bluuebunny/crossref_metadata_2025 huggingface dataset:
Reduction of elevated plasma osteopontin levels with resection of non-small cell lung cancer (NSCLC)
Authors: Blasberg J. D. , Pass H. I. , Flores R. M. , Donington J. S.
Published: August 2020

11019

Background: Plasma osteopontin (OPN) levels in advanced NSCLC correlate with response to therapy and survival but the role plasma OPN in diagnosis or monitoring of early stage NSCLC has not been investigated. We hypothesize that plasma OPN levels are elevated in early stage NSCLC and that resection results in a measurable reduction. Methods: Pre-operative (pre-op) plasma OPN levels (ng/ml) were measured by ELISA (IBL-Japan) in a discovery set of 60 early stage NSCLC patients and compared to 56 current or former smokers. Pre-op OPN was validated in an independent cohort of 78 resectable NSCLC patients. The pre-op OPN level in the latter cohort was compared to matched postoperative (post-op) OPN levels to monitor the impact of surgery on the biomarker. Results: Discovery set pre-op OPN (271+31) was significantly higher than in smokers (40+2)(p=.001). Pre-op OPN was similar in the validation cohort (357+31, p=.055, demographics in Table ). Post-op OPN (189+19) measured at mean of 23 weeks (range 2–105) was significantly lower than pre-op (p<.0001). Time from surgery significantly impacted post-op OPN, with OPN<6 weeks post-op (282+30) higher than OPN>6 weeks post-op (155+18)(p<.0001). After 6 weeks post-op, resected stage I patients (N=45) had a significant decrease in OPN levels from 373+45 to 142+21 (p<.0001). Multivariate analysis ( Table ) noted a significant correlation between age, albumin and pre-op OPN, and between albumin and pre-op OPN and >6 weeks post-op OPN. No correlation was noted between gender, smoking, histology, diabetes or stage and the pre- or >6 weeks post-op OPN. Conclusions: Plasma OPN levels in early stage NSCLC patients are significantly elevated compared to smokers. The elevated pre-op OPN levels were validated in an independent cohort of early stage NSCLC patients. A significant decrease in OPN was noted following resection. Peri-operative reductions in plasma OPN may serve as a marker for response to therapy and warrant investigation into prognostic significance in early stage NSCLC. [Table: see text]

[Table: see text]
Epidermal growth factor (EGF) gene polymorphism, gastroesophageal reflux disease (GERD), and esophageal adenocarcinoma (EAC) risk
Authors: Cheung W. Y. , Zhai R. , Kulke M. , Heist R. , Asomaning K. , Ma C. , Wang Z. , Su L. , Christiani D. , Liu G.
Published: August 2020

11029

Background: Single nucleotide polymorphisms (SNPs) of key cancer genes, such as EGF A61G, are associated with an elevated risk of EAC, but the lack of full penetrance indicates that the effects of these SNPs on esophageal carcinogenesis are modified by additional genetic or environmental variables. Since GERD is an established risk factor for EAC, we evaluated whether the association between EGF polymorphism and EAC development is altered by the presence of GERD. Methods: EGF genotyping of DNA samples was performed and GERD history was collected for 309 EAC patients and 275 matched healthy controls. Associations between genotypes and EAC risk were examined with adjusted logistic regression. Genotype-GERD relationships were explored using analyses stratified by GERD history and joint effects models that considered severity and duration of GERD symptoms. Results: Baseline characteristics were comparable between cases and controls except that EGF variants (A/G or G/G) were more common (p=0.02) and GERD was more prevalent (p<0.001) in cases than in controls. When compared to the EGF wild type A/A genotype, the G/G variant was associated with an increased risk of EAC (OR 1.9; 95% CI, 1.2–3.0; p=0.007). Stratified analyses revealed that the G/G variant contributed to a substantial increase in EAC risk among individuals with GERD, but a slight decrease in risk for GERD-free individuals (see table). In the joint effects models, the odds of EAC was also highest for G/G patients who either experienced frequent GERD of more than once per week (OR 21.8; 95% CI, 5.1–94.0; p<0.001) or suffered GERD for longer than 15 years (OR 22.4; 95% CI, 6.5–77.6; p<0.001). There was a highly significant interaction between the G/G genotype and the presence of GERD (p<0.001). Conclusions: EGF A61G polymorphism exerts its effect on EAC susceptibility through an interaction with GERD. Performing EGF genotyping for patients with severe or longstanding GERD can help to identify individuals at the greatest risk of EAC. [Table: see text]

No significant financial relationships to disclose.
TS-1 in patients with capecitabine-resistant breast cancer
Authors: Yamamoto D. , Yoshida H. , Iwase S. , Odagiri H. , Kitamura K.
Published: August 2020

1103

Background: TS-1 is a novel oral anticancer drug, composed of tegafur, gimestat and otastat potassium in a molar ratio of 1:0.4:1, based on the biochemical modulation of 5-Fuorouracil. To evaluate the efficacy and safety of TS-1 in patients with capecitabine-resistant metastatic breast cancer (MBC). Methods: Forty patients with MBC who failed capecitabine-based chemotherapy, received TS-1 (100 mg/m2) at four centers. Resistance to capecitabine was defined as either progression of disease during treatment, failure to achieve regression of disease after at least four courses, or rapid recurrence after completion of therapy. Results: From January 2006 to May 2008, 40 pts were enrolled. Baseline characteristics of the pts were: median age 50 years (range 34–78), median ECOG PS 0 (range 0–2), and adequate bone marrow, renal, and hepatic functions. Median number of metastatic sites was 2 (range 1–5). The pts were evaluable for response and toxicity. Ten pts (25 %) achieved a partial response, 12 patients (30 %) patients had stable disease, and 18 (45 %) progressive disease. The median time to disease progression was 26.6 weeks. The most treatment-related adverse events were grade 1/2 in intensity. 7 pts experienced serious TS-1- related gastrointestinal disorder requiring dose modifications in 3 pts and treatment discontinuation in 4 pt. Further, interestingly, 6 of the 40 patients (15.0%) who received TS-1 did hand-foot syndrome (HFS), although 20 of the 40 patients (50.0%) who had received capecitabine, developed HFS. Conclusions: This study confirms that TS-1 achieves a high tumor control rate in pretreated MBC pts and is active in patients with capecitabine-resistant breast cancer. Response rates were comparable to or better than those seen with other therapies for patients with capecitabine-resistant MBC. TS-1 should be considered the reference treatment in this setting based on consistently high efficacy and good tolerability.

