (T) plus bevacizumab (B) and T plus capecitabine (X) showed a benefit in progression free survival (PFS) compared to T alone. Life-threatening or highly symptomatic situations require poly-chemotherapies in MBC patients; therefore a combination of all 3 drugs appears reasonable. Methods: TABEA (NCT01200212) is a prospective, randomized, open label, phase III trial comparing T plus B +/- X as 1st-line therapy in MBC. Patients with histologically confirmed HER2- locally advanced or MBC were included. All patients received T (paclitaxel 80 mg/m2 i.v. d1,8,15 q22 or docetaxel 75 mg/m2 i.v. d1 q22) and B (15 mg/kg i.v. d1 q22) (TB) and were randomized to X (1800 mg/m² daily d1-14 q22) in addition and concurrently to TB (TBX) or TB alone. Randomization was stratified by receptor status, planned taxane, and disease free interval (≤ or >12 months). Primary objective was PFS. Secondary objectives were response rate and duration, clinical benefit rate (CR, PR, stable disease ≥ 24 weeks), 3yr overall survival, PFS in patients ≥ 65 years, toxicity, and compliance. Sample size calculation assumed a PFS of 10 and 13.3 months for TB and TBX, respectively (HR=0.75) requiring 432 patients and 386 events with 2-sided α=0.05 and β=0.2. Interim analysis was planned after 25% of required events (n=96). Results: Planned interim futility and safety analyses after 100 documented events in 202 patients have shown no efficacy benefit and higher toxicity in the TBX arm. For PFS, HR=1.061, 95% CI (0.715, 1.576) was observed, futility boundary was crossed. Overall grade 3-4 adverse events (e.g., thrombopenia, diarrhea, hand-foot-syndrome) (72.3 vs. 57.4%, p=0.039)and serious adverse events (40.6 vs. 24.8%, p=0.016) rates were higher for TBX after 16.3 months median follow up. There were 6 deaths in the TBX vs. 1 in the TB arm. Recruitment and therapy were stopped on 5th Oct 2012 following the advice from the IDMC. Conclusions: TABEA failed to show an improvement using the 3 drug regimen TBX in high-risk MBC patients. Clinical trial information: NCT 01200212.
Polymorphisms interaction to predict bevacizumab (BV) efficacy in metastatic breast cancer (MBC) patients (pts): An exploratory retrospective analysis.
Authors: Coltelli Luigi , Fontana Andrea , Bocci Guido , Camerini Andrea , Ferro Antonella , Cazzaniga Marina Elena , Casadei Virginia , Pazzagli Ilaria , Marcucci Lorenzo , Allegrini Giacomo , Lucchesi Sara , Bona Eleonora , Scalese Marco , Orlandi Paola , Villa Federica , Morini Silvano , Amoroso Domenico , Arrighi Giada , Filidei Mario , Falcone Alfredo
Published: March 2020

1086

Background: Previous retrospective studies have attempted to identify a possible role of VEGF single nucleotide polymorphisms (SNPs) to predict BV efficacy in terms of OS and PFS in MBC pts with conflicting results (Schneider 2008, Grimaldi 2011, Lambrechts 2011). Methods: On the basis of these preliminary data, we decided to assess in a MBC population if different VEGF, VEGFR-2, IL-8, IL-6, HIF-1alfa, EPAS-1 and TSP-1 genotypes could predict first line BV + paclitaxel (P) response in terms both of OS and PFS. Analyses were performed on germline DNA obtained from blood samples. Fourteen polymorphisms were investigated by real-time PCR technique. Both single and combinations of SNPs were investigated. The multifactor dimensionality reduction (MDR) methodology was applied to identify a genetic interaction profile for PFS ( http://sourgeforge.net/projects/mdr/ ). Results: 102 pts have been enrolled from 8 Oncology Units. Main pts characteristics are: median age 59 years (range 32-81), ECOG-PS 0/1 in 78%/22%, hormone receptor positive 83%, previous adjuvant chemotherapy 68%, disease free interval (DFI) < 12 months 27%. After a median follow up of 17.4 months (1.9-54.7), mPFS was 11.6 months (95% CI: 10.6-12.6) and mOS was 32.4 months (95% CI: 25.9-38.9). None of SNPs were individually associated with PFS. Conversely, a genetic interaction profile consisting of VEGFR-2 rs11133360 and IL-8 rs4073 was significantly associated with PFS. mPFS was 14 months (95% CI: 11.7-16.3) and 10.9 months (95% CI: 9.3-12.4) for the favorable and unfavorable genetic profile, respectively (HR=0.63, 95% CI: 0.4-0-99, p= 0.046). Furthermore, at the multivariate analysis hormone receptor positive (HR=0.22, 95% CI: 0.12-0-41, p<0.0001), DFI >12 months (HR= 0.4, 95% CI: 0.2-0.82, p= 0.011) and BV maintenance (HR=0.63, 95% CI: 0.25.0.71, p=0.001) were significantly associated with a better PFS. Conclusions: Genetic interaction between VEGFR-2 rs11133360 and IL-8 rs4073 polymorphisms could predict BV response in terms of PFS. With a longer follow-up correlations with OS will be investigated. Prospective study is planned. Study supported by the non-profit foundation F.A.R.O.
Use of mutational profiling of metastatic ER+/HER2- breast cancers and the coexistence of KRAS, MET, BRAF, and FGFR3 with PIK3CA mutations.
Authors: Fumagalli Debora , Salgado Roberto , Criscitiello Carmen , Pugliano Lina , Laios Ioanna , Wilson Timothy , Larsimont Denis , Piccart-Gebhart Martine J. , Michiels Stefan , Lackner Mark , Sotiriou Christos , Loi Sherene
Published: March 2020

