bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of the genetic variants in the nucleotide excision repair genes XPA and XPC with cisplatin-induced hearing loss in patients with osteosarcoma.
Authors: Hagleitner Melanie M. , Coenen Marieke J.H. , Gelderblom Hans , Hoogerbrugge Peter , Guchelaar Henk-jan , Te Loo Dunja Maroeslea W.M.
Published: March 2020

10077

Background: Cisplatin is a widely used and effective chemotherapeutic agent in the treatment of osteosarcoma. However, cisplatin-induced ototoxicity is a serious problem, affecting more than 60% of patients and compromising language and cognitive development. Unfortunately, individuals at risk to develop ototoxicity cannot be identified upfront. Genetic variants in genes involved in the metabolism of cisplatin may predispose to cisplatin-induced hearing loss and help to identify patients at risk. Methods: In a candidate gene pathway approach, we selected 224 SNPs in 30 candidate genes related to Platinum-DNA repair pathways and genotyped for a discovery group of 105 patients with osteosarcoma for these variants. Cisplatin-induced ototoxicity (n = 47), defined as the development of grade 2–4 hearing impairment using Common Terminology Criteria for Adverse Events (CTCAE version 3), showing a hearing loss of >25 dB at frequencies of 4–8 kHz, was associated with genetic variation. A replication study was performed in a independent cohort of 51 patients with osteosarcoma. Genotyping was performed using the Illumina GoldenGate assay. Association analysis and meta-analysis were performed using the whole genome association analysis toolset PLINK. Results: In the discovery cohort a total of 13 SNPs were significantly (p value < 0.05) associated with ototoxicity. Upon meta-analysis, addition of the replication set resulted in lower p-values for 2 SNPs. The two SNPs showing a strong association with hearing loss in patients with osteosarcoma were rs2805835 in the gene XPA (p-value 0.01, OR=2.7 (95%CI: 1.20-6.15) and rs2227999 in XPC (p-value 0.02; OR=3.2 (95% CI:1.19-8.80). Conclusions: The Nucleotide Excision Repair (NER) genes XPA and XPC form an important molecular mechanism by which cisplatin DNA adducts can be repaired and it has recently been shown that these genes have a high expression in the cochlea. Our data suggest that genetic variants in these genes, may contribute to cisplatin ototoxicity. This study should be viewed as the first step in the development of genetic markers to predict cisplatin-induced ototoxicity in individual patients.
Quantitative hormone receptors, triple-negative breast cancer (TNBC), and molecular subtypes: A collaborative effort of the BIG-NCI NABCG.
Authors: Cheang Maggie Chon U. , Martin Miguel , Nielsen Torsten O. , Prat Aleix , Rodriguez-Lescure Alvaro , Ruiz Amparo , Chia Stephen K. L. , Shepherd Lois E. , Voduc David , Bernard Philip Seth , Ellis Matthew James , Perou Charles M. , Di Leo Angelo , Carey Lisa A. ,   on behalf of Breast International Group-North American Breast Cancer Group
Published: March 2020

1008

Background: Most TNBC trials focusing on biology of the basal-like subtype (BLBC) allow borderline (1-10% staining) estrogen receptor (ER) and progesterone receptor (PgR) expression by immunohistochemistry (IHC); however the optimal ER and PgR cut points to enrich for non-luminal subtypes has not been studied. In this study,we compared quantitative ER/PgR status with gene expression-based intrinsic subtype in order to determine if borderline cases should be included in TNBC trials. Methods: ER, PgR, and HER2 status was determined by central review of tumors collected from three phase III randomized trials: GEICAM 9906 (n=820), NCIC CTG MA.5 (n=476) and MA.12 (n=398). PAM50 intrinsic subtyping (BLBC, HER2-enriched, Luminal A, Luminal B and Normal-like) was performed using the qRT-PCR-based assay. Quantitative ER/PgR expression by IHC and subtype was tested using ANOVA and Fisher’s exact test. Results: Of 1,694 tumors, 15% were BLBC, 21% HER2-Enriched, 33% Luminal A, 25% Luminal B and 4% Normal-like. BLBC subtypes were significantly associated with low expression of ER and PgR (median = 0.05%) compared to other subtypes (p < 0.001). The vast majority of BLBC (96%) did not express any ER or PgR protein by IHC. BLBC represented 73% of TNBC (borderline cases not included) and significantly more than the additional TNBC with borderline ER/PgR (p < 0.001). Within borderline ER/PgR and HER2-negative cases only, 17% were BLBC and 46% were luminal subtypes (Table). Conclusions: BLBC rarely express ER or PgR by IHC. The majority of borderline TNBC (1-10% ER/PgR) are not BLBC; half of them are categorized as luminal categories that may be endocrine sensitive. TNBC trials seeking to target BLBC tumor biology should use the ASCO/CAP guidelines of 0% as the cutoffs for ER and PgR negativity. [Table: see text]
Explored prognostic factors for survival in patients with advanced GIST treated with standard dose imatinib (IM): Results from the BFR14 phase III trial of the French Sarcoma Group.
Authors: Pérol David , Ray-Coquard Isabelle , Bui Nguyen Binh , Adenis Antoine , Rios Maria , Bertucci François , Duffaud Florence , Cupissol Didier , Chevreau Christine , Bompas Emmanuelle , Domont Julien , Chabaud Sylvie , Blay Jean-Yves , Le Cesne Axel
Published: March 2020