No significant financial relationships to disclose.
Expression and epigenetic silencing of ECRG4gene in breast cancer
Authors: Fei F. , Shao Z.
Published: August 2020

11046

Previous whole-genome expression array studies in our laboratory had shown the expression of ECRG4 (esophageal cancer related gene 4) was significantly down-regulated in primary breast cancer. The present study was undertaken to investigate the expression and epigenetic regulation ofECRG4in human breast cancer cell lines and primary carcinomas. Here we showed that the expression ofECRG4, as measured by quantitative reverse transcription-PCR, was noticeably increased in 3 methylated breast cancer cell lines (MDA-MB-435, Bcap-37, MCF-7), after treated with 5-aza-2’-deoxycytidine - a demethylation agent. Analysis from 16 paired tissue samples revealed expression of ECRG4 was significantly reverse-correlated with methylation (Spearman correlation coefficient r=-0.419, P=0.017). Analysis of 67 additional samples showed that the ECRG4 CpGs island was in high methylation level in 59.7% of cancer tissues compared with 14.9% in tumor adjacent tissues,with an odds ratio of 3.393 (95% CI, 1.912–6.021,P=8.39E-8). And patients with high methylation level had a higher tumor grade. 90% samples were high methylation levels in grade III vs. 50% in grade I-II (95% CI, 1.063–76.213, P=0.033). In conclusion, the inactivation of ECRG4 gene by hypermethylation appears to be a frequent molecular event in development of primary breast cancer and may be involved in the carcinogenesis of this cancer.

No significant financial relationships to disclose.
Association of baseline c-reactive protein with incident cancer and survival in cancer patients
Authors: Allin K. H. , Bojesen S. E. , Nordestgaard B. G.
Published: August 2020

11052

Background: We tested the hypothesis that baseline plasma levels of C-reactive protein (CRP) associate with risk of incident cancer in the general population, and early death in cancer patients. Methods: 10,408 individuals from the Danish general population, who had CRP measured at baseline, were followed for up to 16 years; 1,624 developed cancer and of these, 998 died during follow-up. Follow-up was 100% complete. We excluded individuals with a cancer diagnosis at baseline. Results: Baseline CRP levels >3 vs. <1 mg/L were associated with multifactorially adjusted hazard ratios of 1.3 (95% CI, 1.0–1.6) for cancer of any type, of 2.2 (1.0–4.6) for lung cancer, of 1.9 (0.8–4.6) for colorectal cancer, and of 0.7 (0.4–1.4) for breast cancer. Corresponding hazard ratios for the highest vs. the lowest quintile of baseline CRP levels were 1.3 (1.0–1.6), 2.1 (1.2–3.8), 1.7 (0.8–3.2), and 0.9 (0.5–1.7), respectively. Multifactorially adjusted hazard ratios for early death in cancer patients were 1.8 (1.2–2.7) for CRP >3 vs. <1 mg/L and 1.4 (1.1–1.7) for the highest vs. the lowest quintile. Elevated CRP levels associated with early death in cancer patients with localized disease, but not in cancer patients with metastases (interaction; P=.03). Conclusions: Elevated levels of CRP in cancer-free individuals are associated with increased risk of cancer of any type, of lung cancer, and possibly of colorectal cancer. Moreover, elevated levels of baseline CRP associate with early death after a diagnosis of any cancer, particularly in patients without metastases.

No significant financial relationships to disclose.
The differences in rate and duration of complete remission between HER2-positive and HER2-negative inflammatory breast carcinoma
Authors: Kolarevic D. , Tomasevic Z. , Andjelic Dekic N. , Milosevic S. , Jelic S.
Published: August 2020

1106

Background: Inflammatory breast carcinoma (IBC) is rare but aggressive form of breast cancer. Up to 38% of IBC are HER-2+. According to literature, complete remission (CR) can be achived in more than 50% of patients with combinatination of chemotherapy and trastuzumab. However, trastuzumab is still not available in all countries. The aim of this study was to evaluate the rate and duration of CR to induction chemotherapy alone, without trastuzumab, in HER-2+ and HER-2- IBC pts and compare our results to literature data. Methods: The data were analized for 3,452 breast carcinoma patients registered at the Institute for Oncology and Radiology of Serbia (IORS) during one year. Among them, 281 pts had IBC, defined as pathologically confirmed skin lymphangiosis or BC with classical clinical signs of cancer mastitis. Responses have been evaluated clinically and by mammography after every 3–4 cycles of chemotherapy. CR was estimated as a complete disappearance of previously palpable breast tumour; no clinical and mammography signs of cancer mastitis; no enlarged regional lymph nodes and disappearance of all metastatic sites in stage IV. HER-2 status (IHC, Dako) was assessed in 88 patients (70.9%) and 25/88 (28.4%) were HER-2 3+. Results: We investigated 124 IBC pts with complete medical records. The overall incidence of IBC was 8.1%. Median age at diagnosis was 59 (ranges 35–81). The rate of CR is evaluated separately in subset of HER2+ and HER2- IBC. 100 pts received FAC induction chemotherapy (median number of cycles was 6) and remainder received CMF regimen (median number of cycles was 5), trastuzumab none. Only seven pts (5,6%), all treated with FAC achieved CR. Among them, four had HER-2 3+ (4/25; CR 16%) and three HER2 negative IBC (3/99; CR 3%). Median duration of CR in HER-2+ subset was 15 months (range 7–36+) and in HER-2- 18 months (range 7–101+). Conclusions: Our study shows that incidence of IBC in Serbia is higher than reported in the literature, 8,1% vs 1–4%. Also, it has been shown that very low percentage of IBC patients achieved CR after chemotherapy alone, esspecialy in HER-2- subset of IBC-only 3%, compared to 16% in HER-2+ group, even in the absence of trastuzumab, while the duration of CR in both groups were similar.