11003

Background: ER+/HER2- breast cancers (BCs) constitute the most frequent BC subtype. Their response to endocrine therapy and degree of estrogen dependence are heterogeneous. There is little data available about the genetic changes associated with disease progression in this subtype. This information could facilitate drug development. Methods: A series of 132 ER+/HER2- BC patients diagnosed between 1982 and 2008, with known local-regional (n=10) or distant (n=98) relapse or both (n=24), and available FFPE blocks from their primary (P; n=132) and paired relapse (R; n=49) were identified at a single institution. ER and HER2 status were centrally confirmed. 120 mutations from 11 actionable genes and PTEN protein expression were determined using Fluidigm-based real-time PCR and IHC, respectively. Results: At primary diagnosis, median age was 57 years (27-90); median tumor size 2.5 cm (0.5-11); 75% had positive nodes, 26.5% were pre-menopausal; 80% received adjuvant hormonal treatment. Mutation frequency in P and R samples is presented in the Table. PIK3CA mutations were identified in 44% (58/132) P samples. HRAS, AKT1 and PIK3CA mutations were mutually exclusive. 62.5% (5/8) of KRAS-mutated, 75% (6/8) of MET-mutated, 100% (2/2) of BRAF-mutated and 33.3% (1/3) of FGFR3-mutated P had coexistent PIK3CA mutations. For the 49 evaluated pairs, high concordance for the mutations status was found between P and R. Conclusions: KRAS, BRAF, MET and FGFR3 mutations, found at relatively high frequency in this population of relapsed ER+/HER2- BCs, could represent clinically relevant targets and contribute to mechanisms of recurrence, particularly in PIK3CA-mutated BCs. Mutation profiling of additional paired samples is ongoing and clinical outcome data will be presented. [Table: see text]
Concurrent driver mutations in non-small cell lung cancer (NSCLC) patients (p) on targeted therapy uncovered by comprehensive molecular profiling.
Authors: Blakely Collin M. , Lin Luping , Asthana Saurabh , Sidiropoulos Nikoletta , Nelson Tyrrell , Bastian Boris C. , Gubens Matthew A. , Taylor Barry S. , Bivona Trever Grant
Published: March 2020

11004

Background: NSCLC p with EGFR mutations respond initially to EGFR tyrosine kinase inhibitors (TKIs) but invariably develop acquired EGFR TKI resistance. Prior studies identified the EGFR T790M mutation and activation of MET, PI3K, AXL, HER2 and the MAPK pathway as drivers of acquired EGFR TKI resistance. To date, comprehensive molecular profiling to identify actionable modifiers of EGFR TKI response has not been conducted in NSCLC p on therapy. Methods: We performed next generation sequencing (NGS) using a 263-gene Nimblegen custom cancer panel on DNA isolated from primary patient lung adenocarcinoma FFPE specimens prior to initiating standard erlotinib treatment and upon the development of acquired erlotinib resistance after only 3 months of therapy. Results: In the pretreatment sample, we confirmed the presence of the EGFRL858R mutation in 95% of the sequencing reads and discovered a concurrent BRAF V600E mutation with a frequency of ~ 6%. NGS performed on the acquired erlotinib resistance sample revealed acquisition of the EGFR T790M mutation with a frequency of ~ 14%. Notably, the frequency of the BRAF V600E mutation increased 10-fold upon acquired erlotinib resistance from ~ 6% in the pretreatment tumor to ~ 60% in the recurrent tumor. We found that overexpression of BRAF V600E in H3255 human NSCLC, which harbor EGFR L858R (but not BRAF V600E) and are erlotinib sensitive, caused resistance to erlotinib treatment (10-fold increase in erlotinib IC50). BRAF V600E-mediated erlotinib resistance was reversed by treatment with the BRAF inhibitor vemurafenib. Additional functional studies are ongoing and the complete dataset will be presented. Conclusions: These results indicate that EGFR-mutant NSCLC can harbor additional oncogenic driver mutations in BRAF at low frequencies prior to therapy. EGFR TKI treatment can lead to expansion of BRAF V600E expressing tumor cells, resulting in acquired EGFR TKI resistance that can be reversed by BRAF inhibitor treatment. The data demonstrate the utility of routine molecular profiling of NSCLC p on targeted therapy and offer unprecedented insight into the genetic basis of therapeutic resistance.
Prognostic relevance at 5 years of the early monitoring of neoadjuvant chemotherapy using FDG PET in luminal HER2-negative breast cancer.
Authors: Humbert Olivier , Berriolo-Riedinger Alina , Cochet Alexandre , Gauthier Mélanie , Charon-Barra Celine , Desmoulins Isabelle , Guiu Séverine , Toubeau Michel , Dygai-Cochet Inna , Coutant Charles , Fumoleau Pierre , Brunotte Francois
Published: March 2020

11007

Background: To evaluate, in the luminal breast cancer subtype, the prognostic value of tumor glucose metabolism at baseline and of its changes after one cycle of neoadjuvant chemotherapy (NAC). Methods: This prospective study included 61 women with immunophenotypically defined luminal HER2-negative breast cancer treated with NAC. 18F-FDG PET was performed at baseline. Hepatic activity was used as a reference to distinguish between low-metabolic and hypermetabolic tumors. In hypermetabolic tumors, a PET exam was repeated after the first course of NAC. The relative change in the maximal Standardized Uptake Value of the tumor (ΔSUV), corresponding to the metabolic response, was calculated. Results: Forty-two women had hypermetabolic tumors at baseline, corresponding to more proliferative breast cancers with higher Ki-67 expression (p=0.017) and higher grade (p=0.04). Nineteen women had low-metabolic tumors with lower proliferation indexes. Worse overall survival was associated with larger tumor size (>5cm, HR=6.52, P=0.009) and with hypermetabolic tumors achieving a low metabolic response after one cycle of NAC (ΔSUV<16%, HR=10.63, P=0.004). Five-year overall survival in these poor-response patients was 49.22% (95% CI=[14.76%-76.90%]). In contrast, overall survival in women with low-metabolic tumors or hypermetabolic/good-response tumors (ΔSUV≥16%) was good, 100% and 96.15%, respectively (95% CI=[75.69%-99.45%]). Conclusions: In luminal HER2-negative breast tumors, tumor metabolism at baseline and changes after the first course of NAC are surrogate markers of patients’ survival. A subgroup of women with hypermetabolic/bad-responding tumors correlated with poor prognosis can be identified. These results may create the ability to tailor the NAC regimen to the metabolic response at an early stage.
Tumor markers of efficacy and resistance to cetuximab (C) treatment in metastatic colorectal cancer (mCRC): Results from CALGB 80203 (Alliance).
Authors: Hurwitz Herbert , Cushman Stephanie , Jiang Chen , Shterev Ivo , Mahoney Michelle R. , Niedzwiecki Donna , Mayer Robert J. , Venook Alan Paul , Owzar Kouros , Nixon Andrew B. ,   Alliance for Clinical Trials in Oncology
Published: March 2020