10092

Background: Factors predicting progression free survival (PFS) and overall survival (OS) of patients (pts) with advanced GIST treated with 400 mg daily dose IM included in the BFR14 study with a median follow up of 54 months (CI95%:47-61) was investigated evaluating added prognostic factors. Methods: 434 pts were included in this prospective multicenter trial from June 2002 to July 2009. After 1, 3 and 5 yrs of IM 400mg/day, pts free from progression were randomly offered to continue or interrupt (I arm) IM. Prognostic factors for overall survival were investigated in the entire cohort (randomized and not randomized pts) included in the BFR14. Survival was defined from the date of inclusion to the date of death for OS or to the first occurrence of disease progression under imatinib or death for PFS. A multivariate cox model including statistical significant baseline characteristics tested in univariate were included in a backward procedure d to identify independent prognostic factors for PFS then OS. Results: As of January 2012, there were 285 progressions (65%) and 161 deaths (37%). The median PFS of the entire cohort was 29 months (CI95%: 24-33) and the 4 and 5-yrs PFS were 31% and 24% respectively. A low tumour volume at inclusion, PS (0), sex (female), CD34 positivity on tumor cells were the four independent prognostic factors of a higher PFS. The 5-yrs OS was 54% (CI95%: 48-60). A higher OS was independently predicted by gender (female), PS (0), platelets count (<400 giga/L) and CD34 expression on GIST cells. Median PFS and OS were slightly superior in this more recent series as compared to B2222 consistently with the improved outcome of patients with low tumor volume. Conclusions: OS and PFS are predicted by gender, PS and CD34 expression in this large series of pts treated with standard dose IM. The biological significance of CD34 expression on tumor cells has to be explored in GIST.
The role of surgical cytoreduction before imatinib therapy in patients with advanced GIST.
Authors: An Hojung , Ryu Min-Hee , Ryoo Baek-Yeol , Sohn Byeong Seok , Kim Ki-Hun , Oh Sung Tae , Yu Chang Sik , Yook Jeong Hwan , Kim Byung Sik , Kang Yoon-Koo
Published: March 2020

10093

Background: Despite dramatic improvement of survival with introduction of imatinib mesylate, resistance to imatinib eventually develops in most of patients with advanced gastrointestinal stromal tumor (GIST). It is well known that baseline tumor size is an important factor related to imatinib resistance. We hypothesize that decreasing tumor size by surgery before starting imatinib may delay the emergence of resistance and improve prognosis in patients with advanced GIST. Methods: From 2001 to 2010, 102 patients with initially metastatic GIST and 147 patients with recurrent GIST were enrolled in this analysis. Patients with local relapse only were excluded because they were potentially curable by surgery alone. Patients were categorized into two groups according to the extent of cytoreduction; i.e., patients whose initial tumor bulk reduced >75% surgically before starting imatinib (group A) and the others (group B). Results: Among total 249 patients, 62 patients received initial surgery. 35 (14%) patients whose tumor bulk reduced > 75% were categorized into group A, and the remaining 214 (86%) were in group B. In group A, the median age was younger; more patients were initially metastatic; peritoneal metastases were more frequent; but liver metastases were less. The total tumor size was significantly reduced from median 122 mm before cytoreduction to 0 mm after on CT scans in group A. With a median follow-up of 42.7 months, progression-free survival (PFS) tended to be better in group A than in group B in univariate analysis (HR=0.60; 95% CI, 0.36-1.02; p=0.061), but PFS was not statistically different between the two groups in multivariate analysis (p=0.488). Meanwhile, absence of KIT exon 11 mutation (p=0.007), baseline total tumor size > 150mm (p=0.043), and granulocyte count > 5000/mm3 (p=0.009) remained independent poor prognostic factors. Conclusions: Despite marked decrease of total tumor size, the outcomes were not significantly improved in patients receiving initial cytoreduction more than 75% of baseline tumor bulk before starting imatinib. These results suggest that initial cytoreduction does not have beneficial role in advanced GIST, so imatinib should be still the first treatment of choice in this population.
Characteristics of gastrointestinal stromal tumor (GIST) patients receiving short-term versus long-term imatinib (IM) adjuvant therapy: A chart review analysis.
Authors: Guerin Annie , Conley Anthony Paul , Sasane Medha , Gauthier Genevieve , Schwiep Frances , Keir Christopher Hunt , Wu Eric Q.
Published: March 2020

10094

Background: In clinical practice, significant variability is seen in duration of adjuvant IM use. The objective of this study is to compare characteristics of GIST pts receiving adjuvant IM for a short (6-12 months) vs extended period (≥24 months) to better understand factors that may influence treatment (trt) duration decisions. Methods: Physician prescribing patterns and clinical information on adult pts with primary resectable Kit positive GIST initiating IM ≤84 days post-surgery was collected from 248 U.S. oncologists using online data collection forms. In addition to physicians’ perception of short- vs long-term use, pts’ risk assessment, trt, demographics, and comorbidities were collected for 246 short-term and 395 long-term IM pts. Characteristics were compared using Wilcoxon and Chi-square tests. Results: While pts were similar in age [59.0 vs. 58.1, P =.23], ethnicity, and region of residence, the short-term group included fewer males (57.7% vs 69.6%, P <.01) and had a higher prevalence of cardiovascular (11.4% vs 5.8%, P = .01) and ischemic heart diseases (5.3% vs 1.5%, P<.01). Differences were also observed in indicators of pre-treatment risk profile (tumor size, location, and rupture during surgery, mitotic count, and Miettinen score) (Table). Findings were consistent with main reasons reported by physicians for prescribing adjuvant IM over longer duration; in addition to pt risk profile (76.6%), tolerability (70.6%), younger pts (59.7%), safety (39.1%), trt response (29.8%), and economic reasons (26.2%) were other reasons impacting trt decisions. Conclusions: Pt risk is an important factor in physicians’ decisions to prescribe adjuvant IM for extended duration. However, age, tolerability, and comorbidities, also play an important role. [Table: see text]
Effect of five years of imatinib on cure for patients with advanced GIST: Updated survival results from the prospective randomized phase III BFR14 trial.
Authors: Bertucci François , Ray-Coquard Isabelle Laure , Bui Nguyen Binh , Adenis Antoine , Rios Maria , Duffaud Florence , Cupissol Didier , Chevreau Christine , Bompas Emmanuelle , Domont Julien , Chabaud Sylvie , Pérol David , Blay Jean-Yves , Cesne Axel Le
Published: March 2020

