bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II study of eribulin mesylate (E7389) halichondrin b analog in patients with refractory breast cancer
Authors: Blum J. L. , Pruitt B. , Fabian C. J. , Rivera R. R. , Shuster D. E. , Meneses N. L. , Chandrawansa K. , Fang F. , Fields S. Z. , Vahdat L. 
Published: March 2020

1034 Background: Eribulin is a structurally simplified analog of halichondrin B, which inhibits microtubule dynamics via a novel mechanism characterized by suppression of microtubule growth, lack of effect on microtubule depolymerization, and sequestration of tubulin into nonfunctional aggregates. This study was designed to assess the activity and tolerance of eribulin in chemotherapy refractory patients with advanced breast cancer. Methods: Eribulin was evaluated in a single-arm Phase II trial in female patients with refractory breast cancer, ECOG performance status of 0–1, measurable disease, and neuropathy ≤ Grade 2. Patients received ≥ 1 prior chemotherapy regimen, including an anthracycline and a taxane. Eribulin was administered as a 2–5 min IV bolus of 1.4 mg/m2 on Days 1, 8, and 15 of a 28-Day cycle (Group 1). The schedule was modified to Days 1 and 8 of a 21-Day cycle (Group 2), because of dose delays. The primary efficacy endpoint was ORR according to RECIST criteria based upon independent review (IR) of tumor assessment. Results: Of 104 patients enrolled, 103 received eribulin treatment: 70 in Group 1, 33 in Group 2. Median age was 55 yrs (range 32–84). Patients had received a median of 4 prior chemotherapy regimens (range 1–11). Sixty-one percent of tumors were ER+, 14% Her2/neu 3+, and 29% were triple (ER, PR, Her-2) negative. The incidence of dose interruption, delay, or omission during Cycle 1 was 63% (Group 1) and 18% (Group 2). The most common drug related toxicities were neutropenia (75%, Grades 3: 31%, Grade 4: 30%, febrile neutropenia: 3.9%), fatigue (52%, Grade 3: 2.9%, no Grade 4), alopecia (Grade 1/2: 41%), nausea (37%, Grade 3: 1%, no Grade 4), and anemia (36%, Grade 3: 1%, no Grade 4). Peripheral neuropathy occurred in 34% of patients (Grade 3: 3.9%, no Grade 4). Best overall response rate (all PR) by IR was 14.5% and 15.2% in Groups 1 and 2, respectively; the combined ORR was 14.7% (95 % CI: 9–23%). Median PFS was 85 days, and the 6 mo PFS rate was 31%. Conclusions: Eribulin given as a 2–5 min IV infusion on Days 1, 8 of a 21-Day cycle or Days 1, 8, 15 of a 28-Day cycle exhibited a 15% PR rate by IR and a low incidence of Grade 3 neuropathy in this heavily chemotherapy pretreated population. The most common toxicity was neutropenia. The 21-Day schedule had an acceptable toxicity profile. No significant financial relationships to disclose.
Randomized study comparing nab-paclitaxel with solvent-based paclitaxel in Chinese patients (pts) with metastatic breast cancer (MBC)
Authors: Guan Z. , Feng F. , Li Q. L. , Jiang Z. , Shen Z. , Yu S. , Feng J. , Huang J. , Yao Z. , Hawkins M. J. 