11011

Background: Beyond KRAS status, there are no validated markers for anti-EGFR therapy in mCRC. While expression of genes within the EGF signaling axis has been reported to correlate with benefit, most reports used data from non-randomized trials which cannot distinguish between general prognostic markers and markers that predict for benefit from C. CALGB 80203 was a 238-patient (pt), 4-arm, randomized phase II study of FOLFOX or FOLFIRI +/- C in mCRC pts. Formalin-fixed, paraffin-embedded (FFPE) tumor samples from CALGB 80203 were analyzed for gene expression of HER family ligands, receptors and regulators. Methods: FFPE tumor samples from consenting pts were analyzed for AREG, BTC, CD73, DUSP4, EGF, EGFR, EPGN, EREG, HB-EGF, HER2, HER3, HER4, PHLDA1 and TGFa by RT-qPCR. Interaction between baseline gene expression levels and treatment (C) with respect to progression-free survival (PFS) and overall survival (OS) was modeled using a multiplicative Cox proportional hazards model. Results: Baseline tumor tissue was available from 103 pts; 55% of tumors were KRAS wild type (WT). Two prognostic markers were identified; higher tumor mRNA levels of HER2 (HR=0.64, p=0.002) and EREG (HR=0.89, p=0.016) were associated with longer PFS across all pts. Potential predictive markers of benefit for C were identified. In KRAS WT tumors, lower HER3 expression was associated with longer OS from C treatment while higher HER3 expression was associated with shorter OS from C treatment (chemo + C: HR=1.15; chemo only: HR=0.48, interaction p=0.029). No association was observed for HER3 and outcome in KRAS mutant (MT) tumors. Interestingly, higher CD73 expression was associated with longer PFS in C-treated pts in both KRASWT (chemo + C: HR=0.91; chemo only: HR=1.57, interaction p=0.026) and MT tumors (chemo + C: HR=0.80; chemo only: HR=1.29, p=0.025). Conclusions: In one of the first reports using data from a randomized study, gene expression of HER3 and CD73 were identified as potential predictive markers for C. These data implicate not only HER axis signaling but also immune modulation as potential mechanisms of C action and sensitivity, and warrant confirmation in other large randomized trials.
Massively parallel sequencing (MPS) of circulating DNA in patients with metastatic colorectal cancer (mCRC): Prognostic significance and early changes during chemotherapy (CT).
Authors: Tie Jeanne , Kinde Isaac , Wong Hui-Li , McKendrick Joseph James , Gibbs Peter , Singh Madhu Sudan , Karapetis Christos Stelios , Desai Jayesh , Tran Ben , Roebert Justin Kelvin , Kinzler Kenneth W. , Vogelstein Bert
Published: March 2020

11015

Background: Prognostic and predictive biomarkers in mCRC are urgently needed. Circulating tumor cells are a promising blood biomarker, but are detectable in only a minority of pts. Recently, analysis of circulating tumor DNA (ctDNA) has shown promise as a liquid biopsy, reflecting the evolving mutational status of the tumor. Here we explored baseline ctDNA as a prognostic marker, and early changes in ctDNA as a marker of CT response. Methods: Serial plasma samples and CEA were collected at baseline (D1), day 3 (D3) and cycle 2 day 1 (C2D1) from 40 mCRC pts receiving standard combination CT. Restaging scans performed at 8 weeks were centrally assessed using RECIST criteria. Samples were analyzed at Johns Hopkins Kimmel Cancer Center. Initially tumor tissue was analyzed for hotspot mutations in TP53, APC, KRAS, BRAF, PIK3CA and FBXW7. The same mutation was queried and quantified in plasma using a MPS platform (Safe-SeqS). Log-rank test was used to compare survival curves and Wilcoxon matched pairs test was used to compare paired plasma samples. Results: Preliminary data is available on 19 pts in this ongoing study. Using our initial panel at least 1 mutation was found in 16 of 19 (84.2%) tumors (7 KRAS, 3 TP53, 3 BRAF, 2 APC and 1 PIK3CA), with matching ctDNA found for each pt. For the remaining 3 cases a further panel of mutations is being analyzed. Median D1 cell free DNA (cfDNA) and ctDNA levels were 1.98 ng/ul (0.15 – 57.18) and 523 mutant fragments (frag)/ml (0.4 – 109,876), respectively. Pts with D1 cfDNA of ≥ 2.5 compared with < 2.5 had shorter median overall survival (OS; 6.9 v 12.2 months, p = 0.0086), with a trend for shorter progression-free survival (PFS; 3.6 v 8.2 months, p = 0.3477). A surge of ctDNA level from D1 to D3 was typically observed (median increase: 91.2 frag/ml, p = 0.0313), followed by a drop (median decrease from D1 to C2D1: 208.8 frag/ml, p = 0.0098). All pts with a decrease in ctDNA at C2D1 had a reduction in tumor size at 8 weeks. Conclusions: In all cases of mCRC where tumor mutation was identified, matching ctDNA was detected in plasma. Circulating DNA is a promising marker of prognosis. Early changes in DNA levels may be a useful marker of tumor response.
Study to explore the willingness of patients (pts) to undergo biopsy at the time of breast cancer (BC) recurrence.
Authors: Francl Mia Ivy , Sun Sophie , Villa Diego , Gelmon Karen A. , Lohrisch Caroline A.
Published: March 2020