10095

Background: We previously demonstrated that interruption of imatinib (IM) after 1, 3, and 5 yrs in responding patients (pts) with advanced GIST is associated with rapid relapse but reintroduction of IM allowed tumor control in almost all pts. Here, we examined the outcome of patients randomized in the interruption arm (I arm), and notably the characteristics of those not yet progressing. Methods: This prospective multicenter BFR14 study was initiated in June 2002 and closed for inclusion in July 2009. Seventy-one non-progressing patients were randomized in the I arm after 1 (N=32), 3 (N=25) and 5 years (N=14) of IM 400 mg/day. IM (same dose) was reintroduced in case of progressive disease (PD). Results: The median follow-up (FU) from randomization was 74, 48 and 22 months for pts randomized at 1, 3 and 5 yrs of IM treatment respectively. Updated survival data (January 2012) are summarized in the table. Out of the 3 pts not progressing in the I arm at 1 yr, 1 pt had refused to stop IM and 1 pt had a localized GIST with small residual disease at inclusion. Out of the 3 pts not progressing in the I arm at 3 yrs, 1 pt had refused to stop IM and 2 pts were included after complete resection of both primary tumor and metastases with a small residual disease. The FU of pts randomized at 5 yrs was short but out of the 5 non progressive pts, 2 are considered in PD on functional imaging (January 2012), 2 had a locally advanced GIST subsequently operated during IM and before randomization, and 1 had no target lesion at inclusion (resection of synchronous metastases). Conclusions: All but one pts with residual masses under IM and randomized in the I arm have relapsed. Six out of 7 patients not yet progressing in the I arm had reached complete remission following surgery at inclusion or before randomization (initial resection/debulking of metastases). [Table: see text]
Genome-wide analysis and characterization of an online sarcoma cohort.
Authors: Barnholt Kimberly E , Do Chuong B , Kiefer Amy K , Nelson Marisa , Garber Judy Ellen , Robson Mark E. , Maki Robert G. , Demetri George D. , Wojcicki Anne
Published: March 2020

10097

Background: Recruitment of an adequately sized cohort for genome-wide studies presents a serious challenge for rare diseases such as sarcoma. Traditional barriers to participation include proximity of clinical centers and motivation or ability to travel. 23andMe’s web-based platform provides increased accessibility to research participation, facilitating rapid recruitment of patients (pts) and enabling a large-scale genome-wide association study (GWAS) of sarcoma. Methods: Sarcoma pts were recruited through web and email campaigns, patient advocacy groups, physician offices, and events. Pts provide IRB-approved consent, complete surveys, and receive updates about research progress through an online account. In collaboration with an uncompensated panel of academic experts, an online survey was developed to collect patient-reported data on diagnosis, family history, symptoms and treatment. Results: This web-based approach has accrued the largest genotyped, recontactable sarcoma cohort to date. In 20 months, 772 sarcoma pts have enrolled, 683 have been genotyped and 611 have provided data online. The cohort is primarily of European ancestry (92%), disproportionately female (72%), with an average age of 51 (± 15 years). More than 88% of pts indicated a soft tissue sarcoma diagnosis, with leiomyosarcoma, liposarcoma and “malignant fibrous histiocytoma” being the most commonly reported subtypes. Over 36% of pts report undergoing active treatment of some type. Association scans were conducted across a set of 8,058,452 imputed SNPs, using 568 unrelated sarcoma cases of European ancestry and >70,000 unrelated population controls from the 23andMe database. Initial results have identified no significant genome-wide associations for general sarcoma risk, despite having >90% power to detect risk variants with >5% minor allele frequency and odds ratio >2.5, suggesting the absence of common variants with strong shared effects across sarcoma subtypes. Conclusions: This pilot study demonstrates feasibility of rapid recruitment and longitudinal engagement of pts through online technology. Such techniques may significantly accelerate, and in some cases fully enable, large-scale genomic studies of sarcoma and other rare diseases.
HAGE (DDX43) protein expression as an independent biomarker of poor clinical outcome of breast cancer (BC) and potential as a therapeutic target for ER-negative BC.
Authors: Chan Stephen , Abdel-Fatah Tarek M. A. , McArdle Stephanie , Moseley Paul , Johnson Catherine , Green Andrew R. , Ellis Ian O. , Rees Robert
Published: March 2020

1013

Background: Recently, we have confirmed that HAGE is involved in promoting proliferation as assessed by increased thymidine incorporation and our preliminary results using shRNA to permanently knockdown HAGE expression also suggests the involvement of HAGE in tumor motility and metastasis. In this study we aimed to analyze the expression of HAGE in large well-characterized BC cohorts to determine its relationship with other clinico-pathological parameters and to investigate its prognostic value. Methods: HAGE protein expression was assessed in: a) 40 normal breast tissue (NBT), b) 60 invasive BCs and their matching NBT, c) BC cell lines, d) A series of 1650 consecutive cases of primary BC who treated with adjuvant CMF and/or endocrine therapies. Further validation was performed in 2 independent series of high risk ER- BC: a) 300 ER –BC who did not received any CT and b) 396 ER- BC treated with adjuvant anthracycline (ATC) based CT. Results: The NBT showed negative HAGE expression (HAGE-) throughout. HAGE overexpression (HAGE+) was observed in 10% of BC and was significantly associated with aggressive clinico-pathological features including: ER-, high grade and triple negative phenotypes. Moreover, HAGE+ expression showed an adverse outcome with a 2-4 fold increase in the risk of death, recurrence and metastases (ps<0.00001) compared to HAGE-; ps<0.0001. Using a multivariate Cox regression model including ER status, grade, size and tumour stage, HAGE expression was confirmed as a powerful independent prognostic factor (p<0.0001). The poor clinical outcome of HAGE+ was further confirmed in high risk (NPI>3.4) ER- patients who did not received any CT (p<0.0001). While, adjuvant CT either CMF or ATC had a positive impact on HAGE+/high risk ER- BC as HAGE+ had a similar risk of death, recurrence and distant metastases to HAGE- expression. Conclusions: This is the first report which shows HAGE to be a potential predictor for poor prognosis in BC patients, and may be an attractive novel target for molecular and vaccine therapy for those patients. A prospective trial of adjuvant chemotherapy/vaccine to confirm this finding is warranted.
Metformin in early breast cancer (BC): A prospective, open-label, neoadjuvant “window of opportunity” study.
Authors: Niraula Saroj , Dowling Ryan JO , Enis Marguerite , Chang Martin , Done Susan , Hood Nicky , Escallon Jaime , Leong Wey , McCready David R. , Reedijk Michael , Stambolic Vuk , Goodwin Pamela Jean
Published: March 2020

