bluuebunny/crossref_metadata_2025 huggingface dataset:
Guidelines for the definitions of time-to-event endpoints in randomized clinical trials: Results of the DATECAN Project for Sarcomas and GISTs.
Authors: Bellera Carine A. , Ouali Monia , Penel Nicolas , Bonvalot Sylvie , Casali Paolo Giovanni , Delannes Martine , Nielsen Ole Steen , Mathoulin-Pelissier Simone ,   DATECAN Group
Published: March 2020

10570

Background: With the necessity of reducing randomized clinical trial (RCT) duration, cost and number of patients, surrogate endpoints of overall survival (OS) are increasingly being used as replacement for OS in cancer RCTs. However, most of these endpoints currently lack of standardized definition enabling a comparison of RCT results. Some recommendations have been proposed for specific cancer sites but they do not rely on a formal consensus methodology. The objective of the Definition for the Assessment of Time-to-event Endpoints in Cancer trials (DATECAN) project is to provide guidelines to standardize definitions of time-to-event endpoints in RCTs for different cancer sites. We present results for sarcomas and GISTs. Methods: We relied on the modified Delphi consensus method, a validated formalized consensus process for the development of practice guidelines. International experts with various backgrounds and expertise were involved. First, the coordinating committee, a group of statisticians and epidemiologists involved in the design and conduct of RCTs, led a comprehensive literature review to identify time-to-event endpoints and events of interest. The steering committee, which included additional medical experts, validated the list and prepared the questionnaire sent for rating to an independent expert committee. Results: The consensus process is finalized. It involved 2 rounds of scoring (28 experts) and 1 in-person meeting (in parallel to ASCO'12). Each expert had to rate on a 1-9 scale if s/he agreed or not for including events (e.g. death related to primitive cancer) in the definition of time-to-event endpoints (e.g. progression-free survival). 16 events were rated for inclusion or not in the definitions of 14 time-to-event endpoints. Consensus was reached for 73% of the events after the 2 rounds of scoring. Consensus was finalized at the in-person meeting for the remaining events. Conclusions: The DATECAN guidelines should help standardizing definitions of commonly used endpoints. This process should (i) facilitate the comparison of RCTs and (ii) improve the quality of future RCTs by providing better estimation of sample size and treatment effect.
Metronomic continuous oral cyclophosphamide as second and further line in soft-tissue sarcomas (STS) of the adult.
Authors: Comandone Alessandro , Boglione Antonella , Giubellino Elena , Bergnolo Paola , Gino Giancarlo , Brach del Prever Elena Maria , Turbiglio Marco , Piana Raimondo , Pochettino Paolo , Linari Alessandra , Dal Canton Orietta , Chiado Cutin Simona , Garetto Ferdinando , Oliva Cristiano , Ottaviani Davide , Pazienza Paola
Published: March 2020

10572

Background: In STS third line treatment is poorly defined. However many patients (pts), after aggressive therapy as first and second line progress in their disease ask to be treated. Oral cyclophosphamide (CPM) was already used in breast cancer, prostate cancer and in elderly pts with STS with favourable results. Aim of our study was to define the feasibility, tolerability and activity of oral CPM as third line and further line chemotherapy Methods: 45 pts (19 M; 26 F) with advanced or metastatic STS heavily pretreated were included. Oral CPM was given daily at total dose of 50 mg/day without interruption excepted for toxicity or progressive disease Results: Median age was 60 (32-81), histological subtypes were: leiomyosarcoma 12, liposarcoma 10, condrosarcoma 5, sinovialsarcoma 4, sarcoma NOS 4, other 10. Primary sites were: extremities 21, retroperitoneum 19, trunk 5. 41 pts were metastatic, 4 locally advanced. 41 pts were pretreated with chemotheraphy (15 were in II line, 17 in III line, 7 in IV line, 2 in V line). Median PS (ECOG) was 2 . Median duration of theraphy was 4 months (1-38). Progression free survival (PFS) ranged from 0 to 42+ months (median 4 months). Treatment was well tolerated, we registred only one episode of leucopenia G2 and one of asthenia G2. No complete responses were seen. Only 3 minimal responses and 18 stable disease were seen. Conclusions: Oral CPM showed a mild activity and good tolerability in advanced soft tissue and metastatic STS. It could be an appropriate solution as second line and further therapy and in unfit or elderly pts.
Serum protein acidic and rich in cysteine (SPARC) as a prognostic marker in soft tissue sarcoma.
Authors: Morgan Sherif S. , Nagle Raymond B. , Cranmer Lee D.
Published: March 2020

10581

Background: SPARC is a matricellular secreted glycoprotein that performs several functions, including modulating cellular adhesion and proliferation. It has been implicated in tumorigenesis and identified as an adverse prognostic factor in a number of cancers. The specific mechanisms involved have yet to be identified. Agents targeting SPARC-expressing tumors, such as nanoparticle albumin-bound-paclitaxel (NAB-P), have been developed. Soft tissue sarcomas (STS) represent a heterogeneous group of tumors with inadequate systemic therapies. Our objective was to explore the pattern of SPARC expression and its prognostic significance in STS. Methods: Formalin-fixed paraffin-embedded tissue sections were stained by immunohistochemistry using a mouse monoclonal antibody for SPARC (Abnova). Staining intensity was scored blindly. Patient survival was determined from patients’ medical records. Kaplan-Meier and log-rank analyses were used to compare survival by SPARC expression level. Results: 27 tissue specimens of various STS subtypes were investigated (Table). Elevated SPARC expression was observed in 56% of specimens, but did not correlate with underlying histology. Overall survival segregated into 2 groups based on SPARC levels. Patients who expressed low-to-moderate levels of SPARC exhibited median survival of 22.1 months, while the median survival of patients with moderate-to-high expression levels was 4.4 months (log rank; p=0.0016). Conclusions: A significant proportion of STS specimens exhibit elevated SPARC expression. Elevated SPARC does not correlate with underlying histology, although analysis of a greater number of specimens might reveal subtypes with more frequently elevated expression. Overall survival segregates strongly by degree of SPARC expression, with elevated expression being adverse. Our results suggest that analysis in STS of agents targeting SPARC, such as NAB-P, should be stratified by extent of SPARC expression. [Table: see text]
Evaluating surgery and first-line imatinib (ima) treatment patterns for patients with gastrointestinal stromal tumors (GIST).
Authors: Eaddy Michael , Seal Brian S. , Green Mark R. , Stafkey-Mailey Dana
Published: March 2020