1102

Background: Physicians (MDs) may not request a biopsy (BX) when metastatic (M1) diagnosis is certain, however, there is increasing awareness of the value of tissue for cancer discovery. In addition, biomarkers can change from initial BC to M1 in 20%, affecting treatment. With ethics approval we investigated under what conditions BC pts would agree to a BX of recurrent cancer, to guide MD practice. Methods: Consenting English speaking pts with M1, or at least 3 months post adjuvant therapy, were asked to complete a survey (at home or with research assistant) about willingness to undergo BX at M1. Demographic and disease information was collected. The BX scenarios increased in inconvenience/discomfort and decreased in direct benefit to pt. Results: Among 204 participants, mean age was 60 (29-92), 71% were caucasian, 73% completed more than high school, 84% lived within 1 hour of the cancer centre. 87 (43%) pts had no relapse (M0) and 116 (57%) had M1 (including 20 [17%] with local relapse only, 21 [18%] de novo M1). 82 (71%) of M1 pts reported having had a BX for M1. When it required only image guidance and minimal discomfort (eg ultrasound guided liver BX), 86% of M1 pts would have a BX to join a trial and 81% would for pure research; 69% and 76% of M0 pts would have a BX to join a trial, or for research only, respectively. The Table shows the responses for the most invasive BX. Conclusions: Two thirds of BC pts would undergo the most invasive/inconvenient BX to join a trial, and half would for pure research. This demonstrates a large degree of altruism in this BC population. Willingness increased as direct benefit increased and the pain/inconvenience decreased. This data suggests MDs should not be hesitant to ask BC pts for a BX at M1. This study was limited to English speaking pts and most were well educated, thus it may not reflect all cultural attitudes toward BX. [Table: see text]
Nondisruptive mutations of TP53 and overall survival (OS) in advanced non-small-cell lung cancer (NSCLC) patients (p).
Authors: Carcereny Costa Enric , Bertran-Alamillo Jordi , Molina-Vila Miguel Angel , Gervais Radj , Massuti Bartomeu , Bonanno Laura , Moran Teresa , Majem Margarita , Felip Enriqueta , Garcia-Campelo M. Rosario , Vergnenegre Alain , Viteri Ramirez Santiago , Gasco Amaya , Wannesson Luciano , Mayo-de las Casas Clara , Pujantell-Pastor Laia , Favaretto Adolfo G. , Karachaliou Niki , Rosell Rafael ,   Spanish Lung Cancer Group
Published: March 2020

11029

Background: The tumor suppressor TP53 is the most commonly mutated gene in lung cancer. Early-stage NSCLC p with TP53 mutations may have worse prognosis and be more radio/chemoresistant. However, few studies have addressed the issue of TP53 mutations in advanced NSCLC. We have retrospectively examined the influence of TP53 mutations on OS in 241 advanced NSCLC p. Methods: 99 EGFR-wild-type (wt), chemotherapy-treated p from 5 European hospitals and 142 EGFR-mutated (mut), erlotinib-treated p from two clinical studies were included. Exons 5, 6, 7 and 8 of TP53were analyzed by high resolution melting (HRM). All mutated samples were reconfirmed by sequencing. Mutations were classified as disruptive or non-disruptive based on their predicted effects on the function of the p53 protein. Results: TP53 mutations were detected in 31% of EGFR-wt and 24% of EGFR-mut p. OS results are available for 57 EGFR-wt p and 90 EGFR-mut p. Among EGFR-wt p, OS was 22 months (m) for p without TP53 mutations, 20m for p with disruptive TP53 mutations, and 9 m for p with non-disruptive TP53 mutations (P=0.09). Among EGFR-mut p, OS was 31 m for p without TP53 mutations, not reached for p with disruptive TP53 mutations, and 15 m for p with non-disruptive TP53 mutations (P=0.05). Complete OS results for all 241 p will be presented. Conclusions: Non-disruptive mutations in the TP53 gene are associated with shorter OS in advanced NSCLC p, both in EGFR-wt p treated with chemotherapy and in EGFR-mut p treated with erlotinib.These p could benefit from treatment to reactivate mutant p53.
Angiogenic marker associated with resistance to neoadjuvant chemoradiotherapy in rectal cancer.
Authors: Kim Hanjo , Lee Min Young , Ahn Tae Sung , Yun Jina , Kim Kyoungha , Kim Se Hyung , Kim Hyun Jung , Lee Sang Cheol , Bae Sang-Byung , Kim Chan Kyu , Lee Namsu , PARK Seong Kyu , Lee Kyu Taek , Won Jong-Ho , Hong Dae Sik , Park Hee Sook , Park Suk-Young , Lee Moon Soo , Baek Moo Jun
Published: March 2020