Published: March 2020

1038 Background: The results of a large clinical study comparing solvent-based paclitaxel 175 mg/m2 with 130-nM albumin-bound paclitaxel (nab-paclitaxel) 260 mg/m2 demonstrated that nab-paclitaxel had greater efficacy and a favorable safety profile in pts with MBC (Gradishar et al., JCO, 2005; 23:7794). The maximum tolerated dose of nab-paclitaxel was 300 mg/m2 infused over 30 minutes without premedication in Chinese pts with solid tumors (Teng et al., Ai Zheng, 2004;23:1431). The aim of this randomized study is to compare the response rates and to evaluate the safety of nab-paclitaxel with those of solvent-based paclitaxel in Chinese pts with MBC. Methods: In this open-label, multicenter study, 210 pts with MBC were assigned to either solvent-based paclitaxel 175 mg/m2 intravenously (IV) over 3 hours every 3 weeks (q3w) with standard premedication (steroids and antihistamines) or nab-paclitaxel 260 mg/m2 IV over 30 minutes q3w with no premedication for 1–6 cycles. The primary endpoints were the overall response rate (ORR, complete or partial response) and toxicity. Stable disease (SD) at =16 weeks was measured. All pts who received at least 1 dose of study drug were evaluable for study endpoints. Results: 210 pts (median age, 50 years; 70% postmenopausal) were enrolled from 29 June 2005 - 1 August 2006. Efficacy results are summarized in the Table . The common toxicities occurring at =20% were alopecia (78%), peripheral neuropathy (75%, 7% gr 3), neutropenia (65%), leucopenia (60%), myalgia (39%), arthralgia (23%), and nausea (21%) and were similar between groups (P = NS). Gr 3/4 neutropenia, measured on days 1 and 8, were similar between groups (p = 0.202). Conclusions: Compared to solvent- based paclitaxel, treatment with nab-paclitaxel was associated with a higher response rate and longer time to progression without increased toxicity. These comparative data in Chinese pts are almost identical to results previously reported in Caucasian pts (Gradishar et al, JCO, 2005). [Table: see text] [Table: see text]
Anti-leukemia activity of histone deacetylase (HDAC) inhibitor LBH589 involves depletion of EZH2 and DNA methyltransferase (DNMT) 1 through disruption of their chaperone association with heat shock protein (hsp) 90
Authors: Bhalla K. N. , Fiskus W. , Herger B. , Rao R. , Ustun C. , Jillella A. , Atadja P. 
Published: March 2020

10501 Background: LBH589 is a hydroxamate pan-HDAC inhibitor (HA-HDI) that also inhibits HDAC6, which induces acetylation of hsp90 and hsp70. This inhibits the ATP binding and chaperone function of hsp90. We recently reported that treatment with LBH589 depletes the levels of the polycomb repressive complex (PRC) 2 proteins EZH (enhancer of zeste homolog) 2, Suz12 and EED in AML cells. Since EZH2 has been shown to interact with and modulate the DNA methyltransferase activity of DNMT1, which affects its binding to the EZH2-targeted gene promoters, we determined the effects of LBH589 on the levels and interaction between EZH2 and DNMT1 in the CML blast crisis (CML-BC) K562 and LAMA-84 cells as well as in primary AML samples. Methods: Following exposure to 20 to 100 nM of LBH589 for 8 and 24 hours. immunoprecipitation and/or immunoblot analyses were performed to determine hsp90 binding and levels of DNMT1 and EZH2, as well as induction of JunB and loss of clonogenic survival of leukemia cells. Results: Treatment with LBH589 disrupted the chaperone association of DNMT1 and EZH2 with hsp90, resulting in polyubiquitylation and proteasomal degradation of DNMT1. Similar findings were also noted following treatment of leukemia cells with the hsp90 inhibitor, 17-DMAG. DNMT1 depletion by LBH589 was associated with induction of JunB in cultured and primary leukemia cells, which was further enhanced by co-treatment with decitabine. Consistent with this, methylation specific PCR analysis demonstrated increased demethylation of the JunB promoter. Co-treatment with decitabine and LBH589 or DMAG inhibited colony growth of the leukemia cells significantly more than treatment with either agent alone (p<0.05). Conclusions: These findings indicate that in addition to mediating histone acetylation and demethylation, LBH589 treatment induces epigenetic DNA demethylation by targeted depletion of EZH2 and DNMT1 in human leukemia cells. These results support the rationale for testing novel anti- leukemia combinations for epigenetic targeting that include LBH589, decitabine and/or histone methyltransferase inhibitors. No significant financial relationships to disclose.