10590

Background: In 2002, ima was FDA approved for advanced metastatic GIST, followed in 2008 with an indication for adjuvant therapy. Real-world data on changing patterns of ima therapy, including adjuvant management, is sparse. This study evaluated changes in treatment patterns, resection rates, and corresponding costs of care among patients receiving first-line (1LT) ima for GIST over an 8-yr period, with a breakpoint around time of initial reporting of phase III adjuvant therapy data showing survival benefit. Methods: The study was conducted Jan 1, 2003–Dec 31, 2010 utilizing pharmacy/medical claims data from a large health plan. Patients with a GIST-related ICD9 code who also received ima were eligible, and excluded if they received any chemotherapy prior to date of first diagnosis or ima. All were designated into 1 of 3 cohorts: metastatic disease at first recognition (MP), non-metastatic non-surgical (NS) patients, and non-metastatic patients undergoing a GIST-related surgical procedure before ima (SP). Patients were followed from diagnosis to end of study period or loss of continuous eligibility. Results: Patient assignment across the disease extent and surgery/no surgery cohorts by the phase III reporting event is shown in the Table. A change in distribution of primary disease presentation and/or management across two time intervals is suggested by marked decrease in percentage of MP (54.9%→36.1%) and greater than doubling of SP patients presumably receiving adjuvant therapy following initial resection attempt. In the study population, 18.8% of patients who initiated 1LT with ima went on to 2LT (73.7% sunitinib); 5.9% receive 3LT (44.4% nilotinib and 38.9% sorafenib); <1% receive 4LT (66.7% sorafenib). In general, 1LT was more costly than subsequent therapies. Across all lines of care, oral TKI drug acquisition cost was the dominant determinant of total cost of care. Conclusions: A change in distribution of primary disease presentation and/or management across the two time intervals is suggested. In each cohort, overall cost of care was largely a function of TKI acquisition cost. [Table: see text]
Triple-negative breast cancer survival in women age 75 and older.
Authors: Malmgren Judith April , Kaplan Henry G. , Atwood Mary K.
Published: March 2020

1060

Background: Triple-negative breast cancer (TNBC) is associated with a high recurrence rate and poor prognosis, despite high initial response to chemotherapy. It is not known if TNBC patients 75 years older, an age group less likely to be treated with adjuvant chemotherapy, have the same mortality risk as younger women. Methods: We conducted a prospective cohort study of all women presenting with primary TNBC, age 21-89, stage I-III from 1998-2009 identified and tracked by our registry (n=529). Clinical characteristics were chart abstracted at diagnosis and follow up. The Kaplan-Meier method and log rank test were used for disease specific survival (DSS) and overall survival (OS) by age. Results: Mean follow up was 6.6 years, range 1.98-13.41 years. Distribution by age was 92% <75 years (n = 485) and 8% 75+ years (n = 44). The two age groups did not differ by histologic or nuclear grade, stage, or radiation therapy receipt (age 75+ by stage: I = 46%, II = 34%, III 21%, age <75: I = 37%, II = 46%, III = 17% [not significant]). Patients 75 and older were less likely to be treated with adjuvant chemotherapy (32% vs. 91%, Pearson chi square test = 119.32, p <.001). 5 year DSS was not significantly different for patients age <75 years compared to patients age 75+ years (85% vs. 84%). However, 5 year OS was significantly worse for 75 year and older patients (65%) compared to <75 year old patients (83%) (log rank test = 13.97, p < .001). Conclusions: In our institutional cohort, triple-negative breast cancer in older women had similar prognostic indicators (stage and histologic grade) compared to younger women and older women had equivalent disease specific survival in spite of substantially less chemotherapy treatment. At 5 years post diagnosis, women 75 years and older were 18% more likely to die of causes other than breast cancer.
Prognostic effect of beta blockers (BB) in triple-negative breast cancer (TNBC) patients.
Authors: Munzone Elisabetta , Botteri Edoardo , Rotmensz Nicole , Cipolla Carlo Maria , Zanelotti Arnaldo , Adamoli Laura , Viale Giuseppe , Goldhirsch Aron , Gandini Sara
Published: March 2020