1019

Background: There is growing evidence that metformin may exert anti-cancer effects through indirect (insulin-mediated) or direct (insulin-independent) mechanisms. Here, we report final results of a neo-adjuvant “window-of-opportunity” study of metformin in women with operable BC. Methods: Newly diagnosed, untreated, non-diabetic BC patients received metformin 500 mg tid after diagnostic core-biopsy until definitive surgery(no other treatment). Clinical [weight, symptoms, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C-30)] and biologic characteristics [insulin, glucose, homeostatic model assessment (HOMA), C-reactive protein (CRP), leptin] were compared pre- and post-metformin as were Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL, an apoptotic marker) and Ki67 (primary end-point) scored blinded by manual count of positive nuclear-staining. The planned sample-size of 40 patients gave 90% power to detect a 5.5 percentage point change in Ki67. Results: Thirty-nine patients were enrolled and mean age was 51 years; metformin was given for 18 days (median), range 13-40 days. Twenty patients had T1 and 19 T2/T3 tumors; 16 tumors were grade III; 24 were N0; 32 ER/PR positive, 5 HER-2 positive. Grade 1-2 self-limiting diarrhea, anorexia and abdominal distention occurred in 50%, 41% and 32%. EORTC QLQ scores were stable in all function domains and overall scores. Main study outcomes are tabulated here. Conclusions: Short-term preoperative metformin was well-tolerated and resulted in clinical and cellular effects in keeping with beneficial anti-cancer effects as demonstrated by improved insulin resistance (HOMA), decreased proliferation (ki67) and increased apoptosis (TUNEL). [Table: see text]
Comparison of molecular (BluePrint+MammaPrint) and pathological subtypes for breast cancer among the first 800 patients from the EORTC 10041/BIG 3-04 (MINDACT) trial.
Authors: Viale Giuseppe , Slaets Leen , De Snoo Femke , van 't Veer Laura J. , Rutgers Emiel J. , Piccart-Gebhart Martine J. , Bogaerts Jan , van den Akker Jeroen , Engelen Kristel , Russo Leila , Dell'Orto Patrizia , Cardoso Fatima
Published: March 2020

1022

Background: Biology has become the main driver of breast cancer therapy. Intrinsic biological subtypes by gene expression profiling have been identified. Pathology can be used to define surrogates of these subtypes but these are not always concordant, which may lead to different treatment plans. We investigated the concordance between BluePrint (BP) + MammaPrint (MP) (micro array based) breast cancer subtypes and pathological surrogates (based on ER, PR, HER2, and Ki67). Contrary to the Perou gene set (evolved into PAM50), BluePrint was trained using pathological data. Methods: Using available data (centrally assessed pathology and genomic) from the MINDACT pilot phase (Rutgers et al 2011) 621 tumors were analyzed. Two pathology classifications were used: one with 4 categories and one with 5 categories (Goldhirsch et al 2011). Based on BP 3 subtypes are formed: Luminal, HER2 and Basal. The Luminal subtype is further split into Luminal A (MP low risk) and Luminal B (MP high risk). Results: See table. Conclusions: All pathological Basal cases are BP Basal, apart from 1 BP HER2 case. Of the BP Basal cases, 15 are not pathological Basal: 1 is Luminal A, 11 are Luminal B (of which 8 are IHC ER/PR borderline (≥1% and < 10%)) and 3 are HER2. All pathological Luminal (A & B) that are BP HER2 are HER2- by TargetPrint. 25 of the 26 pathological HER2+ that are BP Luminal A are ER+. Most discordant cases are seen within the Luminal subtype, indicating that Ki67 discriminates Luminal A vs. B differently than MammaPrint does. The observed subtype discrepancies reveal potential important impact for treatment-decision making. MINDACT will provide important information. [Table: see text]
Prognostic and predictive impact of Ki-67 before and after neoadjuvant chemotherapy on PCR and survival: Results of the GeparTrio trial.
Authors: Von Minckwitz Gunter , Mueller Berit , Blohmer Jens U. , Kaufmann Manfred , Eidtmann Holger , Eiermann WOLFGANG , Gerber Bernd , Tesch Hans , Hilfrich Joern , Huober Jens Bodo , Fehm Tanja N. , Barinoff Jana , Jackisch Christian , Prinzler Judith , Ruediger Thomas , Erbstoesser Erhard , Loibl Sibylle , Denkert Carsten
Published: March 2020

