bluuebunny/crossref_metadata_2025_split huggingface dataset:
CALGB 150002: Correlation of HER2 and chromosome 17 (ch17) copy number with trastuzumab (T) efficacy in CALGB 9840, paclitaxel (P) with or without T in HER2+ and HER2- metastatic breast cancer (MBC)
Authors: Kaufman P. A. , Broadwater G. , Lezon-Geyda K. , Dressler L. G. , Berry D. , Friedman P. , Winer E. P. , Hudis C. , Ellis M. J. , Seidman A. D. , Harris L. N. 
Published: March 2020

1009 Background: Accurate assessment of HER-2 is critical in MBC and predicts benefit from T. We have previously shown low level amplification of HER-2 associated with ch17 polysomy is common in IHC 2+ cases that are FISH(-). However, the clinical relevance of this is unknown. Methods: CALGB 150002, a correlative companion to 9840, was designed to assess the predictive role of HER-2 in MBC pts treated with weekly vs q 3W P ± T. Pts HER-2(-) locally were randomized to ±T. 585 pts were enrolled in 9840; 304 blocks were available for central analysis with DAKO HercepTest (IHC) and Pathvysion (FISH). Logistic regression was used to test HER-2:ch17 ratio and HER-2 copy # as predictor of response rate (RR) to T in HER-2(+) pts. 1-sided Fisher’s Exact Test was used to compare RR of P vs P+T in pts with ch17 polysomy on central testing (>2.2 copies ch17/cell), but defined as HER-2(-) locally and randomized to T. Results: In pts HER-2(+) locally, FISH is a significant predictor of RR to P+T. A higher HER-2:ch17 ratio is associated with a higher RR by logistic regression (p=0.033, n=95). No interaction is seen between HER-2 and P schedule, p=0.71. On central testing of cases IHC(-) locally, 16/140 (11%) were IHC 3+ and 5/133 (4%) HER-2 amplified. In 21 HER-2(-) cases reclassified as HER-2 3+ or FISH (+) centrally, we do not find a difference in RR to P vs P+T. However among 133 cases HER-2(-) locally and central FISH(-) we find 32 with ch17 polysomy (copy # ch17 = 2.2); 12 treated with P alone, and 19 with P+T (see table for RR). Conclusions: These data suggest a higher RR to P+T in HER-2(+) pts with a higher HER-2:ch17 ratio, consistent with a relationship between RR to T and HER-2 copy #. In FISH(-) cases we note an increased RR to P+T vs P in cases with ch17 polysomy, typically reported clinically as HER-2(-). This analysis suggests that T might be effective in a subpopulation of breast cancer conventionally defined as HER-2(-), but in fact displaying low level HER-2 amplification. [Table: see text] [Table: see text]
Goserelin plus anastrozole in the treatment of premenopausal hormone receptor positive, recurrent or metastatic breast cancer
Authors: Carlson R. W. , Schurman C. M. , Rivera E. , Chung C. T. , Phan S. C. , Dice E. K. , Thomas E. , Valero V. 
Published: March 2020

1030 Background: Aromatase inhibitors (AIs) are highly active in postmenopausal women with hormone receptor positive breast cancer. However, the AIs do not suppress ovarian estrogen synthesis and are not effective in premenopausal women. This phase II study was initiated to estimate the activity of anastrozole when given with ovarian suppression by goserelin in premenopausal women with ER and/or PgR positive metastatic breast cancer. Methods: Premenopausal women with measurable recurrent or metastatic, ER and/or PgR positive breast cancer; no prior AI or LH-RH agonist/antagonist; no adjuvant chemotherapy within 6 months; ECOG performance status of 0–2; adequate organ function; and who provided signed, informed consent were eligible. A 2 stage phase II design was utilized. Treatment was with goserelin 3.6 mg SQ q4wk and anastrozole 1 mg/day begun on day 22 of protocol treatment. Treatment was continued to disease progression. Results: 35 patients (pts) were enrolled. Three were excluded from analysis for the following: 1 postmenopausal, 1 consent withdrawal, 1 early oophorectomy. Of the remaining 32 pts, median age was 43 yrs (range 26–51 yrs), 18 (56%) had prior chemotherapy, and 9 (28%) had prior SERM. Pts were Asian/Middle Eastern 22%, Caucasian 62%, Black 13%, Hispanic 3%. Disease sites were lymph node 50%, breast 44%, bone 81%, lung 41%, liver 22%, pleural effusion 6% and soft tissue 6%. Receptor status was ER+/PgR+ 75%, ER+/PgR- 22% and ER-/PgR+ 3%. Response: Treatment resulted in complete response (CR) in 1(3%), partial response (PR) in 11(34%), stable disease 6+ mos (SD) in 11(34%), and clinical benefit (CR+PR+SD) 23 (72%). Median TTP was 8 mos (range 2 - 63+ mos); median OS was 26 mos (range 11 - 63+ mos). Estradiol levels were detectable in 30/31 pts at baseline (median 56 pg/ml, range <10 - 273 pg/ml). Mean estradiol levels (pg/ml) were 75 at baseline, 21 at 1 mos, 19 at 3 mos, and 15 at 6 mos. TOXICITY: One grade 3 weight loss. All other toxicities were grade 1–2. Conclusions: Ovarian suppression with goserelin in combination with anastrozole is well tolerated and highly active in the treatment of premenopausal, hormone receptor-positive metastatic breast cancer. Support provided by AstraZeneca Pharmaceuticals No significant financial relationships to disclose.
A phase I study of trastuzumab-MCC-DM1 (T-DM1), a first-in-class HER2 antibody-drug conjugate (ADC), in patients (pts) with HER2+ metastatic breast cancer (BC)
Authors: Beeram M. , Krop I. , Modi S. , Tolcher A. , Rabbee N. , Girish S. , Tibbitts J. , Holden S. , Lutzker S. , Burris H. 
Published: March 2020