1061

Background: BB drugs have been used for decades worldwide, typically to treat hypertension and arrhythmias. Despite its therapeutic indication, evidence from recent epidemiological studies suggested that BB intake can improve prognosis of patients (pts) with cancer. With the present study we aimed at assessing whether BB intake is associated with improved prognosis in postmenopausal pts with TNBC, which represents one of the most aggressive cancers. Methods: We retrospectively identified 659 postmenopausal pts operated between 1997 and 2008 at the European Institute of Oncology, Milan, for a primary TNBC. Pts with advanced disease at diagnosis, presurgical systemic treatment or history of other cancers were excluded. The effect of BB intake on the risk of breast cancer recurrence and death from breast cancer (BC) was evaluated through competing risk survival analyses and multivariable Cox regression models. Results: At the time of cancer diagnosis, 61 pts (9.3%) out of 659 were currently using BB, while 598 (90.7%) were not. Median age was 63 years for the BB users and 60 years for the non-users (p value 0.048). All other characteristics—such as tumor size, lymph-nodal involvement, Ki-67, tumor grade, perivascular invasion, type of surgery and adjuvant therapy—were equally distributed between BB users and non-users. Median follow-up was 6 years for both groups. The 5-year cumulative incidence of BC recurrences was 11.7% and 24.1% for BB users and non-users, respectively (p = 0.030). After adjusting for age, tumor size, lymph nodal involvement, grade, perivascular invasion and use of other antihypertensive drugs, the beneficial impact of BB use remained statistically significant, with an hazard ratio of 0.44 (95% CI 0.21-0.98; p = 0.044). The 5-year cumulative incidence of BC deaths was 8.2% and 12.5% for BB users and non-users, respectively (p = 0.185). Hypertension and antihypertensive drugs other than BB did not have any significant impact on recurrence and survival. Conclusions: In this series of postmenopausal pts with primary TNBC, BB intake was associated with a significantly decreased risk of BC recurrence. Additional studies evaluating the potential benefits of BB on cancer prognosis are warranted.
Androgen receptor (AR), E-cadherin, and Ki-67 as prognostic markers in triple-negative breast cancer (TNBC).
Authors: Ricciardi Giuseppina R. R. , Adamo Barbara , Ferraro Giuseppa , Franchina Tindara , Zanghì Mariangela , Buda Carmelo , Trimarchi Giuseppe , Cardia Roberta , Tuccari Giovanni , Adamo Vincenzo
Published: March 2020

1062

Background: TNBC is an aggressive subset of breast cancer (BC) with central nervous system and visceral metastatic involvement and it represents a molecular subtype without specific target therapy. Methods: This observational, retrospectivestudy included 45 TNBC. The aim of this study was to evaluate the expression of some molecular determinants such as the AR, E-cadherin and Ki-67 in relation to histological type, time to relapse and overall survival.Immunohistochemistry (IHC) was carried out on formalin-fixed paraffin-embedded tumor samples obtained from patients (pts) defined TNBC, since ER and PgR were 0% and HER2 negative (IHC score 0/1 or FISH not amplified). Results: Median age was 58.8 years (range 39-77). The main histological type was ductal in 35 pts (77.7%), lobular in 7 (15.5%), medullary in 3(6.6%). 29 pts (64.4%) had a G3 tumor. Tumor stage was: I 6/45 (13.3%), IIA 21/45 (46.6%), IIIA 11/45 (24.4%), IIIB 3/45 (6.6%) and IV 4/45 (8.8%). All patients received treatments; the most frequently used regimens were anthracycline and taxanes. The androgen receptor was positive (IHC >10%) in 12/45 (26.6%). E-cadherin expression was semi-quantitatively analyzed according to the percentage of cells showing membrane positivity: 0 (0 to 10%); 1+ (10 to 30%); 2+ (30 to 70%); 3+ (> 70%). E-cadherin expression was considered positive if the score was ≥ 2, and negative when score was ≤ 1. This expression was negative in 24/45 (53.3%) cases. The Ki-67 index was ≥ 25% in 17/45(37.7%). The statistical analysis showed that patients with AR negative and Ki-67 positive expression have a significant correlation with the ductal histotype and G3 tumors (p < 0.001). Multivariate analysis showed that the patients with AR and E-cadherin negative but Ki-67 positive expression showed significantly (p < 0.001) worse overall survival time than those with either AR and E-cadherin positive but Ki-67 negative expression. Conclusions: Our data suggest that the combination of AR and E-cadherin expression as well as Ki-67 status might be useful prognostic markers in TNBC.
Anaplastic lymphoma kinase (ALK): A potential oncogenic driver in triple-negative breast cancer?
Authors: Sachdev Jasgit C. , Naini Pranitha , Arteta-Bulos Rafael , Vontela Namratha , Hout David Richard , Hirsch Fred R. , Morris Stephan , Osarogiagbon Raymond U.
Published: March 2020

1067

Background: TNBC, a molecularly heterogeneous subset of breast cancer, has an aggressive clinical course and no established targets for therapy. Wild-type ALK gene amplification by fluorescence in situ hybridization (FISH) was noted in 6/9 inflammatory TNBC specimens (Robertson et al. SABCS, P3-01-18). The status of ALK, full-length or fused, in non-inflammatory TNBC has not been described. Identification of a biomarker such as ALK in TNBC would be clinically significant, given the ongoing development of multiple ALK inhibitors. We screened for ALK expression in TNBC specimens with a novel patented qRT-PCR assay (Insight ALK Screen). Methods: We tested archived formalin-fixed, paraffin-embedded blocks of TNBC tissue. Evaluable specimens had sufficient tumor material for 10 slides with 5-micron sections. Insight ALK Screen was performed using previously described methodology (Hout, et al. AACR 2011, Abstract 2220). We subjected ALK Screen positive specimens to ALK break-apart FISH (Vysis) and direct sequencing analysis. Results: See clinical characteristics (Table). Insufficient RNA: 8/40 (20%). Insight ALK Screen-positive: 8/32 (25%). Break-apart FISH performed on these 8 specimens suggested 3/8 to be positive for ALK translocation and 2/8 to contain amplification of ALK without a translocation. The ALK-amplified specimens were subsequently confirmed with sequencing of RNA-PCR products to express full-length ALK. One additional ALK Screen-positive, FISH-negative specimen had full-length ALK expression confirmed on sequencing. Further analysis of the other 2 ALK Screen-positive cases is pending. Conclusions: ALK expression was seen in ~25% of TNBC specimens screened by Insight ALK Screen. We observed both ALK translocations and amplification/overexpression of full-length ALK. We are testing additional specimens by FISH and immunohistochemistry to evaluate the full spectrum of ALK alterations in TNBC. Updated data will be presented. [Table: see text]
Sixteen years follow-up results of a randomized phase II trial of neoadjuvant FAC compared with CMF in stage III breast cancer.
Authors: Zwenger Ariel Osvaldo , Leone Julieta , Vallejo Carlos Teodoro , Perez Juan Eduardo , Romero Alberto Omar , Machiavelli Mario Raul , Romero Acuna Luis , Dominguez Maria Ester , Langui Mario , Fasce Hebe Margot , Leone Bernardo Amadeo , Ortiz Eduardo , Leone Jose Pablo , Iturbe Julian
Published: March 2020