1023

Background: We previously reported as a result of the GeparTrio phase III trial that response-guided neoadjuvant chemotherapy (CT) with TACx8 or TAC/NX, compared to TACx6, can improve survival especially in hormone-receptor (HR)-positive tumors. As this benefit could not be predicted by pathological complete response (pCR), better surrogate response markers are warranted. Methods: 2072 patients with operable or locally advanced breast cancer were treated with 2 cycles TAC before interim response assessment. Responders were randomized to additional TACx4 or TACx6 and non-responders to TACx4 or NXx4. We centrally measured Ki-67 in1165 pre-CT core biopsies and in 676 post-CT surgical samples. Counting patients with a pCR as having 0% Ki-67, 757 pre-/ post-CT pairs were available. Ki-67 percentage levels were grouped to low (0-15%), moderate (15.01-35%), and high (35.01-100%) according to cut-point finding analysis in a training and validation cohort. Results: pCR rates were 4.2%, 12.9%, and 29.0% in tumors with low, moderate, and high pre-CT Ki-67 levels (p<0.0001). Pre-CT Ki-67 levels significantly predicted disease-free survival (DFS) (log rank p<0.0001) overall, in the HR+ (p<0.0001), but not in the HR- (p=0.5) subgroup. Post-CT Ki-67 levels correlated with DFS (p<0.0001). Patients with low post-CT Ki-67 levels showed comparable outcome to patients with pCR. Patients with increased Ki-67 levels from before to after CT showed an impaired outcome compared to patients with stable or decreased Ki-67 levels (p<0.0001). However, post-CT Ki-67 levels appeared to have more prognostic relevance than Ki-67 changes. Low post-CT Ki-67 levels were not more frequent after response-guided treatments (response-guided vs conventional: p=0.153; TACx6 vs TACx8: p=0.335; TACx6 vs TAC/NX: p=0.420). Similar negative results were found for HR+ and HR- subgroups. Conclusions: Pre-CT Ki-67 levels are predictive for pCR and prognostic for DFS. Post-CT Ki-67 levels and changes between pre-and post-CT-Ki-67 levels are prognostic for DFS. As neither could predict different treatment effects on DFS, Ki67 cannot replace pCR as a surrogate marker for outcome after neo-adjuvant CT.
Association of a compact 13-gene VEGF signature with OS in E2100.
Authors: Willis Scooter , Miller Kathy , Young Brandon F , Perou Charles M. , Hu Zhiyuan , Sparano Joseph , Gray Robert James , Sledge George W. , Davidson Nancy E. , Leyland-Jones Brian
Published: March 2020

1027

Background: E2100, an open-label, randomized, phase III trial, demonstrated a significant improvement in progression free survival and overall response rate with paclitaxel plus bevacizumab compared with paclitaxel alone as initial chemotherapy for patients with HER2-negative metastatic breast cancer. Genentech completed additional clinical trials and submitted these data to the FDA. On 18 Nov, 2011, the FDA Commissioner revoked the agency’s approval of bevacizumab for the breast cancer indication because of the lack of evidence of an improvement in overall survival or a clinical benefit to patients sufficient to outweigh the risks. However, the Commissioner “encouraged Genentech to consider additional studies to identify if there are select subgroups of women who might benefit from this drug”. Hu et al. (BMC Medicine 2009) published a compact 13 gene VEGF-signature associated with distant metastases and poor outcomes. Supervised analyses comparing patients with distant metastases versus primary tumors or regional metastases showed that the distant metastases were distinct and distinguished by the lack of expression of fibroblast/mesenchymal genes, and by the high expression of a 13 gene profile that included VEGF, ANGPTL4, ADM and the monocarboxylic acid transporter SLC16A3. Methods: We have investigated the VEGF signature in silico on Illumina DASL analysis of 122 FFPE samples remaining from E2100. Results: PFS benefit is seen for pacli + bev vs pacli in both treatment arms with the low VEGF signature (HR 0.45 95% CI .27-.77 p .009 n 67) and with the high VEGF signature (HR 0.57 95% CI .32-1.0 p .015 n 55). However, OS benefit is only seen for pacli + bev vs pacli in the high VEGF group (HR 0.56 95% CI .30-1.05 p .02 n 52) and not in patients with the low VEGF signature (HR 1.12 95% CI .66-1.90 p .81 n 67). Conclusions: Hence, this signature, which suggests that the response to hypoxia includes the ability to promote new blood and lymphatic vessel formation, shows great potential as a predictive biomarker of those patients to whom bevacizumab would convey an OS advantage benefit. We note with great caution that this exploratory analysis of trial subset is underpowered, hence, this compact VEGF signature is being pursued in other bevacizumab trial sets.
Single institution experience with neoadjuvant chemotherapy for metaplastic breast cancer (MBC).
Authors: Kaminsky Anna , Bhargava Rohit , McGuire Kandace P , Puhalla Shannon
Published: March 2020

1038

Background: Metaplastic breast carcinoma (MBC) is a rare subtype that accounts for <1% of all breast carcinomas. MBC is frequently triple negative and neoadjuvant chemotherapy (NAC) is often used in triple negative breast cancer (TNBC). The objective of this analysis is to ascertain response rates of MBC to NAC as compared to non-metaplastic TNBC. Methods: We searched the Magee Women’s Cancer Center of UPMC IRB-approved neo-adjuvant treatment database which contains outcome data on 594 patients treated from 2004-2010. 116 patients with triple negative breast cancer (ER /PR negative or ER /PR weakly positive (H score of 10 or less) and HER2 negative or indeterminate (HER2 1+ or 2+ without amplification by FISH)), were identified. Nine of these TNBCs had metaplastic subtype and 2 groups were analyzed: metaplastic breast carcinoma (MBC) (N= 9) and non-metaplastic breast carcinoma (NMBC) (N = 107). Tumor volume reduction (TVR), pathologic complete response (pCR), recurrence and mortality were compared in both groups. Results: Mean follow up in MBC group was 43 months and no patients were lost to follow up. Mean tumor size on presentation in MBC group was 4.47 cm while in NMBC group it was 3.33 cm. pCR was noted in 0/9 MBC and 43/107 NMBC cases (p = 0.0253). 6/9 patients had mastectomy, 2/9 had breast conserving surgery (BCS) and 1/9 patients did not have a surgery yet. Average TVR was 28% in MBC cases compared to 74% in NMBCs when cases with pCR were included (p = 0.0001) and 56% when cases with pCR were excluded (p = 0.0202). Follow up on 9 MBC cases revealed 1 recurrence and subsequent death (11%). Follow up on 64 NMBC patients who failed to achieve pCR revealed 22 recurrences (34%) and 18 of them subsequently died (28%).Follow up on 43 NMBC cases that achieved pCR revealed 3 recurrences (7%) and 1 death (2%). Conclusions: MBC was characterized by larger size at baseline as compared to NMBC. There were no pCR’s seen in MBC, but some MBC did achieve response that allowed for breast conservation. Although the average tumor volume reduction was significantly less in MBC compared to NMBC, the NMBC that failed to achieve pCR fared much worse than MBC who did not achieve pCR. Therefore, the triple negative paradox is likely not applicable to MBC.
Association of body mass index and outcome in advanced breast cancer.
Authors: Andreetta Claudia , Driol Pamela , Bonotto Marta , Gerratana Lorenzo , Valent Francesca , Russo Stefania , Minisini Alessandro , Pascoletti Gaetano , Moroso Stefano , Sottile Roberta , Mansutti Mauro , Fasola Gianpiero , Puglisi Fabio
Published: March 2020