No significant financial relationships to disclose.
Xanthine oxidoreductase and chemosensitivity in non-small cell lung cancer
Authors: Myint R. , Batus M. , Bonomi P. , Gattuso P. , Warren W. H. , Liptay M. , Faber P. , Basu S. , Xu X. , Kim A. W.
Published: August 2020

11077

Background: Xanthine oxidoreductase (XOR) is an enzyme involved in the degradation of purines into uric acid and reactive oxygen species and activation of the MAP kinase pathway involved in apoptosis. Decreased XOR expression was shown in recent studies to be associated with more aggressive disease in breast (Linder et al. Clin Cancer Res. 2005;11:4372–4381) and gastric cancers (Linder et al. J Clin Pathol. 2006;59:965–971). The goal of our study was to show that decreased XOR expression was associated with decreased survival in non-small cell lung cancer (NSCLC). Methods: Tissue specimens from 82 patients (pts) were stained using a XOR specific antibody (36 male and 46 female, age range from 40 to 92 years). These included 41 adenocarcinoma, 31 squamous cell, 8 poorly/moderately differentiated, and 2 bronchioloalveolar. XOR staining intensity was measured on a scale of 0 through 4 (0 being no staining). XOR intensity was correlated with clinical characteristics and outcomes using log rank and COX PH regression analysis. Results: Of the 82 pts, 34 received adjuvant chemo, and of these, 15 specimens had low XOR intensity (0–1). These 15 pts received adjuvant chemo and had a median survival of 543 days. In comparison, 19 of the 34 pts receiving adjuvant chemo had specimens with high XOR intensity (2–4). Their median survival was significantly longer at 2,023 days (p=0.007, hazard ratio=0.33). Conclusions: Although we had a small sample size, in our retrospective study, we found that pts who received adjuvant chemo had a longer survival if their tumors expressed high levels of XOR. XOR could be a potential predictor for responsiveness to adjuvant chemo in patients with NSCLC. Pts with decreased XOR may be less responsive to chemo and thus be able to avoid a toxic treatment if it is not significantly beneficial. [Table: see text]

No significant financial relationships to disclose.
Expression of metastasis-associated gene products and liver metastases in pancreatic endocrine tumors
Authors: Helm J. , Strosberg J. , Henderson-Jackson E. , Hafez N. , Hakam A. , Nasir N. A. , Coppola D. , Malafa M. P. , Larry K. K. , Nasir A.
Published: August 2020

11089

Background: Outcomes in well-differentiated pancreatic endocrine tumors can be difficult to predict using pathologic criteria. We recently identified a novel set of 3 metastasis-associated genes by microarray: Palladin, p21, RUNX1T1. Our aim was to evaluate the potential for these markers, individually or in combination, to predict liver metastases as an indicator of adverse outcome. Methods: Palladin, p21, and RUNX1T1 immunostains were done on a tissue microarray of 39 resected primary pancreatic endocrine neoplasms, 14 of which had hepatic metastases. The Allred score was determined as the sum of stain intensity (scored 0–3) and % cells stained (scored 0–5). Receiver operating characteristic (ROC) analysis was used to choose the cutpoint in Allred score (high vs low protein expression) to optimize sensitivity and specificity for predicting liver metastases. Results: Nearly all tumors with liver metastases showed high Palladin and p21 levels (Allred score > 3 and > 4, respectively), while protein expression was lower in the majority of non-metastatic tumors. In contrast, RUNX1T1 expression was low (Allred score < 4) in most tumors with liver metastases, but higher in all except one of the non-metastatic tumors. Individual test sensitivities for predicting liver metastases were 100% for high Palladin, 93% for high p21 and 85% for low RUNX1T1, while corresponding specificities were 63%, 75%, and 96%. Tumors were correctly classified as being metastatic or not (predictive accuracy) by Palladin, p21, or RUNX1T1 expression in 76%, 76%, and 92% of cases, respectively. If abnormal expression of even one of 3 proteins is considered a positive test (parallel testing), then sensitivity of all 3 together for predicting liver metastases was 100%, specificity 48%, and predictive accuracy 68%. Conclusions: 1) High Palladin, high p21, or low RUNX1T1 expression have good sensitivity and specificity for predicting liver metastases in pancreatic endocrine tumors. 2) Parallel testing with all 3 markers achieved 100% sensitivity but at a cost of reduced specificity. 3) Differential expression of these biomarkers may predict aggressive tumor behavior that warrants more aggressive management.