11030

Background: The ability to achieve pathologic down staging after neoadjuvant chemoradiotherapy (CRT) is correlated with improved survival. However, there is no effective method of predicting which patients will response to neoadjuvant CRT. Neoadjuvant CRT can change the expression of angiogenic factors. However, little is known about its possible changes in response to preoperative CRT. We examined the expression of angiogenic factors in rectal cancer tissues before preoperative CRT and after surgery. Methods: Fifty five patients with locally advanced rectal cancer were studied. All patients were given preoperative CRT of 5040 cGy for 5-6 weeks with concurrent administration of 5-fluorouracil and leucovorin. Surgical resection was performed 6–8 weeks later in all patients. Immunohistochemical staining for angiogenenic markers (vascular endothelial growth factor [VEGF], placenta growth factor [PLGF], hypoxia inducible factor 1α [HIF 1α], stromal cell derived factor [SDF 1α]) were performed on specimens obtained before preoperative CRT and after surgery. A semiquantitative-immunohistochemical score established from the extension and intensity of the angiogenic factors was used for analysis. Results: The positive expression rate of VEGF, PLGF, SDF 1α, and HIF 1α was 56.4% (31/55), 65.5% (36/55), 70.9% (39/55), and 47.3% (26/55), respectively. The expression rate of VEGF, PLGF, SDF 1α, and HIF 1α was increased by 3.6% (2/55), 7.3% (4/55), 30.9% (17/55), and 1.8% (1/55) after neoadjuvant CRT, respectively. Expression of VEGF, PLGF, and HIF 1α protein was downregulated after neoadjuvant CRT in the rectal cancer tissues (P < 0.001, P = 0.001, P = 0.044, respectively). However, SDF 1α was upregulated after neoadjuvant CRT (P < 0.001). And also, upregulated expression of SDF 1α after neoadjuvant CRT was significantly associated with resistance to CRT (P = 0.035). However, SDF 1α showed no correlation with other clinical factors (age, sex, clinical stage). Conclusions: Expression of SDF-1α was increased in the rectal cancer tissue after neoadjuvant CRT, as well as has been associated with CRT resistance. Our data suggests that SDF 1α should be evaluated as new target for antiangiogenic therapy.
LAMC2 as a prognostic marker that promotes metastasis of lung adenocarcinoma through epithelial-mensenchymal transition (EMT).
Authors: Moon Yongwha , Park Kang-seo , Kim John , Sarfaraz Sami , Voeller Donna , Trung Pham , Wang Yisong , Giaccone Giuseppe
Published: March 2020

11034

Background: Metastasis is the main cause of death in non-small cell lung cancer (NSCLC) patients. Genes responsible for NSCLC metastasis are unknown. LAMC2 is one of the 3 chains (α3, β3, γ2) of laminin 332, an important component of basement membranes, and LAMC2 involvement in metastasis is unclear. Methods: We have established a metastasis model in nude mice by repeated intracardiac injection of A549 lung adenocarcinoma cells. After 3-4 rounds of intracardiac injections, 100% metastasis penetrance was obtained. Microarray analysis was performed to identify genes differentially expressed between parental (A549P) and round-3 (A549R3) cells. In vitro migration/invasion and in vivo metastasis assays were performed in LAMC2-overexpressed A549P, LAMC2-knockdown A549R4, PC9, H358, and H322 cells. Public RNA microarray data of human NSCLC (GSE8894, GSE3141; n=249) and LAMC2 immunohistochemistry (IHC) of stage I NSCLC TMA samples (n=250) were analyzed to correlate LAMC2 and prognosis. Results: We identified LAMC2 as a putative metastasis marker of NSCLC through gene expression profiling of A549 cells enriched for metastasis in mice. Ectopic LAMC2 expression increased migration/invasion, whereas LAMC2 knockdown decreased migration/invasion in vitro. Conditioned media containing secreted LAMC2 promoted cell migration/invasion, which were blocked by LAMC2 knockdown or LAMC2 neutralizing antibody. Ectopic LAMC2 expression induced mesenchymal but decreased epithelial markers, indicating EMT, whereas LAMC2 knockdown elicited the opposite. A549R4 LAMC2 knockdown cells showed less metastatic activity than A549R4shRNA control cells in mice. In public microarray data high LAMC2 mRNA predicted high risk of recurrence (GSE8894, P=0.022; GSE3141, P=0.029) in adenocarcinoma (AC) but not squamous carcinoma (SC). Our IHC study showed that high LAMC2 predicted high risk of recurrence (hazard ratio =1.8; P=0.040) and death (hazard ratio=1.9; P=0.028) in AC but not SC by multivariate analysis. Conclusions: LAMC2 promotes metastasis through activation of EMT pathways, and is a potential prognostic marker and therapeutic target of metastasis in lung adenocarcinoma.
Fecal metabolome and microflora differences between colorectal cancer patients and healthy adults.
Authors: Weir Tiffany , Marschke Robert Frederick , Brown Regina J. , O'Malia Joanne , Dickson Erica , Bazan Marlon , Sheflin Amy , Heuberger Adam , Borresen Erica , Pettine Stefan , Ryan Elizabeth
Published: March 2020

11050

Background: High throughput genomic technologies such as 454 pyrosequencing and metabolomics platforms are now available to explore the relationships between gastrointestinal microflora, metabolism and colorectal cancer (CRC). Recent efforts to characterize the colorectal cancer microbiome have led to the identification of numerous bacteria whose presence or absence is associated with diseased tissue. Methods: Stool samples were collected from 10 healthy adults and 11 colorectal cancer patients prior to surgery at the University of Colorado Health-Poudre Valley Hospital in Fort Collins, CO. Fecal samples were processed for isolation of microbial DNA and sequenced using the 454 pyrosequencing platform. Metabolites were extracted using acidified water for short chain fatty acids (SCFA) and 3:2:2 isopropanol:acetonitrile:water to obtain global metabolite profiles utilizing Gas Chromatography-Mass Spectrometry (GC-MS). Results: There were no significant differences in the overall microbial community structure associated with disease state, but several bacterial genera, particularly butyrate-producing species, were under-represented in the CRC samples, while a mucin-degrading species, Akkermansia muciniphila, was about 4-fold higher in CRC (p<0.01). Consequently, the chemoprotective SCFA, butyrate, was significantly lower in CRC samples than in those from healthy adults (p<0.0001) and GC-MS profiling revealed that there were higher levels of amino acids in stool samples from CRC patients and higher poly and monounsaturated fatty acids in stool from healthy adults (p<0.01). Conclusions: This systems biology approach may allow us to identify functional groups of gastrointestinal bacteria and their associated metabolites as novel therapeutic and chemopreventive targets. The Colorado Agricultural Experiment Station, Shipley Foundation and the NIH R03CA150070 supported this work.
Effect of BRM promoter variants on survival outcomes of stage III-IV non-small cell lung cancer (NSCLC) patients.
Authors: Cuffe Sinead , Cheng Lu , Azad Abul Kalam , Brhane Yonathan , Cheng Dangxiao , Chen Zhuo , Qiu Xin , Boyd Kevin , Emami Marjan , Leighl Natasha B. , Der Sandy , Xu Wei , Shepherd Frances A. , Tsao Ming Sound , Reisman David , Liu Geoffrey
Published: March 2020