1044

Background: Obesity represents a well-known risk factor for the development of breast cancer and an adverse prognostic factor in early disease. Overweight is associated with reduced efficacy of aromatase inhibitors in adjuvant setting. Few data have been reported about the potential relationship of overweight and outcome in advanced breast cancer (ABC). Methods: We retrospectively evaluated body mass index (BMI) in a consecutive series of 400 ABC patients treated at our institution. BMI was calculated at baseline of diagnosis of ABC. We evaluated association of BMI and other prognostic and predictive markers with Progression Free Survival (PFS) and Overall Survival (OS). We evaluated PFS at first and subsequent lines of chemotherapy (CT) and endocrine therapy (ET). Overweight patients were defined as having BMI > 25. Results: Overweight patients were 52%. Median age of the population was 58 years. Median OS was 33.7 months. Overall, 76% of patients presented with ER+ and 17.7% with HER2+ ABC.Overweight was associated with increased age at diagnosis, menopausal status and luminal B or triple negative immunophenotype. At multivariate analysis, BMI > 25 was associated with better PFS at first-line ET (HR= 0.68, 95% CI 0.46-0.99). BMI was not associated with OS. Conclusions: BMI at baseline does not seem to be an adverse prognostic factor for ABC patients. Overweight may be associated with better PFS in endocrine responsive ABC treated with ET, especially in first-line setting. The role of BMI in ABC deserves to be further investigated.
Impact of biomarkers in predictivity of the efficacy and toxicity of a combination of panitumumab plus FEC 100 followed by docetaxel in a phase II neoadjuvant trial for triple-negative breast cancer (TNBC) patients.
Authors: Nabholtz Jean-Marc A. , Dauplat Marie-Melanie , Abrial Catherine , Weber Beatrice E. , Mouret-Reynier Marie-Ange , Gligorov Joseph , Tredan Olivier , Vanlemmens Laurence , Petit Thierry , Mayer FranÃƒÂ§oise , Jouannaud Christelle , Tubiana-Mathieu Nicole , Kwiatkowski Fabrice , Cayre Anne , Chalabi Nassera , Chollet Philippe J. M. , Penault-Llorca Frederique
Published: March 2020

1051

Background: We evaluated the combination of a standard chemotherapy with panitumumab as neoadjuvant therapy of operable TNBC. Complete pathologic response (pCR) was the primary endpoint, with toxicity and biologic ancillary studies as secondary endpoints. Methods: Sixty patients with stage II-IIIA disease were prospectively included in this multicentre pilot study. Systemic therapy (ST) consisted of 4 cycles of FEC 100 (500/100/500 mg/m2) q.3 weeks followed by 4 cycles of T (100 mg/m2) q.3 weeks, in combination with panitumumab (9 mg/kg) for 8 cycles q.3 weeks. All patients underwent surgery at completion of ST. Paraffin-embedded samples and frozen samples have been systematically realised before and after neaodjuvant treatment in order to evalutate the biological profile of the tumor. Patients characteristics are : median age 50 ; median tumor size : 40 mm ; invasive ductal carcinoma : 96% ; Scarff-Bloom-Richardson Grade III : 70%, grade II : 30%, ki-67-positive : 100%, EGFR-positive : 78%, cytokeratine5-6-positive : 48% and p53-positive : 59%. Pathological response showed a pCR according to Sataloff’s classification of 52.38% and according to Chevallier’s classification of 46.52%. Skin toxicity was the main side-effect : Cutaneous toxicity grade IV : 5%, grade III : 30%, grade II : 20%. Neutropenia grade IV : 27% ; febrile neutropenia : 5%. Infection : 0%. Hand-foot syndrome grade III : 3.3%. Ungueal toxicity grade III : 1.6%, grade II : 20%. Results: We have tested the predictive value of ki-67, EGFR, cytokeratine 5-6 and p53. Only ki-67 is predictive of a pCR according to Chevallier’s classification (p=0.026), with a cut-off of 40% of positive cells (ROC curve): 62% of pCR if ki-67> 40% versus 23% if not (relative risk : 2.7). Low EGFR, high p53, and high cytokeratine 5-6 tended to be associated with poor reponse. No correlations were found between cutaneous toxicities and these biomarkers. The cutaneous toxicities were not predictive. Conclusions: HighKi-67 is predictive of more pCR. High EGFR, low p53 and low cytokeratine 5-6 tended to be associated with better response, but the data are not significant.
Genetic variation in CYP19A1 and response to exemestane: Survival in early breast cancer in the Dutch TEAM trial.
Authors: Houtsma Daniel , Fontein Duveken , Wessels Judith A. M. , Seynaeve Caroline M. , van De Velde Cock JH , Nortier J. W. R. , Guchelaar Henk-jan , Gelderblom Hans
Published: March 2020