1073

Background: Neoadjuvant chemotherapy allows direct evaluation of the tumor’s sensitivity to therapy, eradication of micrometastatic disease and the possibility of performing breast conserving surgery. The aim of this study was to describe long-term results of neoadjuvant chemotherapy in stage III breast cancer patients (pts). Methods: We evaluated 126 pts with stage III breast cancer that participated in a phase-II randomized trial of neoadjuvant 5-fluorouracil, doxorubicin and cyclophosphamide (FAC every 21 days) compared with cyclophosphamide, methotrexate and 5-fluorouracil (CMF days 1 and 8 every 28). Chemotherapy was administered for three cycles prior to definitive surgery and radiotherapy, and then for six cycles as adjuvant. Response was assessed by WHO criteria. Results: Pts characteristics were well balanced in both groups (FAC: 64pts, CMF: 62pts). Median follow-up was 4.5 years (range 0.2-16.4). No significant difference was found regarding acute and long-term toxicity; however, alopecia was more frequent in FAC group. Breast conserving surgery was performed in 13.5% of pts with no difference between groups. Objective response rate (OR) was similar in both groups but pathological complete response was achieved by 4 pts who received FAC. Although both groups had similar locoregional and distant recurrences, contralateral breast cancer was higher in the CMF group (6.5% vs 1.6%, P=NS). Disease free survival (DFS) and overall survival (OS) data are shown in the table. After 16 years of follow-up, 42.1% (n=53) of pts are still alive. Disease progression was the principal cause of death in both groups (78.9% vs 84.2%). Conclusions: To the best of our knowledge, this is the first study to report long-term outcomes of FAC and CMF in the neoadjuvant setting. Within the sensitivity of our study, both regimens showed similar OR, long-term toxicity, DFS and OS rate at 16 years. Around 40% of pts are currently alive. Clinical trial information: NCT00002696. [Table: see text]
The effect of HCV serological status on doxorubicin-based chemotherapy-induced toxicity and disease-free survival in breast cancer patients.
Authors: Abd-El-Moneim Salah-Eldin , Welaya Karim Youssry , El-Assal Shaaban , Salama Ossama Eissa , Ghanem Hamdy M.
Published: March 2020

1075

Background: Breast cancer and HCV are two frequent diseases in Egypt. There is a considerable probability of concurrent affection. This concurrence creates a subpopulation which needs special evaluation and care. Methods: To evaluate a subset of Egyptian breast cancer patients receiving doxorubicin based adjuvant chemotherapy, with HCV seropositivity (Group 2) compared to HCV seronegative patients (Group 1). 102 breast cancer patients, planned to receive Doxorubicin based adjuvant chemotherapy, at the Oncology Department, Alexandria Faculty of Medicine, were recruited since June 2009. Pretreatment evaluation included serological testing for HCV. FAC adjuvant chemotherapy was given. Results: HCV seropositivity was detected in 52 cases. Two cases in Group 2 developed toxic hepatitis and discontinued treatment and follow up. The remaining 100 patients suffered comparable toxicities, except for more frequent SGOT and SGPT elevations in Group 2. Diarrhea was more frequent in Group 2. Treatment delays and dose reductions were more frequently observed in Group 2. The 24 month disease-free survival and relapse pattern were not significantly different between the two groups. Conclusions: Patients receiving chemotherapy should undergo screening for the virus. Most patients with HCV were able to tolerate chemotherapy and continue the initial chemotherapy plan, without significant change in the toxicity profile or the natural course of their malignancy. Dose or regimen adjustments may be of help to less tolerant patients. A preemptive 10% initial Doxorubicin dose reduction might reduce the frequency of severe toxicity. The assistance of a gastroenterologist in HCV positive breast cancer patients, planned for chemotherapy is important.
Chemotherapy (CTX) treatment patterns for early-stage breast cancer (ESBC): Changing use of anthracyclines (A).
Authors: Serrurier Katherine M. , Hwang Jimmy , McGuire Joseph P. , Lichtensztajn Daphne , Griffin Ann C. , Gomez Scarlett Lin , Kurian Allison W. , Melisko Michelle E. , Rugo Hope S.
Published: March 2020