11057

Background: BRM, a key catalytic subunit of the SWI/SNF chromatin remodeling complex, is a putative tumor susceptibility gene in NSCLC. Loss of BRM expression occurs in 15% of NSCLC, and has been linked to adverse outcome. Recently, our group has shown that variants of two novel BRM promoter insertion polymorphisms (BRM-741, BRM-1321) lead to loss of BRM expression by recruiting histone deacetylases; individuals carrying homozygous variants for both polymorphisms have doubled NSCLC risk; pharmacological reversal of these epigenetic changes is a potentially viable therapeutic strategy. We thus evaluated the effect of BRM promoter variants on survival outcomes of advanced NSCLC patients, where initial clinical trials are likely to be focused. Methods: 564 stage III-IV NSCLC patients were genotyped for the BRM promoter variants using Taqman. Association of BRM variants and overall (OS) and progression-free survival (PFS) were assessed using Cox proportional hazard models adjusted for prognostic variables. Results: Among our patients, 73% were Caucasian, 52% male, median age 63yrs, 55% stage IV disease, and 67% adenocarcinoma. Median OS was 1.6yrs; median follow up, 3.6yrs. The frequency of homozygosity was BRM-741, 23%; BRM-1321, 21%; both, 12%. Homozygous variants of BRM-741 were strongly associated with worse OS (adjusted HR [aHR] 2.3 [p=2x10E-8]) and PFS (aHR 2.0 [p=2x10E-7]) compared to the wild types. Similar findings were observed for BRM-1321 homozygous variants (aHR for OS 1.8 [p=8x10E-5] and aHR for PFS 1.6 [p=2x10E-4]). Carrying homozygous variants of both BRM-741 and BRM-1321 was associated with substantially worse OS (aHR 2.3 [p=1x10E-5]) and PFS (aHR 2.2 [p=3x10E-6]), with similar associations seen among the stage III (aHR for OS 2.3 [p=6x10E-6]) and stage IV (aHR for OS 2.5 [p=5x10E-6]) patients. Conclusions: The same two homozygous BRM promoter variants that are associated with increased risk of NSCLC are also strongly associated with adverse OS and PFS in this cohort of stage III-IV NSCLC patients. Validation of results in a clinical trial dataset is underway, and will better elucidate the prognostic significance of these BRM promoter variants.
SPIO-enhanced MR imaging at 3T for the detection of metastases in sentinel nodes in patients with breast cancer.
Authors: Motomura Kazuyoshi , Takahashi Hiroyo , Nakayama Takahiro , Tamaki Yasuhiro , Nakanishi Katsuyuki
Published: March 2020

1107

Background: We previously demonstrated the usefulness of SPIO-enhanced MR imaging at 1.5T for the detection of metastases in sentinel nodes localized by computed tomography lymphography (CT-LG) in patients with breast cancer (Ann Surg Oncol 2011, ASCO 2012). The aim of this study was to evaluate the accuracy of MR imaging at 3T with SPIO enhancement for the detection of metastases in sentinel nodes. Methods: This study included 60 patients with breast cancer and clinically negative nodes. Sentinel nodes identified by CT-LG were evaluated prospectively using SPIO-enhanced MR imaging at 3T. A node was considered non-metastatic if it showed a homogenous low signal intensity and metastatic if the entire node or a focal area did not show a low signal intensity on MR imaging. Sentinel nodes located by CT-LG were removed, and imaging results and histopathological findings were compared. Results: The mean patient age was 54.2 years (range, 33-78). Sentinel nodes were identified by CT-LG successfully in 59 (98.3%) of 60 patients. The mean number of sentinel nodes identified by CT-LG was 1.43 (range, 1-3). All 16 patients with positive sentinel nodes definitively diagnosed by pathology demonstrated metastases on SPIO-enhanced MR imaging. Five (31.3%) of them had micrometastases. Forty-one of 43 patients with negative sentinel nodes definitively diagnosed by pathology were non-metastatic on imaging studies. The sensitivity, specificity and accuracy of MR imaging for the diagnosis of sentinel node metastases were 100%, 95.3%, and 96.6%, respectively. No adverse events were associated with either CT or MR imaging. Conclusions: SPIO-enhanced MR imaging at 3T is useful for accurate diagnosis of sentinel node metastases, and therefore sentinel node biopsy may be avoided for most patients with breast cancer.
The predictive role of integrated BRCA1 and HERC2 mRNA expression in advanced non-small cell lung cancer (NSCLC) patients (p) treated with platinum-based first-line chemotherapy.
Authors: Bonanno Laura , Costa Carlota , Sanchez Jose Javier , Majem Margarita , Gimenez Capitan Ana , Rodriguez Ignacio , Vergnenegre Alain , Massuti Bartomeu , Favaretto Adolfo G. , Rugge Massimo , Pallares Cinta , Taron Miquel , Rosell Rafael
Published: March 2020