10518

Background: In patients with endocrine-sensitive breast cancer treated with adjuvant aromatase inhibitors (AI) it is unclear which patients will develop a recurrence and who will benefit from AI’s. Variations in the aromatase gene (CYP19A1) are associated with altered estrogen levels and altered aromatase activity. The aim of this study was to examine the effect of SNPs in the CYP19A1 gene on survival in a prospective cohort of breast cancer patients treated with adjuvant exemestane. Methods: Patients of whom tissue was available and who were treated with five years of exemestane were selected from the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. DNA was isolated from tumor samples and 30 SNPs were identified using a tagging SNP approach, aiming for 80% coverage of CYP19A1. Genotypes were determined with taqman assays. Primary endpoint of the study was relapse-free survival (RFS) and secondary endpoint was overall survival (OS). A Kaplan-Meier analysis was performed and Cox proportional hazards models assessed survival differences. Analyses were adjusted for age at diagnosis, tumor size, nodal status, histological grade, surgery, adjuvant radiotherapy and chemotherapy. Results: 807 patients were included in the analyses and genotypes were obtained in 722 cases. A significant association with worse RFS was found with two SNPs: rs7176005 and rs16964211, showing hazard ratios (HR) of 3.48 and 5.42 for the homozygeous variant types respectively. These SNPs, as well as a third SNP, rs6493497, were also significantly associated with OS (HR 5.87, 5.3 and 3.36 respectively). Conclusions: Germline variations in the CYP19A1 gene are related to a worse outcome in early breast cancer patients treated with exemestane. These findings may contribute to the individualization of hormonal therapy in breast cancer. The relation between RFS and SNP’s in CYP19A1. [Table: see text]
64Cu-DOTA-trastuzumab-PET imaging in patients with HER2-positive breast cancer.
Authors: Tamura Kenji , Kurihara Hiroaki , Yonemori Kan , Takahashi Kazuhiro , Wada Yasuhiro , Hasegawa Koki , Koizumi Fumiaki , Tsuda Hitoshi , Kodaira Makoto , Yunokawa Mayu , Shimizu Chikako , Ando Masashi , Watanabe Yasuyoshi , Fujiwara Yasuhiro
Published: March 2020

10519

Background: Targeting of HER2 with trastuzumab (T) is a well-established strategy in the metastatic and adjuvant setting in HER2 positive breast cancer (HER2-BC). Although HER2 status is routinely determined using immunohistochemistry or fluorescence in situ hybridization, technical problem can arise when lesions are poorly accessible. HER2 expression can vary during the course of the disease, and there can be discordance in HER2 expression across tumor lesion even in the same patients. Noninvasive HER2 imaging is crucial needed to solve these problems. Previous imaging using 111In or 89Zn- trastuzumab produced high radiation exposure to patients by their long half life (=67.9and 78.4h) and low resolution image. Half life of 64Cu is 12.7h. We performed a feasibility study of the 64Cu-1, 4, 7, 10- tetraazacylododecane-N,N',N",N"'-tetraacetic acid (DOTA)-T to perform PET imaging in patients with HER2-BC. Methods: Patients with HER2-BC received 150 MBq of 64Cu-DOTA-T and underwent PET scan 1, 24 and 48h after the injection. Six patients were evaluated internal dosimetry by collecting radioactivity data of blood and normal tissue in each time point from PET study, and radiation exposure by collecting clothes, linen and urine to test feasibility for outpatients. Results: Fifteen patients who received T therapy were enrolled in the “first-in-human” trial. All patients had no severe toxicity. Radiation excretion evaluating clothes, linen were under background level. Radiation exposure of 64Cu-DOTA-T was equivalent to that of conventional 18F-FDG-PET. Distribution of liver, kidney, spleen, and blood vessel was 2-8 SUV, and uptake in other normal tissue was low. At visual examination, in two patients brain metastases were clearly visualized by 64Cu-DOTA-T-PET, suggesting that there are disruptions of the blood-brain barrier at the site of the brain metastases. The sternum bone metastasis was well visualized and quantitatively monitored according to the response by T. Primary breast cancers, lymph node metastases and lung metastases could also be visualized at the lesion indentified by CT. Conclusions: 64Cu-DOTA-T-PET was feasible test even for outpatient, and provides specific and high resolution image in HER2 positive lesion.
The effect of two BRM promoter variants on the risk of stage I/II upper aerodigestive tract cancers.
Authors: Wong Kit Man , Qiu Xiaoping , Cheng Dangxiao , Azad Abul Kalam , Palepu Prakruthi R. , Mirshams Maryam , Patel Devalben , Chen Zhuo , Roberts Heidi , Knox Jennifer J. , Wong Rebecca , Darling Gail Elizabeth , Waldron John N , Goldstein David P , Leighl Natasha B. , Shepherd Frances A. , Tsao Ming Sound , Der Sandy , Reisman David , Liu Geoffrey
Published: March 2020

10522

Background: BRM is a key subunit of the chromatin remodeling complex SWI/SNF and a putative tumor suppressor gene that is silenced in 15-20% of many solid tumors (PMID 15722796). Evidence suggests that it is epigenetically regulated, as two BRM promoter insertion variants (BRM-741 and BRM-1321) may lead to gene silencing by recruiting histone deacetylases. The presence of both homozygous BRM-741 and BRM-1321 highly correlate with loss of BRM expression and function in lung tumors, while increasing smoking-related lung cancer by two-fold (PMID 21478907). Also, the pharmacologic reversal of epigenetic changes of BRM offers a potential novel therapeutic approach (PMID 21478905). We assessed whether these BRM variants are associated with the risk of upper aerodigestive tract cancers, focusing on Stage I/II tumors that would most benefit from new screening and prevention strategies. Methods: BRM was genotyped by qPCR using TaqMan probes. 1,008 controls were matched to 595 cases by frequency distribution based on age, gender and smoking status. Multivariate logistic regression generated adjusted odds ratios (aOR). Results: The 595 cases were: 115 esophageal, 278 lung, and 202 head and neck cancers. 51% were adenocarcinomas; 60% were Stage I. The frequency of homozygozity was: BRM-741, 26%; BRM-1321, 23%; both variants, 15%. In the combined analysis, there was significant correlation between malignancy and homozygous BRM-741 (aOR 1.91 (95%CI 1.3-2.4); p=0.001) or BRM-1321 (aOR 1.94 (95%CI 1.4-2.7; p=3x10E-4). Being homozygous for both BRM variants carried an even greater risk (aOR 2.45 (95%CI 1.6-3.9); p=1x10E-5). This correlation was similar for adenocarcinomas (aOR 2.53 (95%CI 1.4-4.2); p=6x10E-4) and squamous cell carcinomas (aOR 2.33 (95%CI 1.3-4.4); p=8x10E-4). The increased cancer risk was also similar between these subgroups: head and neck, esophageal and lung cancers; Stage I and II patients; smokers and non-smokers. Conclusions: The two homozygous BRM variants increase the risk of early stage upper aerodigestive tumors by more than two-fold independent of smoking status. BRM promoter variants and their potential epigenetic effect may be early events in the evolution of these cancers.
Prospective study of oncogenic mutations in circulating cell-free DNA (cfDNA) using a multiplex sequencing platform for patient (pt) allocation to phase I clinical trials.
Authors: Ong Michael , Mateo Joaquin , Pope Lorna , Mulick Cassidy Amy , Yap Timothy Anthony , Perkins Geraldine , Riisnaes Ruth , Flohr Penelope , Thway Khin , Saeed Sadiya , Denholm Katie Ann , Toloui Helen Nicole , Moran Kirsty , Lewis Jen Kate , Corral Jaime Jesus , Biondo Andrea , Molife L Rhoda , Kaye Stanley B. , Banerji Udai , De Bono Johann Sebastian
Published: March 2020