No significant financial relationships to disclose.
Dependence of malignant proliferation associated with loss of PTEN on glucose concentration in the hyperglycemic range: Relevance to population studies linking hyperglycemia to unfavorable cancer prognosis
Authors: Pollak M. N. , Blouin M. , Zakikhani M. , Zhao Y. , Algire C.
Published: August 2020

11113

Background: Loss of function of the tumor suppressor PTEN enhances malignant proliferation, but effects on cellular energy metabolism are less well characterized. Population studies show that the metabolic syndrome (characterized by hyperglycemia, hyperinsulinism, and obesity) is increasingly prevalent in affluent societies and is associated with adverse outcome of many cancers, but the molecular basis for this is poorly understood. Methods: We used a tetracycline-inducible PTEN expression vector in the PTEN-null U251 glioma cell line to characterize effects of PTEN on cellular energy metabolism. Results: Forced expression of PTEN led to decreased phospho-AKTSer473, decreased hexokinase II and HIF-1 alpha levels, and increased p53 levels. While proliferation of PTEN-positive cells was insensitive to variation in glucose concentration at levels higher than 2.5 mM, PTEN-null cells significantly increased proliferation with increasing glucose concentration across normal physiologic range to ∼10 mM. PTEN-null cells consumed more glucose than PTEN-positive cells (17.2 ± 2.0 vs. 8.8 ± 1.5 mM/million cells/48 hrs) and produced more lactate (35.9 ± 4.8 vs. 10.7 ± 2.3 mM/million cells/48 hrs). When cells were incubated in presence of 2-deoxy-glucose (2-DG), growth inhibition was greater for PTEN-null cells (47.4% inhibition relative to control without 2-DG) compared with PTEN-positive cells (10.8% inhibition relative to control without 2-DG). Conclusions: Loss of function of PTEN leads to increased glycolysis, and increased dependence on glucose availability. Only in the presence of glucose in the hyperglycemic range are maximal adverse effects of loss of PTEN on cellular proliferation and survival seen. This provides a novel mechanism to explain at least in part the relationship between hyperglycemia and cancer mortality observed in several large population studies. The data also suggest that PTEN status is relevant to selection of tumors likely to respond to experimental therapies that exploit glucose dependency.

No significant financial relationships to disclose.
Effect of trastuzumab on the reduction of hormone receptor expression by neoaduvant chemotherapy in HER2-positive breast cancer
Authors: Hayashi M. , Okumura Y. , Ohsako T. , Arima N. , Nishimura R.
Published: August 2020

11114

Background: Neoadjuvant chemotherapy (NAC) in primary breast cancer is actively used around the world. Lower ER expression is related to an increased sensitivity of NAC and ER/PgR expression decreases after NAC. Estrogen Receptor (ER) function is coordinated by crosstalk with growth factor signaling, especially that of HER2. Moreover, trastuzumab (T) has an established role in the management of HER-2 positive breast cancer in conjunction with chemotherapy. We examined the effectiveness of NAC and changes in the biological markers, particularly the ER/PgR status after NAC with or without T. Methods: Since April 2002, 143 patients with tumors ≥3 cm in diameter or lymph node metastases have received NAC and surgery. The treatment regimen were as follows; ET in 60 cases, FEC-DOC in 68 cases, and T with anthracycline and taxane in 15 cases. The items investigated were ER/PgR, Ki-67, HER2 and p53. The correlation between the changes in these factors after NAC and the treatment regimen was investigated. Results: The clinical response rate (CR+PR) was 84% in all patients. The pathological CR (pCR) rate was 7.7% in the ET, 20.9% in the FEC-DOC and 33.3% in the T regimen. The Ki67 values and ER/PgR status significantly correlated with pCR. Regarding the changes in biological markers, Ki67 values significantly decreased after NAC in all regimens. In the hormone receptor (HR) positive cases, ER and PgR positive cell rates significantly decreased (ER: 79.8% to 58.3% and PgR: 58.3% to 34.0%). However, in the arm with T, there were no significant changes in ER and PgR positive cell rates (ER: 72.7% to 69.2% and PgR: 50.3% to 38.1%). Conclusions: Lower ER/PgR expression and higher Ki-67 significantly correlated with pCR. Moreover, ER/PgR positive cell rates and Ki67 values significantly decreased after using chemotherapy. However, it appears that the T regimen may restore ER/PgR expression. Thus, ER and HER-2 expression may modify tumor biology via cross-talk even in NAC cases.

No significant financial relationships to disclose.
Relationship between single nucleotide polymorphism of estrogen receptor gene and endocrine therapy efficacy in breast cancer
Authors: Yingchun X. , Zhang F. , Wang H. , Ma Y. , Sun L.
Published: August 2020

1113

Objective: To explore the distribution of single nucleotide polymorphism (SNP) loci of estrogen receptor (ESR1) gene in breast cancer patients and to study the relationship between the SNP genotypes and the efficacy to endocrine therapy. Methods: Fifteen SNP loci ( rs872921 , rs2077647, rs3904766, rs2234693, rs11155816, rs827419 , rs2347867, rs3798759, rs1801132, rs985191 , rs9340931, rs9397463, rs722209 , rs3778099, and rs3798577) of ESR1 gene were selected as genetic markers. PCR-restriction fragment length polymorphisms, PCR-DNA sequencing and allele-specific real time PCR methods were employed to analyze the loci genotype of 240 patients with breast cancer accepted endocrine therapy. Results: The loci rs872921 and rs3904766 were abandoned for poor ploymorphisms, and the other 13 loci had polymorphisms. The frequencies of alleles and genotypes of rs2077647 and rs3798759 were significantly related with the efficacy of endocrine therapy (p < 0. 05). The linkage disequilibrium and the hapotype analysis showed that there were four linkage disequilibrium blocks in ESR1 gene. They were rs2077647∼rs2234693 (LD1), rs2234693∼rs11155816 (LD2), rs9397463∼ rs722209 (LD3), and rs3778099∼rs3798577 (LD4), and the hapotypes of LD2, LD3, s11155816- rs827419 , and rs2347867- rs1801132 were positively related with the efficacy of endocrine therapy (p < 0. 05). Conclusions: Some of the polymorphisms of ESR1 gene and the haplotypes are positively associated with the endocrine therapy efficacy, and maybe account for predicting the endocrine response in breast cancer.