11078

Background: The use of cis- or carboplatin is the backbone of first-line treatment for advanced NSCLC p, and currently no molecular markers of platinum sensitivity are used in routine clinical practice. Preclinical data and retrospective analyses have shown that high BRCA1 expression is associated with resistance to platinum. HERC2 is an E3 ubiquitin ligase promoting DNA repair by interacting with the E3 ubiquitin ligase RNF8 to facilitate the assembly of the RNF8-UBC13 complex, leading to the recruitment of BRCA1 and other DNA repair components responsible for double-strand break repair. Methods: We retrospectively analyzed 71 tumor samples from advanced NSCLC p treated with cis- or carboplatin plus gemcitabine or pemetrexed in the first-line setting. BRCA1 and HERC2 mRNA levels were determined by real-time PCR and categorized using medians as cut-off points. Results: Overall survival (OS) for all 71 p was 10.7 months (m), and progression free survival (PFS) was 7.2 m. Expression of both genes was successfully analyzed in 53 p (74. 6%). Neither gene as a single variable influenced outcome. However, the joint effect of BRCA1 and HERC2 was significant for predictive modeling. Among 30 p with low BRCA1 levels, OS was 15.3 m and PFS was 7.4 m in the 21 p with low HERC2 levels, compared to 7.4 m and 5.9 m, respectively, in the 9 p with high HERC2 levels (OS, P=0.008; PFS, P=0.01). The multivariate analyses identified the combination of low BRCA1 and low HERC2 expression as predictive of longer OS and PFS. In contrast, high levels of either gene were associated with an increased risk of death (HR=3.7, P=0.004) and of progression (HR=1.4, P=0.03). Conclusions: The integrated analysis of multiple DNA repair components can improve available predictive models in NSCLC. BRCA1 and HERC2 low expression levels can predict improved outcome to first-line platinum-based chemotherapy.
The clinical impact and prognostic value of 18F-fluorodeoxyglucose PET/CT in the initial staging non-small cell lung cancer at MD Anderson Cancer Center.
Authors: Takeuchi Satoshi , Khiewvan Benjapa , Swisher Stephen , Rohren Eric , Macapinlac Homer A.
Published: March 2020

11079

Background: 18F-fluorodeoxyglucosePositron Emission Tomography/Computed Tomography (FDG-PET/CT) has an important role for Non-Small Cell lung cancer (NSCLC) management, especially in staging. Our objective was to assess stage migration, the clinical impact, and prognostic value of PET/CT in patients with NSCLC at MD Anderson Cancer Center (MDACC). Methods: We retrospectively reviewed the database from MDACC, and identified 729 NSCLC patients referred for staging between 2006 and 2011. Stage was classified using TNM classification. FDG-PET/CT and conventional imaging staging were compared with all-cause mortality and the survival rates of the respective clinical stage. The management impact of FDG-PET/CT was determined based on conventional imaging and PET/CT management plans. A change in stage was confirmed by histopathology and/or further imaging. Results: We identified 598 NSCLC patients with FDG-PET/CT and conventional imaging performed. FDG-PET/CT changed stage in 28.1 % (16.4 % upstaged, 11.7 % downstaged). Based on FDG-PET/CT, treatment plans were modified in 38 % of patients. Median progression free survival (PFS) and overall survival (OS) was significantly worse in patients with management impact of FDG-PET/CT than patients without impact (PFS, 24.9 v 60.6 months, P < 0.001; OS, 66.7 v 115.9 months, P < 0.001). Multivariate analysis showed that the impact of FDG-PET/CT impact on management was an independent prognostic factor for DFS (hazard ratio [HR] = 2.08; 95 % CI, 1.63 to 2.65; P < 0.001) and OS (HR = 2.16; 95 % CI, 1.56 to 2.99; P < 0.001). Stage migration from stage I (40/249 patients) showed worse outcome than those without change (PFS, 21.0 v 60.0 months, P < 0.001; OS, 64.7 v 115.9 months, P = 0.003). Conclusions: FDG-PET/CT has major role in NSCLC management. The added staging information provided by FDG-PET/CT as compared to conventional imaging resulted in a change in management in more than one third NSCLC patients. FDG-PET/CT is also a powerful tool for outcome prediction. Even in patients diagnosed as stage I by conventional method, FDG-PET/CT at initial diagnosis may have an impact on survival.
Prognostic significance of the maximal value of the baseline standardized uptake value on fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography for predicting pathologic malignancy of operable breast cancer.
Authors: Kadoya Takayuki , Aogi Kenjiro , Kiyoto Sachiko , Kanno Emiko , Akimoto Etsushi , Emi Akiko , Shigematsu Hideo , Masumoto Norio , Sugawara Yoshifumi , Okada Morihito
Published: March 2020

11111

Background: [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) is potentially useful in predicting prognosis of breast cancer patients. Methods: 344 breast cancer patients (mean age: 58.0 ± 12.5) with clinical stage IxIII between January 2006 and December 2011, were prospectively evaluated (median follow-up period: 52.0 months). Patients underwent a whole-body FDG PET/CT before operation. The maximal value of the baseline standardized uptake values (SUVmax) were assessed for predicting disease free survival (DFS). For the evaluation of relationship between SUVmax values and prognostic factors such as hormone receptors, human epidermal growth factor receptor 2 (HER2), nuclear grade, lymph node metastasis and tumor size, statistical analyses were performed using Student t test and log-rank test, and p values of less than 0.05 were considered to indicate statistically significant differences. Results: Clinical stage included were I (n =194), II (n=134) and III (n=16). Tumors with estrogen receptor (ER) positive were 292 (84.9%) and negative were 52 (15.1%). Patients were divided into two groups according to cut-off SUVmax established on the basis of receiver operating characteristic analysis (≤3.0 vs >3.0, AUC=0.713). There was a significant difference in DFS between two groups (p=0.001) and, hormone receptor, HER2, nuclear grade, lymph node metastasis were found strong relation to SUVmax values. SUVmax and ER status were predictive factors with multivariable analysis using cox proportional hazard regression model (p=0.033 and p=0.004, respectively). Conclusions: SUVmax on FDG PET/CT before operation has a predictive value for high-grade malignancy and prognosis in operable breast cancer. [Table: see text]
Targeting radiation resistance in p53 mutant tumors with AKT inhibitors.
Authors: Abraham Aswin George , Hamilton Garth , O'Neill Eric
Published: March 2020