The clinical relevance of p53 isoforms modifying the effects of p53 mutation on survival from breast cancer
Authors: Thompson A. , Patten N. , Diot A. , Truong S. C. , Bray S. , Ashfield A. , Baker L. , Quinlan P. , Wu L. , Bourdon J. 
Published: March 2020

10505 Background: p53 is a key gene in the development of breast cancer and response to therapy. Nine splice variants of p53 in breast cancer have been identified, with full length p53, p53beta and p53gamma (both 46kD, C terminal truncated proteins) commonly expressed. This study examined the clinical relevance of splice variants in breast cancer. Methods: Tumors from 248 patients with primary breast cancer were examined for mutation with the Roche p53 mutation chip and p53 isoform expression detected by RT-PCR followed by nested PCR; full clinical and pathological data included median follow up of 6.4 years. Results: p53 mutation, identified in 65/248 (26%) cancers, was significantly associated by Chi square test with shorter survival (p=0.001), histological grade 3 (p<0.001) and estrogen receptor (ER) negative cancers (p<0.001), as expected. Expression of p53 beta or p53 gamma mRNA was associated with p53 mutation (p=0.002, Fisher's exact test). Intriguingly, the patient groups with a mutant p53 cancer but expressing p53 gamma or p53 beta or both isoforms had survival curves comparable to patients with cancer containing wild type p53. Similarly, p53 gamma or p53 beta was associated with ER negative cancers (Chi square; p<0.001), but the group of ER negative tumors expressing p53 gamma or p53 beta had improved survival similar to ER positive cancers. Patients with p53 mutant, p53 beta negative and ER negative cancers comprised half of those who died within 3 years of diagnosis. Conclusions: p53 beta or p53 gamma isoform expression in breast cancer is associated with better prognosis and may moderate disease behaviour even in mutant p53 and ER negative cancers. Manipulation of p53 isoforms in breast cancer may thus offer therapeutic potential. No significant financial relationships to disclose.
Multicentric phase II trial of gemcitabine plus capecitabine combination in the treatment of previously anthracycline(An)-treated metastatic breast cancer (MBC): SOLTI 0301 study
Authors: Ciruelos E. M. , Baselga J. , Cortes-Funes H. , Lluch A. , Mayordomo J. I. , Ojeda B. , Gonzalez E. , Muñoz M. , Rodriguez C. , Cortes J. 
Published: March 2020

1051 Background: Based on clinical activity of capecitabine(C) and gemcitabine (G) on the treatment of MBC, we performed a multicentric phase II trial of the combination to test its efficacy and safety profile. Methods: Sample size of 72 evaluable MBC patients (pts) previously An-treated (neoadjuvant 8%, adjuvant 69%, advanced 30%). Median age: 59 years (35–76 years). Estrogen Receptor positive: 47 (65%). HER2 overexpression: 16 (22%). Prior hormonal/trastuzumab allowed. Soft tissue/ganglionar/pleural/bone disease: 19 (26%); visceral metastasis: 53(74%). Stratification: previous chemotherapy (CT) for advanced disease (none: group 1; any: group 2). Study treatment: oral bid C 1,660 mg/m2/day (d) (d1–14) + iv G 1,000 mg/m2/d (d1&8). Cycles repeated every 3 weeks. RECIST/NCI-CTC 2.0 criteria. Primary end point: Objective Response Rate. Results: Response Rates and Clinical Benefit (CB) are detailed in the table . Median follow-up 7.2 months (m) (0.2–18.4). Median time to progression 11.2 m: group 1, 12 m (95%CI: 6.4–14.5); group 2, 8.9 m (95%CI: 6.9–14).Total and median administered cycles/pt: 479 and 8. Delayed cycles: 103(21.5%): 27% due to hematological toxicity, 11% due to non-hematological toxicity, 62% due to other causes. C dose reduced in 27 cycles (5.6%), 12 of them due to non- hematological toxicity. G dose reduced in 169 cycles (35%), mostly on day 8, and due to hematological toxicity (80% of reduced cycles). Grade 3–4 neutropenia: 32 pts (56%), 1 case of febrile neutropenia. Grade 3–4 non-hematological toxicities: asthenia 8 pts (14%), hand- foot syndrome 6 pts (10.5%), mucositis 3 pts (5%), diarrhea 2 pts (3.5%). Conclusions: Combination of C+G in the treatment of previously anthracycline-treated MBC is safe and active, with a manageable toxicity profile and a good clinical activity. [Table: see text] No significant financial relationships to disclose.