No significant financial relationships to disclose.
Drug Response Indicator Test (DRIT) as a predictive test for treatment outcomes in advanced breast cancer patients (ABC)
Authors: Tkaczuk K. H. , Tait N. S. , Ioffe O. , Tan M. , Mohiuddin M. , Chumsri S. , VanEcho D. A. , Sutula M. J. , Lesko S. , Deamond S. , Ts'o P.
Published: August 2020

1119

Background: There are limited options for selecting an optimal treatment regimen for ABC patients (pts). DRIT is a platform technology that provides a profile of a patient's tumor's sensitivity or resistance to commonly used chemotherapeutic, hormonal, or biological agents as a basis for individualized anticancer treatment approach. DRIT may allow physicians to choose more effective drug treatments before initiation of therapy and improve the efficacy and toxicity profile of cancer therapies. Methods: DRIT analysis is based on fluorescent dye-labeled monoclonal antibody staining followed by computer-assisted microscopy to quantitatively measure expression levels in tumor sections. The interpretation of DRI expression levels results in classification of tumors as sensitive or resistant to treatment with a mechanistically related drug. This study utilized the following drug/DRI combinations: hormonal therapy/estrogen receptor; capecitabine/thymidylate synthase; docetaxel, paclitaxel, abraxane/β-tubulin isoform III; trastuzumab/HER-2; gemcitabine/ribonucleotide reductase. DRIT was performed on the tumor tissue of consented study participants with ABC who were then deemed to be sensitive or resistant to a given agent/agents. We then analyzed retrospectively clinical treatment outcomes (clinically sensitive to therapy defined as-stable disease+partial response+complete response or resistant to therapy-no response to therapy) for 91 treatment interventions in 71 pts with the DRIT tissue data. Results: We found that the DRIT sensitivity was 0.99, with specificity of 0.59, positive predictive value of 0.88, negative predictive value of 0.93 and overall predictive value of 88% for treatment outcomes for this cohort of ABC pts. Conclusions: This study suggests that DRIT can provide more accurate prediction of treatment outcomes for ABC pts than the standard of care approach and therefore has a potential to avoid unnecessary ineffective drug treatment exposure. Prospective study in ABC pts is currently conducted at the UMGCC.

[Table: see text]
Aromatase inhibition in male breast cancer patients: Biological and clinical implications
Authors: Doyen J. , Italiano A. , Largillier R. , Ferrero J. , Fontana X. , Thyss A.
Published: August 2020

1130

Background: Because male breast cancer (MBC) is rare, treatment recommendations are derived from results of trials in female patients (pts). Although, several studies have shown the superiority of third-generation aromatase inhibitors (AI) over tamoxifen in menopausal women with advanced breast cancer, the role of such molecules remains unknown in male pts. We report here the largest experience about the efficacy of AI in MBC pts with advanced disease and their impact on estradiol (E) levels. Methods: MBC pts were selected from the breast cancer database of the Centre Antoine-Lacassagne (Nice, France) as follows: Metastatic disease with at least one measurable or assessable non-measurable lesion, estrogen receptor (ER) and/or or progesterone receptor (PR) positive, availability of complete clinical and histological data, evidence of progressive disease at initiation of AI, receipt of at least one month of treatment with non steroidal (anastrozole, letrozole) or steroidal (exemestane) AI. Sex hormone levels were retrospectively assessed on serum samples from our institutional serum bank. Results: 15 pts entered the study. Median age was 68 (range 39–85). 7 pts received previous lines of hormonal therapy (median = 1) and 3 pts a previous line of chemotherapy before the introduction of AI. The best response was complete response in 2 pts (13%), partial response in 4 pts (27%), stable disease (SD) in 2 pts (13%) and progressive disease (PD) in 7 pts (47%). The median duration of objective response (OR) was 11.6 months (95% confidence interval [CI] 7.6–15.5). At the time of analysis, 8 pts (53%) had died and 7 (47%) were still alive. The median PFS and OS were 4.4 months (95% CI 0.1–8.6) and 33 months (95% CI 18.4–47.6) respectively. The 1-year PFS and OS rates were 20% (95% CI 9.7–30.3) and 84.6% (95% CI 74.6–94.6), respectively. 9 out of 11 pts with available samples had E levels less than the lower limit of the assay during AI treatment. Among the 9 pts with E level decrease, four had OR, one had SD, and four had PD. 1 pt had E levels higher than the upper limit of the assay during AI treatment. This pt showed disease progression. Further data on FSH and testosterone levels will be presented at the meeting. Conclusions: AI are active in MBC pts. This activity is correlated with a significant reduction in E levels.