1083

Background: Anthracyclines (A), given in sequence or combination, have been the mainstay of adjuvant CTX for ESBC. Recent molecular studies have questioned the value of A for ESBC. Trials for ESBC, presented primarily in 2005, have demonstrated similar or improved efficacy with non-anthracycline (NA) CTX. We sought to understand changing use of A for ESBC from 2000-2010 as reported in the population-based 9-county Greater Bay Area Cancer Registry (GBACR). Methods: Using the GBACR database, we recorded use of A or NA based CTX regimens in women with ESBC and no prior CTX from 2000-2010, and correlated type of CTX with tumor stage, receptor status, and age. We evaluated the use of A vs. NA (80% taxane-based) CTX from 2000-2005 and 2006-2010. Results: 16,476 patients (pts) met criteria for inclusion; 2,032 (12%) were excluded (missing information, or CTX not given). Pt characteristics were: median age 52 (range 21-94), stage I (25%), II (56%), and III (19%), 69% HR+. From 2000-2010, 83% received A; overall use of A decreased (87% to 57%), and use of NA increased (13% to 43%). The Table compares use of NA CTX during the two time periods by clinical variables. With short follow-up there was no difference in survival based on use of A vs. NACTX. Conclusions: Use of NA CTX significantly increased during 2006-2010; this trend was independent of age or receptor status and was more pronounced in earlier stage disease. The timing of this change correlated with the presentation of two phase III trials, emphasizing the impact of early data from phase III trials on treatment practice, and confirming results from a large claims database (Giordano). Potential outcome differences will be evaluated in NSABP-B49 and with longer follow-up of this cohort. This study was supported by the UCSF Cancer Registry and CPIC. [Table: see text]
Princess Margaret Cancer Centre (PMCC) Integrated Molecular Profiling in Advanced Cancers Trial (IMPACT) using genotyping and targeted next-generation sequencing (NGS).
Authors: Bedard Philippe L. , Oza Amit M. , Tsao Ming-Sound , Leighl Natasha B. , Shepherd Frances A. , Chen Eric Xueyu , Tannock Ian , Krzyzanowska Monika K. , Dhani Neesha C. , Clarke Blaise , Berman Hal K. , Serra Stefano , Craddock Kenneth J. , Chadwick Dianne , Zhang Tong , Sukhai Mahadeo A. , Yu Celeste , Hansen Aaron Richard , Kamel-Reid Suzanne , Siu Lillian L.
Published: March 2020

11002

Background: IMPACT is an institution-wide screening program to identify patients (pts) treated at PMCC with somatic alterations that can be matched to targeted therapies. Methods: Pts with advanced breast, colorectal (CRC), non-small cell lung (NSCLC), ovarian cancers and selected other solid tumors treated at PMCC were eligible. Tumor DNA was isolated from a FFPE archived sample and genotyped using a customized Sequenom panel (23 genes, 280 mutations) in a CLIA-certified laboratory. Verified mutations were reported in pts electronic health records. Selected FFPE samples were further characterized by NGS with the Illumina MiSeq TruSeq Amplicon Cancer Panel (48 genes, 212 amplicons, ≥500x coverage) for platform validation. Results: From Mar 1/12-Jan 10/13, 485 pts were enrolled with median 1 prior treatment for advanced disease (range 0-6). Of 33 (7%) screen failures, 5% were for insufficient tissue and 2% for clinical deterioration. Median DNA quantity from FFPE = 4250ng (range 15-32550ng). The median time from tissue receipt to reporting was 5 weeks (range 1-23). Mutations were identified by Sequenom in 137/349 (39%) pts, including 24/79 (30%) breast, 40/80 (50%) CRC, 54/88 (61%) NSCLC, 17/78 (22%) ovarian, and 2/24 (8%) other cancers. Mutations detected were: 76 KRAS, 35 PIK3CA, 22 EGFR, 5 NRAS, 5 ERBB2, 5 CTNNB1, 4 BRAF, and 1 AKT1. MiSeq was concordant with Sequenom in 112/113 (99%) pts, with mutations identified in 94/114 (82%). The average number of mutations detected by MiSeq was 1.72/pt (range 0-7) compared with 0.49/pt by Sequenom (range 0-2). After a median follow up of 5.0 months, 31/137 (23%) pts with mutations have been matched to targeted therapies, including 14 pts enrolled in clinical trials (15 trials) matched to their genotype. Of the 10 trial pts with at least one response assessment, 3 PR (1 confirmed) and 2 SD ≥ 24 weeks have been observed. Conclusions: Molecular profiling can be integrated into the routine care of advanced cancer pts. Genotyping and targeted NGS are feasible in a clinical laboratory using stored archival FFPE tumor samples. NGS identifies additional actionable mutations to inform clinical-decision making. Clinical trial information: NCT01505400.
Development and validation of an immuno-PET tracer for patient stratification and therapy monitoring of antibody-drug conjugate therapy.
Authors: Ilovich Ohad , Natarajan Arutselvan , Sathirachinda Ataya , Kimura Richard , Srinivasan Ananth , Gebauer Mathias , Kruip Jochen , Carrez Chantal , Sassoon Ingrid , Blanc Veronique , Sarkar Susanta K. , Gambhir Sanjiv Sam
Published: March 2020