Breast cancers with stem cell-like features delineate endocrine responsiveness
Authors: Rody A. , Karn T. , Solbach C. , Gaetje R. , Diallo R. , Gehrmann M. , von Minckwitz G. , Loibl S. , Holtrich U. , Kaufmann M. 
Published: March 2020

10517 Background: Endocrine responsiveness is one of the most important characteristics of breast cancer. The negative association between expression of the estrogen receptor (ER) and proliferation detected in normal breast is frequently lost in breast cancers leading to receptor independent growth and poor patients’ prognosis. Methods: Microarray analysis of 171 breast cancer samples allowed the discrimination of a KIT+ tumor group by using a set of genes coregulated with the “stem cell factor” receptor KIT. Validation was performed on three independent datasets encompassing 637 samples. Furthermore the response to endocrine treatment only was analyzed in a dataset of 700 patients. Results: KIT+ tumors are transcriptionally related to proposed mammary stem cells. Two types of KIT+ tumors were identified which are characterized by their positive and negative ER status, respectively. The inverse link of ER expression and proliferation is perfectly conserved within the KIT+ tumor groups, while it is uncoupled among half of the KIT-Low ER positive tumors. Those “uncoupled” ER positive tumors with altered ER response are characterized by a prognosis inferior to the ER negative cancers despite an apparent positive ER status (hazard ratio for disease recurrence, 2.07; 95% CI 1.53–2.81; P<0.001). Moreover, the 5 and 10 year survival rates of lymph node negative “uncoupled” tumors are even worse than those of lymph node positive “normal” ER positive cancers. While all ER positive patients seem to profit from endocrine treatment the relative benefit was reduced in uncoupled tumors (21.2 % vs. 31.7 %). Conclusions: The classification of breast cancers according to this biologically based model identified clinical relevant tumor groups whose further characterization will have important implications. Moreover, since the ability to recognize malfunctions in ER pathways largely depends on an appropriate reference system, the KIT+ tumors could allow a dissection of estrogen responsiveness giving crucial insights for prediction of response to endocrine therapy. No significant financial relationships to disclose.
Past use of hormone replacement therapy and risk of invasive breast cancer
Authors: Chen W. Y. , Hankinson S. E. , Rosner B. , Colditz G. A. 