No significant financial relationships to disclose.
Detection of locally advanced breast cancer in the I-SPY TRIAL (CALGB 150007/150012, ACRIN 6657) in the interval between routine screening
Authors: Lin C. , Moore D. , DeMichele A. , Ollila D. , Montgomery L. , Liu M. , Krontiras H. , Gomez R. , Esserman L.
Published: August 2020

1503

Background: It is assumed that most locally advanced breast cancers (LABC) could be detected at an earlier stage with routine screening. However, LABCs may present between screens as interval cancers (IC). ICs present at an earlier age, with higher grade, larger size, and are associated with lower survival, compared to screen-detected cancers (SDC), and comprise 17% of cancers from population-based screening programs. We evaluated the screening history in patients with LABCs from the I SPY TRIAL, to determine the frequency of screening and ICs. Methods: Of 221 pts enrolled in the I-SPY TRIAL, a multisite neoadjuvant study for women with LABCs > 3cm in size, screening history and presentation were retrospectively collected for 154. Two groups, screened (S), defined as a mammogram within 2 years, or non screened (NS), previous mammogram more than 2 years prior, were evaluated (Table). The frequency of ICs at 1 and 2 years was determined in S pts. Frequency of mammographically occult (MO) tumors was determined for all. Results: Of the total, 99 (64%) and 55 (36%) were NS and S, respectively. Mean tumor size for all pts was 6.7cm. Only 11 (20%) of S pts were SDCs and 44 (80%) were ICs, with 24 (63%) diagnosed within 1 year and 14 (37%) between 1 and 2 yrs of their last normal mammogram. 24 (24%) NS patients were younger than the recommended screening age of 40; in the remaining 75 pts, 9 (12%) were MO. Only 20% of IC tumors were MO. ICs were of higher grade (44% vs 11% grade III), and tumor size (7.0cm vs 4.4cm) than their SDC counterparts. 80% of cancers detected in I SPY were NKI70 gene test poor prognosis. Relationship to breast density and subtype is currently being assessed. Conclusions: Women presenting with LABCs have a high likelihood (80%) of an IC. This suggests that the growth rate of LABCs precludes early detection by conventional screening. Understanding the biology of ICs will be important to develop better strategies for prevention and early detection.

[Table: see text]

No significant financial relationships to disclose.
Magnetic Resonance Imaging quantification of breast density in BRCA carriers following gonadotropin releasing hormone agonist (GnRHA)-based hormonal chemoprevention
Authors: Klifa C. , Sand S. , Vora L. , Press M. , Orisamolu A. , Pike M. , Spicer D. , Daniels A. , Blazer K. , Weitzel J.
Published: August 2020

1506

Background: Breast tissue density limits the usefulness of mammography as a surveillance tool in young women. Breast Magnetic Resonance Imaging (MRI) provides high tissue contrast and three-dimensional structural information not impaired by high breast density. We developed a volumetric “MR density” measure of breast structural composition that may be complementary to mammographic breast density. We tested this MR density measure in unaffected women with known high risk of breast cancer due to a BRCA gene mutation (or empiric risk > 30% lifetime), who were recruited in a phase II trial to study the effects of a hormonal chemoprevention regimen. Methods: Nine premenopausal high-risk women age 21 to 48 were treated with intranasal GnRHA (deslorelin), low-dose estradiol, and testosterone daily for 10 months. All patients underwent one contrast-enhanced breast MRI exam before and after treatment. We measured MR density as the ratio of fibroglandular tissue volume to total volume of the breast, at both time points. Our technique involved the semi-automated delineation of the breast and the automated segmentation of fibroglandular from adipose tissue. An “MR index” was also defined to quantify partial voluming effects due to the presence of adipose/fibroglandular edges in the MR data. Results: Eight out of nine patients showed a reduction in MR density (p = 0.026) with treatment. Three patients had less than 5% MR density at baseline, making it difficult to quantitate a change with treatment. All of the remaining six patients had reduced MR density after treatment (mean reduction 35.5%; p = 0.035). Conclusions: We have demonstrated the use of breast MR density as a robust volumetric quantitative measure of breast tissue composition. Our findings suggest that MR could be used to measure hormonal chemoprevention effects in BRCA carriers.

[Table: see text]
Ethnic minority participation in Community Clinical Oncology Program (CCOP) research studies
Authors: Figueroa-Moseley C. D. , Morrow G. R. , Jean-Pierre P. , Purnell J.
Published: August 2020

1550

Background: Low minority participation in clinical research is concerning for both research and for the public health. Objective: The aim of this project was to investigate barriers and successes in minority participation in cancer medical research and cancer clinical trials. More specifically to: (1) determine major environmental, cultural, and economic barriers confronted by minority patients with cancer; and (2) determine the components of an environment that supports greater recruitment and retention of minorities to Clinical Community Oncology Practice (CCOP) cancer studies. Methods: Six focus groups consisting of 8 to 12 current or former minority cancer patients and 18 health care practitioners, from geographically diverse areas, were recruited to participate in this qualitative study. Focus group participants were asked questions about their attitudes and beliefs concerning their cancer and medical research. Health care practitioners were questioned on site recruitment and retention practices. Results: Two major thematic areas emerged for providers: barriers minority recommendation to trials and reasons for why minorities are underrepresented in trials. The three thematic areas for focus group participants were perceptions of medical research, reasons for participation or nonparticipation, and effects of Tuskegee Syphilis Study on participation. Conclusions: The Tuskegee Syphilis Study may have been a major impetus for why many Blacks and other minorities in this sample do not participate in medical research. Providers seem to state what was obviously important in connecting with the community, however, their actions in the community varied. This qualitative study gives voice to communities which mistrust the medical community in general and medical research in particular, and highlights the need for interventions bridging the community and research.