11006

Background: SAR566658 is an antibody-drug immunoconjugate consisting of a humanized monoclonal antibody (huDS6) against the tumor-associated MUC1-sialoglycotope, CA6, conjugated to a cytotoxic maytansinoid (DM4). SAR566658 is currently undergoing phase I clinical trials in patients with CA6-positive solid tumors. A companion diagnostic based on huDS6 may facilitate patient stratification and early evaluation of therapeutic efficacy. The present study describes the development and preclinical evaluation of three novel Copper-64 (t½= 12.7h) labeled antibody fragments (two Fabs and a diabody) derived from the huDS6 antibody. One fragment was chosen based on imaging figures of merit for further specificity evaluations. Methods: The affinity of all fragments and their DOTA conjugates to CA6 was validated using flow cytometry. The DOTA conjugates were labeled with Copper-64 and evaluated in human serum stability studies, in vivo small animal PET imaging and 24-hour biodistribution studies in nude mice bearing either CA6 positive (WISH) or CA6 negative (A2780) subcutaneous tumors. The specificity of the lead tracer was evaluated in vivo via blocking studies and isotype controls. Results: All fragments and their DOTA conjugates had high affinity (Kd = 4-20 nM) for WISH cells. 64Cu-DOTA-B-Fab gave superior results in radio-synthesis (RCY - 60%, SA - 55 GBq/µmole, >99% purity), serum stability (94±5%, n=3) and biodistribution profile. Its two isotype controls gave statistically significant (P<0.05) uptake values in WISH but not A2780 tumors (see table). Blocking with B-Fab or huDS6 prior to tracer administration afforded a 23% (p<0.05, n=8) and 26% (p<0.05, n=7) decrease in WISH tumor uptake, respectively. Conclusions: These preclinical studies suggest that 64Cu-DOTA-B-Fab may be a suitable companion diagnostic for SAR566658 in cancer patients and requires further investigation.[Table: see text]
Integrated genomic analysis by whole exome and transcriptome sequencing of tumor samples from EGFR-mutant non-small-cell lung cancer (NSCLC) patients (p) with acquired resistance to erlotinib.
Authors: Weissman Jonathan S. , Giannikopoulos Petros , St. John John , Uzilov Andrew V. , Costa Carlota , Karachaliou Niki , Sansano Irene , Jantus-Lewintre Eloisa , Stahel Rolf A. , Vergnenegre Alain , Gervais Radj , Perez-Gracia Jose Luis , Lozano Maria D. , Wellde Anne S. , Bordoni Rodolfo , Cardona Zorrilla Andres Felipe , Polkinghorn William Reilly , Wellde George W. , Rosell Rafael , Bivona Trever Grant ,   Cancer Therapeutics Innovation Group
Published: March 2020

11010

Background: NSCLC p with EGFR mutations initially respond to EGFR tyrosine kinase inhibitors (TKIs) but ultimately relapse. Sub-genomic molecular studies indicate that the EGFR T790M mutation and the activation of MET, PI3K, AXL, HER2 and MAPK can lead to acquired resistance to EGFR TKIs. To date, no integrated comprehensive genomic investigation of EGFR TKI resistance has been performed. Methods: FFPE biopsies of erlotinib-sensitive and erlotinib-resistant tumors were obtained from 11 EGFR mutant NSCLC p. DNA was extracted from all tumor and corresponding normal tissue samples and underwent whole exome sequencing using the Illumina HiSeq2500. RNA was extracted from all tumor samples and analyzed by whole transcriptome sequencing, also using the Illumina HiSeq2500. Results: Erlotinib resistant NSCLC specimens harbored upregulation of known resistance drivers including MET and AXL and novel alterations including upregulation of genes that are: 1) recurrently mutated in NSCLC, including ALK, STK11; 2) components of established embryonic stem cell signatures, including targets of Nanog, Oct4, Sox2, c-Myc, 3) neuronal lineage specific regulators, including NTRK3, NRCAM, ALK, LRP4. The analysis also revealed downregulation of several genes that are: 1) components of innate and acquired immunity, including HLA-A, -B, DQ, CD40; 2) phosphatases regulating survival signaling pathways, including PTEN, PTPRD, 3) proapoptotic components, including BNIP3L, IKIP. Conclusions: This study demonstrated the feasibility and utility of comprehensive genomic analysis in the clinical management of NSCLC p receiving targeted therapy. We identified known and novel molecular biomarkers of erlotinib acquired resistance in NSCLC p, and uncovered a previously unappreciated role for genetic events governing stem cell and neuronal phenotypes as well as immune evasion in erlotinib acquired resistance in NSCLC p. Together, our data provide unprecedented insight into the molecular pathogenesis of escape from EGFR oncogene inhibition in NSCLC. We are now conducting a prospective observational study in additional NSCLC p.
Real-time clinical application of next-generation sequencing (NGS): Results from a multicenter program.
Authors: Hansen Aaron Richard , Brown Andrew M. K. , Bedard Philippe L. , Hotte Sebastien J. , Winquist Eric , Goss Glenwood D. , Vergidis Dimitrios , Hirte Hal W. , Welch Stephen , Zhang Tong , Stein Lincoln D. , Ferretti Vincent , Watt Stuart , Jiao Wei , Ng Karen , Petrocelli Teresa , Siu Lillian L. , McPherson John D. , Kamel-Reid Suzanne , Dancey Janet
Published: March 2020

11016

Background: NGS techniques enable the identification of actionable mutations in clinical tumor samples. The objective of this study is to assess feasibility and explore the impact of real-time targeted NGS on therapeutic decision-making. Methods: Patients (pts) with advanced solid tumors underwent a biopsy of a metastatic lesion. The first phase was performed with Sequenom MassARRAY somatic genotyping and Pacific Biosciences RS-targeted NGS. The second phase broadened genomic coverage in both Sequenom and Illumina MiSeq. All pts had a molecular profiling (mp) report issued after identified actionable mutations were verified by Sanger sequencing in a CLIA-lab and reviewed by an expert panel. “Actionability” was defined as having prognostic, predictive or diagnostic implications on patient management. Details of clinical outcomes and subsequent matched therapy, if applicable, were captured. Referring physicians were surveyed on the impact of mutation results on their treatment recommendations. Results: These are summarized in the Table. Conclusions: Broader mp platforms resulted in more identified actionable mutations which required a longer time for verification prior to reporting, but may yield a greater impact on clinical decision-making. However, the matching of pts to drugs based on their molecular profiles depends highly on drug access. For mp to be clinically relevant, it must be coupled with access to approved drugs or to investigational agents on clinical trials. Clinical trial information: NCT01345513. [Table: see text]
A survey of thousands of tumor exomes and transcriptomes to expand clinical opportunities for crizotinib.
Authors: Bowden Emma , Eddy Sean , Williams Paul , Khazanov Nikolay , Bankhead Armand , Cyanam Dinesh , Wyngaard Peter , Rhodes Dan
Published: March 2020