11115

Background: Increasing our understanding of how resistance to radiation occurs, helps us develop more efficient and personalised radiotherapy treatments for cancer patients. Through molecular dissection of events that drive tumour initiation and progression, we have uncovered a functional connection between the most frequent oncogenic mutations that are likely to contribute to therapeutic resistance in 30% of all human tumours. Mutations activating the "AKT" signalling pathway and inactivation of the “TP53” tumour suppressor gene are common mechanisms that cancer cells require to proliferate and escape pre-programmed cell death. We find that in combination these events lead to therapeutic resistance that is reversible by the AKT clinical candidate, MK-2206 and the PI3K inhibitor PI-103. Methods: Using a combination of in vivo and in vitro techniques we have tracked the molecular mechanism for AKT mediated resistance to treatment in solid tumours. This has helped us to simultaneously derive potential biomarkers that could highlight where the greatest efficacy may be achieved in clinical practise. Results: Tumours employ many strategies to inactivate p53; however sequence mutations that result in mutant p53 protein (p53mut) are most often observed. p53mut tumours not only fail to respond to DNA damaging therapy, but are also described to promote therapeutic resistance by dominant negative suppression of p53 dependent promoter activity. We demonstrate that AKT inhibitors- and as proof of concept, the clinical candidate AKT inhibitor, MK-2206, and PI3K inhibitor, PI-103, are effective in treatment of mice with therapeutically resistant tumours with elevated AKT and carrying p53mut. AKT inhibition promotes reduced cellular levels of p53mut via a novel mechanism and promoted re-engagement of cell cycle arrest, senescence and increased sensitivity to ionising radiation in both in vivo and in vitro systems. Conclusions: We show that AKT inhibitors sensitise xenografts carrying p53 mutations to DNA damaging therapy. We have also been identifying potential molecular markers to select the cohort of patient most likely to benefit from this treatment.
Long-term quality of life in patients with breast cancer according to sentinel lymph node biopsy or axillary lymph node dissection: A multicenter cohort study with 6 years follow-up.
Authors: Dabakuyo Tienhan Sandrine , De Gournay Emmanuel , Guyomard Aurelie , Boulet Stephanie , Arveux Patrick , Causeret Sylvain , Gouy Sebastien , Padeano Marie-Martine , Loustalot Catherine , Smail Marc , Sauzedde Jean-Marc , Combier Jean-Philibert , Chevillote Patrick , Rosburger Christian , Bonnetain Franck , Coutant Charles , Fraisse Jean
Published: March 2020

1114

Background: the aim of this study was to assess long term quality of life (QoL) over a period of 6 years in women with a breast cancer (BC) who underwent sentinel lymph node biopsy (SLNB), axillary lymph node dissection (ALND), or SLNB followed by ALND. Methods: The EORTC-QLQ-C30 and the EORTC-QLQ-BR-23 questionnaires were used to assess QoL before surgery, just after surgery, 6, 12 and 72 months later. The Kruskal Wallis test with the Bonferroni correction was used to compare scores. A mixed model analysis of variance for repeated measurements was then applied to assess the longitudinal effect of surgical modalities on QoL. Results: Five hundred and eighteen BC patients were initially included. The median follow-up was 6 years. During the follow-up, 61 patients died. None of the patients of the SLNB group has developed lymphedema during follow-up and the relapse rate was not different between the different groups (p=0.62). Before surgery, global health (GHS) (P = 0.5226) and arm symptoms (BRAS) (P = 0.9902) QoL scores were similar whatever the surgical procedure. BRAS score (p=0.0001) was better in the SNLB group 72 months after surgery. Moreover, compared to ALND patients, patients treated with SLNB had fewer arm symptoms with the follow-up. In addition, body image (P = 0.0005), upset by hair loss (P = 0.0045), systemic therapy side effects (P = 0.0097) and future perspective (P = 0.0375) QoL dimensions remained better 5 to 6 years after diagnosis in patients treated by SLNB. Conclusions: Long term follow-up showed that, SLNB is a safe and acceptable accurate method associated with less morbidity than ALND.
Incidence and characteristics of breast cancer following a diagnosis of ductal carcinoma in situ.
Authors: Lei Xiudong , Dawood Shaheenah S. , Albarracin Constance T. , Dent Rebecca , Gupta Sudeep , Cortes Javier , Mittendorf Elizabeth Ann , Buchholz Thomas A. , Gonzalez-Angulo Ana M.
Published: March 2020

1131

Background: Recent data indicate that the incidence of DCIS is rising. The purpose of this retrospective population based study was to examine incidence of and factors that contribute to the development of a subsequent breast primary. Methods: Using the SEER registry we identified female pts with a primary DCIS diagnosed between 1990 to 2005. Pts who had an invasive or in situ malignancy diagnosed prior to a diagnosis of DCIS were excluded. Cumulative incidence of a subsequent breast primary (invasive/non invasive) was estimated and compared across groups using the Chi-square test. Multivariable logistic regression models were then fitted to determine factors that could predict for the development of a subsequent breast primary. Results: 96,130 pts were identified of whom 14,573 (15.2%) had subsequent primaries. 9,037 (62%) pts had a subsequent primary in the breast of which 5,915 (65.5%) pts had an invasive breast cancer. Among pts who developed an invasive breast cancer 68% had hormone receptor positive disease, 59% had grade I/II disease and 80% had stage I/II disease. 2 and 5-year cumulative incidence of developing a subsequent breast primary was 3.2% and 5.9% respectively. 2 and 5-year cumulative incidence of developing a subsequent invasive breast primary was 1.6% and 3.4% respectively. 5-year cumulative incidence of developing a subsequent breast primary among pts who were of white, black and other race was 5.8%, 6.8% and 6.1% respectively (P<0.001). In the multivariable logistic model the probability of developing a subsequent breast primary decreased with each increasing year of diagnosis of DCIS (OR 0.91, 95%CI 0.91-0.92, p<0.001). Other factors that predicted for the development of a subsequent breast primary included younger age at diagnosis, non-white race and lack of surgical or radiation therapy for DCIS. Conclusions: Our results indicate that a significant proportion of pts with a diagnosis of DCIS go on to develop invasive breast cancer and may warrant further investigation to determine biological risk factors, appropriate screening procedures and possible interventions to decrease incidence. Target groups that may benefit include pts who are young and of non white race at the time of diagnosis of DCIS.