1042 Background: ADCs utilize tumor-specific and/or over-expressed surface antigens that undergo internalization to deliver highly potent anti-tumor agents via linkage to antigen-specific monoclonal antibodies (MoAbs). T-DM1 contains the humanized anti-HER2 MoAb trastuzumab (T) previously demonstrated to prolong survival in HER2+ BC to which a highly potent antimicrotubule drug (DM1) derived from maytansine has been chemically linked. Maytansine has been studied as a free drug with responses noted in breast and lung cancer pts; principal adverse events (AEs) were nausea, vomiting, diarrhea, and neuropathy. The MCC linker employed in T-DM1 provides a stable bond between T and DM1 that is designed to prolong exposure and reduce the toxicity of T-DM1 while maintaining activity; T-DM1 is the first ADC with an MCC linker in clinical trials. T-DM1 has activity in T-resistant HER2+ BC xenografts; its principal preclinical toxicities were reversible transaminase elevations, reversible decreases in platelets, and neuropathy. Methods: This ongoing first-in-human phase I study is evaluating the safety and pharmacokinetics (PK) of T-DM1 given IV q3 weeks to pts with HER2+ metastatic BC who have progressed on a T-containing regimen. Results: Seven pts (median age 58 (range 47–70); all PS 0–1; median number prior chemo regimens 6 (range 5–11)) have received 24 doses of T-DM1 at 5 dose levels (0.3–4.8 mg/kg). Related grade (gr) 1–2 AEs include elevations in hepatic transaminases (2 pts), fatigue (2 pts), anemia (1 pt), and thrombocytopenia (TCP, 1 pt). Related gr 3–4 AEs have been limited to rapidly reversible gr 4 TCP at 4.8 mg/kg (1 pt). There has been no cardiac toxicity. Consistent with preclinical modeling, dose dependent decrease in clearance was observed for T-DM1 across dose levels. One pt at 2.4 mg/kg has maintained an ongoing partial response for 6 cycles. Conclusions: At these initial doses, gr =2 AEs related to T-DM1 have been infrequent and manageable; gr 4 (dose-limiting) rapidly reversible TCP was seen at 4.8 mg/kg. T-DM1 PK is consistent with q3-week dosing. Objective tumor response has been observed. Enrollment is ongoing to determine the maximum tolerated dose of q3-week T-DM1. No significant financial relationships to disclose.
A phase II study of pemetrexed and doxorubicin in patients with advanced or metastatic breast cancer (MBC)
Authors: Blasinska-Morawiec M. , Martin M. , Salas F. , Falcon S. , Rolski J. , Ferrari B. L. , Guedez N. , Simms L. , Gulyas S. , Melemed A. 
Published: March 2020