11017

Background: Cancer driver events occur as a result of chromosomal rearrangements. There are several examples where targeted inhibition of the resulting fusion produces dramatic clinical response. For example, the EML4-ALK fusion in non-small cell lung cancer (NSCLC). Other ALK fusions have been described in NSCLC and other diseases including the NPM-ALK fusion in anaplastic large cell lymphoma (ALCL). The efficacy of crizotinib and other ALK inhibitors are being investigated in these diseases. ALK is also subject to activation via mutation and sensitivity to crizotinib is reported in ALK mutation positive neuroblastoma. Finally, crizotinib has activity not only against ALK, but also against ROS1, MST1R and MET. ROS1 fusions have been found in NSCLC and glioblastoma, and MET amplification events in gastric adenocarcinoma identify additional settings that may benefit from crizotinib treatment. Methods: To further understand the full therapeutic potential of Crizotinib, we undertook a genomic survey of ALK, ROS1, MET and MST1R across 1,000’s of patients from the The Cancer Genome Atlas (TCGA) and Oncomine. Results: We confirmed the presence of EML4-ALK fusions in both lung and colorectal cancer (CRC), and also identified a novel ALK fusion in CRC. ALK hotspot mutations and focal amplifications were confined to neuroblastoma, as previously described. Our survey of ROS1 identified rare novel fusions in NSCLC and glioblastoma, and high-level amplifications in liposarcoma (2%) and rarely in breast cancer (0.2%). No fusions were identified for MET, however high-level amplifications were observed in 1-5% of papillary renal cell carcinoma, the intestinal subtype of gastric adenocarcinoma, oliogodendroglioma, glioblastoma and lung adenocarcinoma. Hotspot mutations were frequently observed in squamous head and neck (11%), and more rarely in hepatocellular carcinoma, small cell lung and ovarian cancers. Conclusions: These results leverage all available genomic profiling data to provide a broadened scope of therapeutic opportunity for inhibitors like crizotinib. With the growing availability of next-generation sequencing, such surveys can support hypothesis-driven development of targeted therapies.
Use of next-generation sequencing (NGS) to identify actionable genomic alterations (GA) in diverse solid tumor types: The Foundation Medicine (FMI) experience with 2,200+ clinical samples.
Authors: Miller Vincent A. , Ross Jeffrey S. , Wang Kai , Ali Siraj M. , Otto Geoff , Curran John , Palma Norma Alonzo , Yelensky Roman , Downing Sean , Stephens Phil , Lipson Doron , Palmer Gary A.
Published: March 2020

11020

Background: ST oncology has been transformed by the linkage of GA with targeted therapeutics. Unfortunately, most STs still have no target detected by clinically available assays. More comprehensive testing platforms are needed to determine GA in ST and thus broaden treatment options. We developed a ST NGS diagnostic assay, optimized for routine clinical FFPE specimens including core and fine needle biopsies and malignant effusions, and analyzed > 2,200 patients’ tumors in a CLIA-certified lab (Foundation Medicine). Methods: Hybridization capture of 3,320 exons from 182 cancer-related genes and 37 introns of 14 genes commonly rearranged in cancer was applied to ≥ 50ng of DNA extracted from 2,200+ consecutive FFPE tumor specimens and sequenced to high unique coverage. GA (base substitutions, small indels, rearrangements, copy number alterations) were categorized as “actionable” if directly linked to a clinically available targeted treatment option or a mechanism-driven clinical trial. Results: 2,112/2,221 (95%) of specimens (most common 1° sites: lung 18%, breast 14%, colon 7%, other 34%) were successfully profiled (mean coverage 1134X). Alterations were reported in 155/182 (85%) of genes. Seventy-six percent of cases harbored ≥1 actionable GA, mean 1.6 (range 0-16); sixty-two percent harbored at least one actionable GA not assayed by available tumor-type specific tests or hotspot panels. This approach has led to novel insights into advanced cancer including: 13 novel, potentially druggable kinase gene fusions; alterations in known drug targets (e.g. ALK, EGFR, ERRB2, KIT, MET, PDGFR α and β, RAF1 and RET) in novel tumor types and new mechanisms of resistance to approved targeted therapies. Several patients demonstrated dramatic responses to treatment with targeted therapies directed against these alterations. Conclusions: Comprehensive NGS genomic profiling was successful in profiling >2,200 unselected clinical cases, identified actionable alterations in 76% of cases and provided additional treatment options for 62% of patients targeting alterations in genes not assayed by available hotspot panels.
BRCA1 like copy number profiles to predict benefit of intensified alkylating chemotherapy in breast cancer.
Authors: Schouten Philip C. , Linn Sabine C. , Aulmann Sebastian , Sinn Hans-Peter , Schneeweiss Andreas , Marme Frederik
Published: March 2020