No significant financial relationships to disclose.
Phase II trial of oral gimatecan in adults with recurrent glioblastoma
Authors: Hu J. , Wen P. Y. , Abrey L. E. , Fadul C. , Drappatz J. , Salem N. , Amato A. , Carminati P. , Supko J. , Hochberg F.
Published: August 2020

2009

Background: Gimatecan is a highly lipophilic oral camptothecin analogue with impressive preclinical activity in glioma models. Methods: We conducted a multicenter two-stage phase II trial to evaluate the efficacy of gimatecan in adults with recurrent glioblastoma. Eligibility criteria included ≤1 prior treatment for recurrent disease, age ≥18, ECOG performance status 0 or 1, and normal organ function. Patients taking enzyme-inducing anti-seizure medications were excluded. Gimatecan 1.22 mg/m2 was given orally once daily for 5 consecutive days during each 28-day cycle. Radiographic response was evaluated by MRI after every second cycle. The primary endpoint of the study was 6 months PFS. A Simon's 2-stage design was used in which 19 patients were evaluated in the first stage, with an additional 36 patients accrued if > 4 patients in stage 1 achieved 6 month PFS. Results: A total of 29 patients were enrolled in the study, with median age of 58 years (range, 25–77 years); 58.6% female; all of whom had received prior surgery, radiation therapy, and at least one regimen of chemotherapy. The daily dose was reduced to 1.0 mg/m2 after four of the first 10 patients experienced grade 4 hematologic toxicity. One patient was removed from trial due to toxicity (grade 3 leukopenia and thrombocytopenia). Treatment delay occurred in 11 patients (38%) and dose reduction was necessary in eight patients (28%). Treatment-related grade 3/4 toxicities included thrombocytopenia (17.2%), leukopenia (17.2%), and neutropenia (10.3%). Only 1/19 patients treated with 1.0 mg/m2/day experienced grade 3/4 hematologic toxicity. The 18% reduction in the daily dose resulted in a 19% decrease in the concentration of total gimatecan in plasma prior to administration of the fifth daily dose (56 ± 23 vs. 45 ± 20 ng/mL) and a 33% decrease in the AUC for dose 5 (8.0±4.8 vs. 5.3±4.2 ng*h/mL). Only one patient had a partial radiographic response by the modified Macdonald criteria and stable disease was the best response in 13 patients. All other patients had progressive disease after two cycles of therapy. Only three patients (12%) were progression-free at 6 months. Median time to progression was 12.0 weeks (95% CI: 7.0, 17.0). Conclusions: Treatment with single-agent gimatecan 1.0 mg/m2/day for 5 days, repeated every 28-days showed minimal efficacy.

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Bevacizumab in combination with radiotherapy plus concomitant and adjuvant temozolomide for newly diagnosed glioblastoma: Update progression-free survival, overall survival, and toxicity
Authors: Gruber M. L. , Raza S. , Gruber D. , Narayana A.
Published: August 2020

2017

Background: Prognosis of glioblastoma (GBM) is very poor. Standard treatment includes surgical resection (SR), radiation (RT), concomitant and adjuvant chemotherapy with temozolomide (TMZ). Our objective is to assess the treatment efficacy, safety and survival in patients with newly-diagnosed GBM treated with RT, TMZ, and bevacizumab in the upfront management. Methods: From 2006–2008, 51 eligible patients (age >18, KPS >70) with newly-diagnosed GBM divided into two groups. Group A (n = 20) was treated with RT (60Gy) and concomitant TMZ (75mg/m2 daily for 42 days) with bevacizumab (10mg/kg every 2 weeks), 29 days following surgery, followed by up to six cycles of adjuvant TMZ (150mg/m2,daily x 7d, q28 with bevacizumab at 10mg/kg days 8 and 22 of each 28 day cycle. Group B (n = 31) received similar treatment without bevacizumab. Both groups were followed up until tumor progression (PFS). Recurrence was defined according to MacDonald Criteria. The end points were PFS, overall survival (OS) and toxicity. Results: Median bevacizumab infusions were 12 (4–32). Median follow-up was14 months for both groups. 6 months PFS survival in Group A was 77.5% and in Group B was 51.6%. Median PFS in Group A was 17 months compared to 7 months in Group B (p < 0.0001, HR = 0.26). Median OS has not been reached in Group A and was 17 months in Group B. One and 2 year OS were 83% and 57% in Group A compared to 72% and 6.5% in Group B (p = 0.02) ). Post-RT and temodar toxicities include thrombocytopenia (1 patient; Gr 3 and fatigue (3 patient;1 Gr 3), bevacizumab related toxicities with RT include leg ulcer with cellulites (1 patient; Gr 3) and pulmonary embolism with thrombocytopenia (1 patient; Gr 4), hypertension (2 patients; Gr 1), and asymptomatic blood products on MRI (2 patients). Conclusions: Bevacizumab has demonstrated efficacy, acceptable toxicity, improved PFS and OS in the upfront management of GBM.

No significant financial relationships to disclose.
Phase II trial of radiation therapy/temozolomide followed by temozolomide/sorafenib in the first-line treatment of glioblastoma multiforme (GBM)
Authors: Lamar R. E. , Spigel D. R. , Burris H. A. , Markus T. M. , Kuzur M. , Ervin T. , Fichtel L. , Greco F. A. , Hainsworth J. D.
Published: August 2020

2018

Background: Anti-angiogenesis agents have recently shown activity in the treatment of patients (pts) with GBM. We added sorafenib, a multi-targeted TKI, to the standard first-line treatment of patients with GBM. Methods: Pts with histologically documented GBM were eligible at diagnosis or after resection. Additional entry criteria: ECOG PS 0 or 1; adequate organ function; ability to swallow pills; standard exclusions for antiangiogenesis agents. All pts initially received radiation therapy (total 60 Gy, 2 Gy by single daily fractions) plus temozolomide (75mg/m2 po daily). Four weeks after completion of radiation therapy, pts received temozolomide (150mg/m2 po days 1–5, repeated every 21 days for 6 cycles) plus sorafenib (400mg po bid daily x 24 weeks). Pts were evaluated every 8 weeks during temozolomide/sorafenib therapy, and every 3 months after therapy ended, until tumor progression. Median PFS was the primary endpoint. Results: Between April 2007 and July 2008, 45 pts were enrolled. The median age was 54 years; 30 pts (67%) had previous partial or complete surgical resection. 39 pts (87%) completed concurrent RT/temozolomide therapy, while 6 pts were removed from treatment (PD 4, toxicity 1, intercurrent event 1). 39 pts began treatment with temozolomide/sorafenib; 3 have completed all planned treatment, 8 remain on treatment, and 28 stopped treatment early (PD 22, toxicity 2, intercurrent event 1, pt decision 3). Best responses are as follows: CR, 1 pt (2%); PR, 5 pts (11%); stable disease, 22 pts (49%); progressive disease, 14 pts (31%). After a median follow-up of 9 months, median PFS for all pts was 6 months (95% confidence intervals, 2.7–7.8 months). Median PFS for pts who received at least 1 dose of sorafenib is also 6 months. The median overall survival is 16 months (95% CI, 7.2-NR months). Grade 3/4 toxicity during temozolomide/sorafenib was uncommon; 7 pts (16%) required dose reductions of sorafenib during their treatment course. Conclusions: The addition of sorafenib to standard treatment with RT/temozolomide is feasible and well tolerated by most pts. Preliminary efficacy is similar to standard therapy; updated results will be presented.