1047 Background: Pemetrexed has a single-agent activity in MBC while doxorubicin is an established agent in breast cancer chemotherapy. This phase II study investigated the combination in patients with advanced or MBC who had not been previously treated with anthracyclines. Primary objective was to evaluate the overall response rate. Methods: Patients received pemetrexed 500 mg/m2 (10-min intravenous infusion) followed by doxorubicin 50 mg/m2 on day 1 of six 21-day cycles. Additional cycles were permitted based upon: absence of progressive disease, adequate cardiac function, and a maximum cumulative limit of doxorubicin 450 mg/m2. Routine folic acid and vitamin B12 supplementation was given to all patients. Results: A total of 79 women with advanced or MBC were enrolled at 15 centers in 7 countries. Major racial groups were Caucasians (50.6%) and Hispanics (24.1%). Median age was 55 years (range, 26–79) and most (91.1%) had performance status of 0 or 1. Patients had either metastatic (72.2 %) or locally advanced disease (27.9%). Sixteen (20.3%) patients had received prior adjuvant chemotherapy. A median of 6 cycles (range, 1–9) was delivered. During the 438 cycles, no doses were omitted, and 7 doses were reduced (3 for pemetrexed, 4 for doxorubicin). A total of 129 doses (29.5%) were delayed, primarily due to scheduling conflicts (84 doses) and neutropenia (19 doses). The relative dose intensity for both drugs was 93%. Overall response rate was 60.8% (95% CI, 49.1–71.6) with complete response in 8 patients (10.1%), partial response in 40 patients (50.6%), and stable disease in 20 patients (25.3%). Maximum CTC grade 3 and 4 toxicities observed in >5% patients were neutropenia (19 patients, 24.1%), leukopenia (8 patients, 10.1%), and vomiting (5 patients, 6.3%). Five deaths occurred during study treatment, 2 of which had causes (diarrhea, pneumonia) possibly related to the study drugs. One patient had resting left ventricular ejection fraction decreased to <50% after 6 cycles and did not receive further treatment. Conclusions: The combination of pemetrexed and doxorubicin was well tolerated and had promising response in patients with advanced or MBC. Survival and time-to-event results are forthcoming. No significant financial relationships to disclose.
Different prognostic value of cytokeratin-19 mRNA-positive circulating tumor cells according to estrogen receptor status in early breast cancer
Authors: Ignatiadis M. , Xenidis N. , Perraki M. , Apostolaki S. , Politaki E. , Kafousi M. , Stathopoulos E. , Sotiriou C. , Georgoulias V. , Mavroudis D. 
Published: March 2020

10500 Background: We have previously shown that the detection of cytokeratin-19 (CK-19) mRNA-positive circulating tumor cells (CTCs) predicts poor clinical outcome in node-negative breast cancer patients. Here, we examined the prognostic value of CK-19 mRNA-positive CTCs in early breast cancer patients focusing on clinically relevant subgroups based on estrogen receptor (ER) status. Methods: We analysed peripheral blood from 448 consecutive patients with stage I-III breast cancer after surgery and before the initiation of any adjuvant treatment for the presence of CK-19 mRNA-positive CTCs using a real-time RT-PCR assay. The effect of CK-19 mRNA-positive CTCs on clinical outcome of patients with ER-positive, ER-negative, and triple-negative (ER/PR/HER2-negative) tumors was investigated. Results: CK-19 mRNA-positive CTCs were detected in 181 (40.4%) of the 448 patients; 109 (41.5%) of 263 patients with ER-positive, 71 (40.6%) of 175 patients with ER-negative and 27 (35%) of 77 patients with triple-negative tumors. There was no significant difference in the proportion of patients with detectable CK-19 mRNA-positive CTCs in the ER-negative and ER-positive subgroups (p=0.856). After a median follow-up of 53 months, patients with CK-19 mRNA-positive CTCs experienced reduced disease-free survival (DFS) (p<0.0005) and overall survival (OS) (p<0.0005); this was mainly observed in patients with ER-negative (p<0.0005 and p<0.0005, respectively) and triple-negative (p=0.008 and p=0.001, respectively) but not with ER-positive (p=0.174 and p=0.364, respectively) tumors. In multivariate analyses, detection of CK-19 mRNA-positive CTCs was the strongest independent prognostic factor associated with reduced DFS and OS in the entire cohort (p<0.0005 and p=0.009, respectively), in ER-negative (p<0.0005 and p=0.003, respectively) and triple-negative (p=0.020 and p=0.022, respectively) but not in ER-positive tumors (p=0.350 and p=0.621, respectively). Conclusions: Detection of CK-19 mRNA-positive CTCs predicts poor clinical outcome at five years follow-up, only in patients with ER-negative and triple-negative, but not with ER-positive, early breast cancer. No significant financial relationships to disclose.
KRAS mutation is highly predictive of cetuximab resistance in metastatic colorectal cancer
Authors: Di Fiore F. , Le Pessot F. , Lamy A. , Charbonnier F. , Sabourin J. , Paillot B. , Frebourg T. , Michel P. 
Published: March 2020