11023

Background: DNA copy number profiles can identify patients with a defect in BRCA1. We previously showed that patients with a BRCA1-like profile benefit from intensified alkylating chemotherapy (IA, 4 cycles 5-fluorouracyl, epirubicin, cyclophosphamide + 1 cycle carboplatin, thiotepa and cyclophosphamide with autologous stem cell transplantation (ASCT)). Presumably, this is because of the defect in error free homologous recombination DNA repair. Here we present an independent study of BRCA1-like profiles to predict benefit of IA chemotherapy (2 cycles induction chemotherapy consisting of 2500 mg/m2 ifosfamide and 40 mg/m2 epirubicin, followed by 12 g/m2 ifosfamide, 900 mg/m2 carboplatin, 180 mg/m2 epirubicin with ASCT) versus adriamycin-cyclophosphamide or cyclophosphamide-methotrexate-5-fluorouracyl regimens in high risk breast cancer. Methods: We isolated tumor DNA from 117 patients of a case-control study of high risk breast cancer patients to apply a marker by treatment interaction study design to assess overall survival. We generated copy number profiles and classified them to be BRCA1-like or non-BRCA1 like. We used Fisher Exact tests to calculate correlations and performed Kaplan-Meier and Cox regression analyses to investigate whether patients with a BRCA1-like tumor benefit from IA chemotherapy compared to an AC/CMF regimen. Results: 16 of 117 (14%) patients had a BRCA1-like profile. BRCA1-like status was associated with high tumor grade (p=0.03), triple negative status (p=0.0005) and high N stage (p=0.03). When corrected for hormone receptor and HER2 status, size, positive lymph nodes, and grade we found that BRCA1 like patients had a 6-fold decreased chance of death (HR: 0.15, 95% confidence interval: 0.03-0.80, p: 0.03) compared to non-BRCA1 like patients (HR: 0.94, 95% confidence interval: 0.53-1.67, p: 0.84). The interaction test between IA chemotherapy and marker status was significant (p: 0.04). Conclusions: We provide independent validation of the previous finding that breast cancer patients with a BRCA1 like copy number profile benefit highly from intensified alkylating chemotherapy.
Fibroblast growth factor receptor 1 (FGFR1) and SRY-related HMG-box (SOX2) amplification in squamous cell carcinoma (SCC) of the lung.
Authors: Gasco Amaya , Mendez Pedro , Ramirez Jose Luis , Viteri Ramirez Santiago , Moran Teresa , Carcereny Costa Enric , Costa Carlota , Gimenez Capitan Ana , Sansano Irene , Perez Maria , Tierno Montserrat , Botia Monica , Taron Miquel , Groen Harry J.M. , Rosell Rafael ,   Spanish Lung Cancer Group
Published: March 2020

11025

Background: SOX2 is a key transcription factor that is amplified in lung SCC. FGFR1 is a receptor tyrosine kinase that promotes cell proliferation, survival and apoptotic resistance through the PLCγ/PKC, RAS/MAPK and PI3K-AKT pathways, respectively. FGFR1 is amplified in 15-25% of lung SCC. Pre-clinical studies of targeted inhibitors showed a growth dependency on FGFR1 amplification both in vitro and in vivo. A European, multicenter clinical trial of second-line treatment with BIBF1120, an FGFR1 inhibitor, will be performed in p with lung SCC with FGFR1 amplification. Methods: We have examined FGFR1 and SOX2 gene copy number (GCN) in 76 lung SCC p by multiplex ligation-dependent probe amplification (MLPA). Genomic DNA (gDNA) was isolated from enriched tumor cells by laser capture microdissection from formalin-fixed paraffin embedded (FFPE) tumor tissue. 50-100 ng of gDNA was analyzed in each of three independent replicates per tumor sample. Two independent probe sets were used for each gene analyzed. For inter-patient GCN comparisons, the results from each patient were normalized against the GCN values derived from FFPE peripheral blood leukocytes. In order to study intra-tumor heterogeneity (TH), we examined FGFR1 and SOX2 GCN in different areas of 4 tumors. In 2 p, TH was examined in serial tumor biopsies and/or resections obtained at different points of disease progression. Results: High FGFR1 amplification was detected in 13/76 (17.10%) and low amplification in 7/76 (9.21%) p. High SOX2 amplification was observed in 38/63 (60.32%) and low amplification in 9/63 (14.28%) p. 46.15% of the FGFR1-amplified tumors were also co-amplified for SOX2. Intra-TH was observed in 2/4 tumors. Survival according to FGFR1 and SOX2 GCN will be presented. In addition, GCN changes in FGFR1, SOX2, PIK3CA, PDGFRA, KDR, EGFR and MET over 10 years of follow-up will be presented for one surgically resected SCC lung p. Conclusions: FGFR1 and SOX2 co-amplification could represent a novel therapeutic target and warrants further research.
Applicability of the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial results in invasive lobular carcinoma.
Authors: Wang Jun , Mittendorf Elizabeth Ann , Sahin Aysegul A. , Yi Min , Caudle Abigail Suzanne , Hunt Kelly , Wu Yun
Published: March 2020

1103

Background: The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial demonstrated that, for patients with clinical T1-T2, N0 breast cancer and one or two positive sentinel lymph nodes undergoing breast conserving therapy, there was no difference in local-regional recurrence (LRR), disease-free survival or overall survival (OS) between patients who underwent sentinel lymph node dissection (SLND) alone or completion axillary lymph node dissection (ALND). However, there were a limited number of invasive lobular carcinoma (ILC) participants (7%) in the study. In addition, it is known that ILC has a different pattern of metastases, frequently presenting as small foci requiring immunohistochemistry for detection. Together, these considerations raise concern regarding the applicability of the ACOSOG Z0011 data to patients with ILC. Methods: Patients with ILC who met the ACOSOG Z0011 eligibility criteria were identified from the Surveillance, Epidemiology, and End Results database (1998-2009). Patients were evaluated based on the extent of axillary surgery: SLND alone or ALND. Clinicaloutcomes of the two groups were compared. Results: At a median follow-up of 71 months, there were no LRRs in the SLND arm, and only 4 (0.45%) in the ALND arm. There were no differences in OS or disease-specific survival between the two groups. Conclusions: Omission of completion ALND is appropriate in patients with ILC who fulfill the ACOSOG Z0011 eligibility criteria.