10525

Background: Studies suggest that tumoral cfDNA can be isolated from plasma and used as a biomarker. Methods: We conducted a prospective study in adult pts with advanced cancer referred for phase I clinical trials Sep09-Dec10 (A: Pilot Phase n=104) and Jan11-Sep11 (B: Expansion Phase n=176). cfDNA and tumor DNA from formalin-fixed paraffin-embedded (FFPE) tissue were isolated, quantified, and analyzed for 238 mutations in 19 oncogenes by the Sequenom OncoCarta Panel 1.0. Mutation data were used for trial allocation when available. Pt data and outcomes were collected. Statistical inferences used Wilcoxon rank-sum and Pearson’s Chi-squared. Results: 280 pts enrolled including breast (60), colorectal (42), ovarian (37), lung (31), and prostate (20); median age 60yrs [23-81]; 93% ECOG PS 0-1. cfDNA in 95% and FFPE in 60% were analyzed. Median time to cfDNA result, trial allocation and consent were 7 [5-14], 6 and 23 d. Median cancer pt cfDNA concentration (ng/ml) (A: 18 [1-1600]; B: 34 [16-1657]) was higher than 20 healthy volunteers (6 [5-13] A: p=0.0001) and higher in metastatic vs locally advanced cancer (A: 21 vs 4 p=0.0006; B: 42 vs 24 p=0.066). Pts with higher than median [cfDNA] had shorter median survival (MST) than below (A: 217 vs 274 d, HR 1.72 95% CI 1.07-2.65, p=0.025; B: MST not reached yet). Mutations were found in 89 pts (32%), including KRAS (11%), PIK3CA (5%), MET (5%), BRAF (4%), and AKT (2%). cfDNA mutations (57 pts, 21.5%) were mainly found above the median [cfDNA] (A: 41 vs 17% χ2=6.9, p=0.009; B: 24 vs 11% χ2=5.0, p=0.025). Of 155 pts with both cfDNA and FFPE available, 68 had mutations detected: 30 identical in cfDNA and FFPE; 28 in FFPE alone and 10 in cfDNA alone. Overall, 153 pts were treated on a phase I trial; 23 pts had relevant mutation data and received a trial targeting the PI3-Akt-mTOR axis. Conclusions: Higher cfDNA is associated with greater disease burden, worse prognosis, and higher mutation detection rate, suggesting cfDNA is tumorally derived. Moreover, cfDNA can be analyzed for oncogenic mutations in a time-frame suitable for clinical decision making, making it a potentially useful non-invasive adjunct to tumour DNA analysis.
Isolation of circulating tumor cells using a novel EMT-based capture method.
Authors: Bitting Rhonda Lynn , Boominathan Rengasamy , Rao Chandra , Embree Elizabeth , George Daniel J. , Connelly Mark C. , Kemeny Gabor , Garcia-Blanco Mariano , Armstrong Andrew J.
Published: March 2020

10533

Background: Circulating tumor cells (CTCs) have potential prognostic, predictive and surrogate implications in oncology. In patients with metastatic castration-resistant prostate cancer (CRPC) and breast cancer (BC), we have shown that CTCs isolated using epithelial cell adhesion molecule (EpCAM) ferromagnetic capture express mesenchymal markers, including N- and O-cadherin, suggesting phenotypic plasticity and the presence of epithelial-mesenchymal transitions (EMT). Therefore, we postulate that during metastasis, tumor cells exist as a spectrum of epithelial to mesenchymal phenotypes and may not be captured with existing EpCAM-based CTC technology. The goal of this study is to identify CTCs in CRPC and BC patients using a novel mesenchymal-based capture method. Methods: In patients with advanced CRPC and BC, two EDTA and one CellSave tube of blood are collected. Using the CellSearch system (Veridex, USA), CTCs are captured with either anti-N-cadherin (N-cad) or anti-O-cadherin (O-cad) ferrofluid and detected cells (events) are defined as beta-catenin and DAPI positive, CD45 negative intact cells. We evaluated the performance of these EMT-based ferrofluids in healthy volunteers, control cells, and in a pilot study of patients with CRPC, and compared enumeration of cells using novel vs. standard EpCAM-based capture methods. Results: In healthy volunteers, rare events were detected using the novel capture methods. In CRPC patients, O-cad capture detected more events in 3 of 5 subjects than EpCAM-based capture, and the majority of captured cells were cytokeratin negative. See table below. Conclusions: These preliminary results suggest that a novel CTC phenotype exists in CRPC based on EMT properties, particularly overexpression of O-cadherin. Further characterization of these cells from patients with advanced PC, BC, and other solid tumors will provide insight into EMT and metastasis biology. [Table: see text]