10502 Background: In metastatic colorectal cancer (MCRC), no molecular predictive markers to cetuximab response have been yet established. The aim was to evaluate whether KRAS gene mutations, EGFR immunochemistery (IHC) and EGFR gene copy number correlate with response to cetuximab. Methods: 59 patients with MCRC treated by cetuximab between July 2004 and December 2005 were retrospectively included. Clinical data were collected and tumour response was evaluated according to RECIST criteria. EGFR IHC was performed using the Dako kit. The EGFR gene copy number was determined by FISH (Fluorescence in-Situ Hybridization). Detection of KRAS gene mutations on exon 2 was performed by sequencing of extracted paraffin-embedded DNA and then by 2 methods, SNaPshot and PCR-LCR, specifically developed to detect small fractions of mutated tumor cells. Response to cetuximab was studied according to clinical data, IHC, FISH and KRAS mutation analysis using the Fischer exact test. Predictive factors of response were determined by logistic regression. Skin reactions were collected but not considered for this analysis as regards the lack of accurate grading in a retrospective study. Times to progression (TTP) were calculated using the Kaplan-Meier method and compared with log-rank test. Results: 12 patients (20.3%) responded to cetuximab (2 patients with complete response and 10 patients with partial response), 19 (32.2%) had stable disease and 28 (47.5%) were in disease progression. A KRAS mutation was detected in 22/59 tumours and, in 6 cases, was missed by sequencing analysis but detected using the SNaPshot and PCR-LCR assays. No KRAS mutation was found in responders patients. KRAS mutation was associated with disease progression (p = 0.0005) and TTP was significantly decreased in mutated KRAS patients (3 vs 5.5 months, p = 0.015). There was no correlation between EGFR IHC and cetuximab response. No EGFR gene copy number increase was detected in responders patients. Predictive factors of cetuximab resistance were KRAS mutation (p=0.003; OR:0.10; 95IC:0.22–0.40) and age<60 (p=0.024; OR:0.13; 95IC:0.02–0.77). Conclusions: KRAS mutation is highly predictive of cetuximab resistance in MCRC. Our study also highlights the need of sensitive methods to ensure an efficient mutation detection. No significant financial relationships to disclose.
Sensitivity of tumor cells deficient in the fanconi anemia pathway to inhibition of ataxia telangiectasia mutated (ATM)
Authors: Kennedy R. D. , Stuckert P. , Archila E. , De LaVega M. , Chen C. , Moreau L. , D'Andrea A. 
Published: March 2020

10509 Loss of the fanconi anemia (FA) pathway function has been described in a number of sporadic tumor types including breast, ovarian, pancreatic, head and neck and hematological malignancies. Functionally, the FA pathway responds to stalled DNA replication following DNA damage. Given the importance of the FA pathway in the response to DNA damage, we hypothesized that cells deficient in this pathway may become hyper-dependent on alternative DNA damage response pathways in order to respond to endogenous genotoxic stress such as occurs during metabolism. Therefore, targeting these alternative pathways could offer therapeutic strategies in FA pathway deficient tumors. To identify new therapeutic targets we treated FA pathway competent and deficient cells with a DNA damage response siRNA library, that individually knocked out 230 genes. We identified a number of gene targets that were specifically toxic to FA pathway deficient cells, amongst which was the DNA damage response kinase Ataxia Telangiectasia Mutated (ATM). To test the requirement for ATM in FA pathway deficient cells, we interbred Fancg ± Atm± mice. Consistent with the siRNA screen result, Fancg-/- Atm-/- mice were non viable and Fancg± Atm-/- and Fancg-/- Atm ± progeny were less frequent that would have been expected. Several human cell lines with FA gene mutations were observed to have constitutive activation of ATM which was markedly reduced on correction with the appropriate wild-type FA gene. Interestingly, FA pathway deficient cells, including the FANCC mutant and FANCG mutant pancreatic cancer cell lines, were selectively sensitive to monotherapy with the ATM inhibitor KU55933, as measured by dose inhibition and colony count assays. FA pathway deficient cells also demonstrated an increased level of chromosomal breakage, cell cycle arrest and apoptosis following KU55933 treatment when compared to FA pathway corrected cells. We conclude that FA pathway deficient cells have an increased requirement for ATM activation in order to respond to sporadic DNA damage. This offers the possibility that monotherapy with ATM inhibitors could be a therapeutic strategy for tumors that are deficient for the FA pathway. No significant financial relationships to disclose.
BRCA1/2 mutations and cancer risk in Asian-Americans
Authors: Kurian A. W. , Chun N. M. , Mills M. A. , Staton A. D. , Crawford B. A. , Ridge Y. , Donlon S. S. , Gong G. D. , West D. W. , Ford J. M. ,   Asian-Caucasian BRCA1/2 Study Group
Published: March 2020