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KAAD-cyclopamine sensitize malignant glioma cells to TRAIL-mediated apoptosis
Authors: Siegelin M.
Published: August 2020

2025

Background: Malignant gliomas are the most aggressive human brain tumors without any curative treatment. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic because TRAIL induces almost selectively apoptosis in cancer cells. The main obstacle in TRAIL-based therapy is that many glioblastoma cells are resistant. In the present study we found that the Hedgehog inhibitor, KAAD-cyclopamine, potently sensitized primary glioma cells to TRAIL-mediated apoptosis. Methods: Established cell lines and isolated primary tumor glioblastoma cells were treated with achievable plasma concentrations of TRAIL, KAAD-cyclopamine, or the combination of both. Apoptosis was assessed by Annexin V/Propidiumiodide staining and subsequent flow cytometric analysis. Activation of caspases and expression of apoptosis related proteins were determined by immunoblotting. For transfection experiments primary glioma cells were electroporated with plasmids encoding the cDNA of c-FLIP and bcl-2. Results: We established a stable culture model for isolated primary human glioma cells. In contrast to cell lines, isolated primary tumor cells from all investigated glioma patients were highly TRAIL resistant. Single treatment with KAAD-cyclopamine or TRAIL does not induce cytotoxicity in malignant glioma cells. However, treatment with KAAD-cyclopamine in combination with TRAIL induces rapid apoptosis in TRAIL-resistant glioma cells. Notably, normal human astrocytes were not affected by the combination treatment consisting of KAAD-cyclopamine and TRAIL. KAAD-cyclopamine led to an upregulation of death receptor 4 and 5 and down-regulation of bcl-2 and c-FLIP. Furthermore, over-expression of both bcl-2 and c-FLIP attenuated KAAD-cyclopamine facilitated TRAIL-mediated apoptosis. Conclusion: The widespread TRAIL resistance in primary glioma cells described here questions the therapeutic clinical benefit of TRAIL as a monotherapeutic agent. Overcoming TRAIL resistance by KAAD-cyclopamine cotreatment might, however, provide a powerful therapeutic option for glioma patients.

No significant financial relationships to disclose.
Effect of daclizumab on TReg counts and EGFRvIII-specific immune responses in GBM
Authors: Sampson J. H. , Archer G. E. , Bigner D. D. , Schmittling R. J. , Herndon J. E. , Davis T. , Friedman H. S. , Keler T. , Reardon D. A. , Mitchell D. A.
Published: August 2020

2034

Background: TRegs are increased in patients with GBM and constitutively express the high affinity interleukin-2 receptor (IL-2Rα). Treatment with an antibody that blocks IL-2Rα signaling functionally inactivates and eliminates TRegs without inducing autoimmune toxicity in murine models. We hypothesized that daclizumab, a commercially-available, IL-2Rα-specific antibody would function identically.Methods: A randomized phase II clinical trial assessed the effects of daclizumab in the context of the cancer vaccine, CDX-110, which is comprised of an EGFRvIII-specific peptide sequence linked to KLH. EGFRvIII is a constitutively activated and immunogenic mutation not expressed in normal tissues, but widely expressed in GBMs and other neoplasms. In patients with newly-diagnosed, EGFRvIII+ GBM, after resection and radiation/TMZ, patients received CDX-110 vaccinations biweekly x 3, then monthly until tumor progression in combination with TMZ (200 mg/m2 x 5/28 days). Half the patients were randomized to receive daclizumab (1mg/Kg x1) at the first vaccine. The others received saline in a double-blinded fashion.Results: There were no drug related SAEs. EGFRvIII-specific immune responses were generated in all patients, and all immune responses were sustained or enhanced during subsequent TMZ cycles. Preliminary analysis (n = 4) suggests that daclizumab reduces Treg (CD4+CD25+CD45RO+FOXP3+) numbers [change 82.4 ± 7.1% from baseline (p = 0.011; t-test)] without reducing overall CD8+ or CD4+ T-cell counts. Tregs decreased only 3.7 + 11.0% after vaccination in the saline treated group during the same interval. Preliminary analysis (n = 4) also suggest that daclizumab enhanced EGFRvIII-specific immune responses (p = 0.01; t-test) and enhanced the titer of cytotoxic EGFRvIII-specific IgG1 isotype antibodies compared to the saline treated group (p = 0.003; t-test) and compared to previously vaccinated patients who did not receive daclizumab (p = 0.0015; t-test). TTP and OS survival in both arms has not been reached. Conclusions: Daclizumab may reduce Treg counts in patients with GBM. TMZ and daclizumab may enhance EGFRvIII-targeted immune responses despite lymphodepletion. These combinations are currently under further investigation.

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