Published: March 2020

10518 Background: Although current use of hormone replacement therapy (HRT) is associated with a greater risk of breast cancer than past use, the effects of longer term past use of HRT are not well quantified. Methods: We examined the relationship between past HRT use and invasive breast cancer risk within the Nurses’ Health Study, a prospective cohort of 121,700 registered nurses aged 30–55 in 1976 who update information on cancer risk factors and outcomes through biennial questionnaires. For this analysis, the follow-up period was 1980 through 2004 and only included person-time for postmenopausal women. Status of HRT use (never, past, or current), type of HRT (oral unopposed estrogen (E alone) or combination oral estrogen + progesterone (E+P)), and duration of HRT use were assessed every 2 years and defined prospectively. Proportional hazards models controlled for age, body mass index, parity, age at first birth, family history of breast cancer, benign breast disease, alcohol consumption, type of menopause, and ages at menarche and menopause. Results: During 1,388,368 person-years of follow-up among postmenopausal women, invasive breast cancer was diagnosed among 1,554 women who had never used HRT, 459 past users of E+P and 527 past users of E alone. Regardless of duration of use, past use of E alone was not associated with breast cancer risk. Although past use of E+P for less than 10 years was not associated with breast cancer risk (RR (95% CI) 1.01 (0.88–1.17) for < 5 years and 0.95 (0.74–1.21) for 5–9.9 years), past use of E+P for greater than 10 years was associated with an increased risk of breast cancer (RR 1.53 (1.09–2.16) for 10–14.9 years and 1.48 (0.87–2.51) for 15 or more years). Results were similar regardless of time since last use, although power was limited for this subgroup analysis. Conclusions: Past use of E+P for greater than 10 years was associated with a persistent elevation in breast cancer risk. The relationship between duration of past use and breast cancer risk did not appear linear, but suggested a possible threshold effect. No significant financial relationships to disclose.
Association of p53 codon 72 polymorphism with resistance to adjuvant therapy in primary breast cancer
Authors: Toyama T. , Zhang Z. , Hamguchi M. , Kondo N. , Iwase H. , Iwata H. , Takahashi S. , Yamashita H. , Fujii Y. 
Published: March 2020

10520 Background: Single-nucleotide polymorphisms (SNPs) in codon 72 of the p53 gene and in the promoter region of the MDM2 gene (SNP309) have been suggested to play a role in many cancers. We investigated whether these SNPs were associated with patient outcome and influence of adjuvant systemic therapy. Method: The genotypes of p53 codon 72 and MDM2 SNP309 were defined among 557 primary Japanese breast cancer patients (median follow-up, 61.7 months). The effects of several variables on survival were tested by Cox's proportional hazards regression analysis. Results: We showed that the Pro/Pro genotype of p53 codon 72 was significantly associated with poorer disease-free survival (DFS) than other genotypes by Kaplan-Meier analysis (P = .049) and multivariate Cox's proportional hazards regression analysis (P = .047, risk ratio of recurrence = 1.67), whereas MDM2 SNP309 status was not associated with DFS. The association of the Pro/Pro p53 genotype with poorer DFS was especially significant in patients who received adjuvant chemotherapy (P = .009). In contrast, among the patients who had received adjuvant hormonal therapy or no adjuvant systemic therapy, p53 codon 72 genotype was not associated with DFS. Conclusion: The Pro/Pro genotype of p53 codon 72 appears to be an independent prognostic marker of breast cancer patients that have received adjuvant systemic therapy, particularly chemotherapy, and may be predictive of therapy resistance. [Table: see text] No significant financial relationships to disclose.
Use of the novel biomarker (HOXB2) to predict response to pancreatectomy for pancreatic cancer
Authors: Biankin A. V. , Kench J. G. , Segara D. , Skalicky D. A. , Biankin S. A. , Cosman P. H. , Merrett N. D. , Musgrove E. A. , Henshall S. M. , Sutherland R. L. 