10512 Background: There are significant differences in breast cancer epidemiology between Caucasian and Asian-Americans and even between different Asian groups. These cancer risks and associated BRCA1/2 mutation prevalence have not been well defined in Asians; BRCA1/2 mutation penetrance might differ due to different risk modifiers. We report on a case-control study of BRCA1/2 mutation prevalence and cancer risk in Asian-American women. Methods: Clinical Data Collection: Chart review from cancer genetics services of 4 North American centers with highest Asian volume. BRCA1/2 Mutation Risk Assessment: BRCAPRO and Myriad II models, CancerGene version 4.3 (University of Texas). BRCA1/2 Mutation Testing: Full sequencing and large rearrangement panel (Myriad Genetics Inc.). Endpoints: BRCA1/2 mutation prevalence and predictive model accuracy (observed versus predicted mutations). Results: 43 of 181 Asians (23.8%) had a BRCA1/2 mutation; 36 (19.9%) had a variant of uncertain significance. The observed prevalence of BRCA1/2 mutations was 23.8% of women, which differs significantly from the predicted prevalence of 12.9% using BRCAPRO (p = 5.6 × 10-9), and the predicted prevalence of 12.6% using Myriad II. This 2-fold difference existed for Chinese, Japanese, and Filipina women (the ethnic sub-groups with enough cases available for comparisons), even though the percent with observed and predicted mutations varied for these three groups. Conclusions: One in 4 clinically tested Asian-Americans has a BRCA1/2 mutation. Standard models significantly under-predict mutations in Asians; consequently, Asians are likely under-tested for BRCA1/2 mutations. These results may reflect lower BRCA1/2-associated cancer risk in Asians compared to Caucasians. Comparison to Caucasian controls and to Asians in Hong Kong is underway, to investigate potential genetic and lifestyle modifiers of BRCA1/2-associated cancer risk. [Table: see text] No significant financial relationships to disclose.
Molecular genetic testing for large genomic deletion and duplication mutations in the BRCA1 and BRCA2 genes for hereditary breast and ovarian cancer
Authors: Wenstrup R. , Judkins T. , Eliason K. , Schoenberger J. , Rajamani S. , Frye C. A. , Burbidge L. A. , Trost J. T. , Deffenbaugh A. M. , Roa B. B. 
Published: March 2020

10513 Background: Mutations in the BRCA1 and BRCA2 genes are comprised of a majority of mutations that are detectable by sequence analysis, and a minority of large genomic deletion and duplication mutations that are detected by methods different than sequencing. Our laboratory developed and implemented a clinical assay for large rearrangements that we refer to as BART (BRCA1/2 Rearrangement Test). We validated the performance of BART using a completely anonymous large number of breast/ovarian cancer patient samples. We also demonstrated superior performance of BART versus other dosage-sensitive methods including Multiplex Ligation-dependent Probe Amplification (MLPA). Methods: BART utilizes quantitative endpoint polymerase chain reaction (PCR) in a multiplexed fluorescent format. Eleven multiplex PCR reactions were designed to contain two amplicons targeting the promoter region, all coding exons, and flanking regions of BRCA1 and BRCA2. An automated likelihood-based analysis application normalizes target amplicon copy number between BRCA1, BRCA2 and three control genes. Deletions and duplications are identified with a statistical confidence level. Results: Based on clinical and family history criteria, 1,035 patients were identified as severe-risk during the initial months of clinical BART analysis at Myriad Genetic Laboratories. All patients were initially tested for Comprehensive BRACAnalysis which includes BRCA1 and BRCA2 full gene sequencing plus large rearrangement panel testing for 5 recurrent BRCA1 mutations. Among severe-risk patients, 302 (29.2%) were positive for a BRCA1 or BRCA2 mutation by sequencing, 9 (0.9%) were positive by large rearrangement panel testing and an additional 27(2.6%) tested positive by BART for large genomic rearrangements. The total detection rate for deleterious mutations in severe-risk individuals was therefore 32.7%. Conclusions: Our initial clinical data indicate that BART testing is appropriate for high-risk patients identified on the basis of personal and family history criteria. No significant financial relationships to disclose.