Published: March 2020

10526 Background: Pancreatectomy is the only therapeutic intervention that offers the chance of long term survival for patients with pancreatic cancer, however, only 10% of patients who undergo pancreatectomy survive > 3 years with prognostic factors only determined after pathological examination of the resected specimen. Identification of a biomarker of response to surgical resection that can be determined preoperatively offers the potential to significantly improve survival and quality of life for patients with PC by improving patient selection for pancreatectomy. Methods: We examined the aberrant expression of over 20 genes identified using transcript profiling or known to be important in carcinogenesis using immunohistochemistry and in-situ hybridisation in a cohort of 124 patients with pancreatic cancer to identify potential biomarkers of prognosis and response to operative resection. Results: Aberrant expression of p53, p21WAF1/CIP1, p27KIP1, p16INK4A, cyclin D1, cyclin E, DPC4/Smad4, EGFR, beta-catenin, sfrp4, LMO4, HOXB2, S100P, S100A6, S100A2, RAI3 and CRBP1 were identified in a significant proportion of PC. Multivariate analysis of clinicopathological variables (tumor size, differentiation, subtype, lymph node metastases, perineural invasion and vascular space invasion), treatment parameters (margin involvement, adjuvant therapy, resection type), and aberrant expression of the above candidate biomarkers identified that HOXB2 expression and resection margin involvement by tumor were the only 2 independent prognostic factors. Patients who had absent HOXB2 expression and had clear margins after pancreaticoduodenectomy (48%) had an actual survival of 40% at 3 years and 21% at 5 years, compared to those with HOXB2 expression and/or positive surgical margins who had all died by 28 months. Conclusion: HOXB2 expression may represent a surrogate marker of advanced disease, can potentially be assessed preoperatively using FNAB, and is currently the best predictor of outcome and response to operative resection to be reported. Preoperative assessment of HOXB2 expression has potential clinical utility in predicting response to operative resection for PC to allow better selection of patients for operative intervention. No significant financial relationships to disclose.
Stage at breast cancer diagnosis is more advanced in BRCA1 carriers but not in BRCA2 carriers
Authors: Kaufman B. , Lahad A. , Krieger M. , Gal M. , Friedman E. , Renbaum P. , Gabizon A. , Paluch-Shimon S. , Catane R. , Levy-Lahad E. 
Published: March 2020

10540 Background: BRCA1-associated tumors are known to have less favorable pathological characteristics, but there is little information on whether this is also reflected in the stage at diagnosis. Methods: Clinical and pathological information was collected on 1,122 consecutive Ashkenazi Jewish breast cancer patients who were tested post-diagnosis for the BRCA1/2 mutations common in this population. Results: Of 1,122 patients, 70 (6.2%) were BRCA1 and 50 (4.5%) were BRCA2 carriers. Mean age at diagnosis was 49.9 yrs. in BRCA1 carriers (p=.0001 vs. non-carriers (NC)) vs. 52.0 yrs. in BRCA2 carriers (p=.02 vs. NC) and 56.0 yrs. in NC. Pure DCIS was less common in BRCA1 carriers (3%) than in BRCA2 carriers (8.2%) and NC (11.8%) (p=.03). Medullary carcinoma was more common in BRCA1 (9.8%) and BRCA2 carriers (6.7%) than in NC (1.5%) (p<.001). Invasive lobular carcinomas were rarer in BRCA1 (1.6%) and BRCA2 (2.2%) compared to NC (8.8%) (p=.012). Hormone receptors (HR) negative was more common in BRCA1 (62%) compared to BRCA2 carriers (21%) (p=.00006) and NC (17%) (p<0.0001). Triple negative tumors (HR and HER2 negative) were more common in BRCA1 carriers (60%) than in BRCA2 carriers (14%) and NC (8.3%) (p=0.001). High grade was more common in BRCA1 (60.4%) and BRCA2 (51.4%) carriers than in NC (36.7%, p=.001). Less favorable pathological features and younger age at diagnosis in BRCA1 carriers were reflected in a more advanced stage at diagnosis. Stage I at diagnosis was found in 34% of BRCA1 carriers (p=.05 vs. NC), 43% of BRCA2 carriers and 46% of NC, stage II in 48% of BRCA1 carriers, 41% of BRCA2 carriers and 37% of NC, and stage III in 17% of BRCA1 carriers, 13.5% of BRCA2 carriers and 13.5% of non-carriers. Conclusions: This consecutive cohort study demonstrates that breast cancers in BRCA1 carriers are characterized by more aggressive pathological features and are diagnosed at more advanced stages than in BRCA2 carriers and non-carriers. This may suggest a differential approach for prevention and surveillance in BRCA1 compared to BRCA2 carriers. No significant financial relationships to disclose.