bluuebunny/crossref_metadata_2025 huggingface dataset:
Cost-effectiveness of the 21-gene recurrence score assay in the setting of multifactorial decision making for chemotherapy in early-stage breast cancer.
Authors: Reed Shelby D. , Dinan Michaela A , Schulman Kevin A. , Lyman Gary H.
Published: March 2020

1525

Background: The objective of this study was to incorporate evidence from two recently-published studies to reevaluate the cost-effectiveness of the 21-gene Recurrence Score (RS) assay (Oncotype DX) in the context of multifactorial decision making to guide the use of chemotherapy for node-negative, estrogen receptor–positive breast cancer in the United States from the societal and healthcare system perspectives. Methods: We developed a decision-analytic model to first cross-classify hypothetical patients by clinicopathologic characteristics according to the Adjuvant! using risk groups and RS risk groups. We generated estimates of long-term costs, survival, and quality-adjusted survival for the RS-guided and non–RS-guided strategies using a probabilistic state transition model. In addition to costs for the 21-gene assay, we assigned attributable costs for chemotherapy, hormonal therapy, monitoring for disease recurrence, and distant recurrence. For the societal perspective, we also considered incremental patient time costs. Costs and survival were discounted at 3% annually. Results: With the RS-guided strategy, 40.4% of patients were expected to receive chemotherapy relative to 47.3% in the non–RS-guided strategy. Targeted use of chemotherapy in the RS-guided strategy was expected to increase survival by 0.19 years (95% CI, 0.09 to 0.32) and 0.16 QALYs (95% CI, 0.08 to 0.28). Lifetime direct medical costs were expected to be $2692 (95% CI, 1546 to 3821) higher with the RS-guided strategy. The incremental cost-effectiveness ratios (ICERs) were $14,059 per life-year saved (95% CI, $6840-$28,912) and $16,677 per QALY (95% CI, $7613-$37,219). When incorporating lower indirect costs of $950 per patient, the ICERs were $9095 per life-year saved (95% CI, dominant-$23,397) and $10,788 per QALY (95% CI, $6840-$30,265). In probabilistic sensitivity analysis, more than 99% of the ICERs were less than $50,000 per life-year saved and per QALY. Conclusions: Our updated cost-effectiveness estimates are supportive of the economic value of the 21-gene RS assay in the setting of node-negative, estrogen receptor–positive breast cancer.
Outcomes from an electronic medical record (EMR)-based standardized tobacco assessment and cessation program in a NCI-designated comprehensive cancer center.
Authors: Warren Graham Walter , Zevon Michael , Hyland Andrew , Hysert Pat , Reed Robert , Long Mary Ann , Houston Teresa , Mahoney Martin , Demmy Todd L. , Cummings K. Michael
Published: March 2020

1529

Background: Tobacco assessment and cessation is advocated by ASCO and national clinical oncology guidelines, but there is little information on large scale clinically efficient models to assess tobacco use and provide cessation in a structured evidence based manner. Automation through the electronic medical record (EMR) could reduce subjective interpretation by clinicians and assist in increasing data tracking accuracy to enhance meaningful use initiatives. Methods: A standard set of evidence based tobacco assessment questions were incorporated into an annotated fixed-variable response system in the EMR delivered by nursing at initial consult and at follow-up. A logic based EMR referral system was developed to determine patient eligibility for mandatory automated referral to a dedicated tobacco cessation service. An evidence based institutional clinical cessation program was developed to provide cessation support to referred patients. The evidence based screening and referral algorithms will be presented. Results: Over 13 months, 677 patients were referred and 529 patients were successfully contacted to date for cessation support. In the 529 patients, 21 (3.9%) were inappropriate referrals (never smokers or long term former smokers), 48 patients (9.1%) did not want to enroll, but wanted to discuss cessation at a later date. Notably, only 18 patients (3.4%) refused any intervention. In a total of 415 patients enrolled in the cessation program, 104 patients (25.1%) were thinking about quitting (contemplation), 134 patients (32.3%) were preparing to quit, 169 patients (40.7%) were quitting (action phase), and 8 patients (1.9%) have relapsed. Tobacco assessments and automated referrals through the EMR took a median of 4 minutes to complete. Conclusions: A large volume of patients were screened and referred to a dedicated cessation program with low patient refusal for intervention without impeding physician workflow. These data suggest that this nursing driven EMR based assessment is a highly efficient clinical model for tobacco assessment and cessation.
Genetic sequence variant (GSV) in TERT-CLPTM1L (5p15.33 locus) and survival in platinum-treated stage-IV non-small cell lung cancer (NSCLC).
Authors: Azad Abul Kalam , Qiu Xiaoping , Cuffe Sinead , Qiu Xin , Boyd Kevin , Kuang Qin , Emami Marjan , Perera Nicole , Palepu Prakruthi R. , Patel Devalben , Chen Zhuo , Cheng Dangxiao , Feld Ronald , Leighl Natasha B. , Shepherd Frances A. , Tsao Ming Sound , Xu Wei , Liu Geoffrey
Published: March 2020

1535

Background: Lung cancer is a leading cause of cancer-related mortality in North America. Besides tobacco smoking, inherited genetic factors can also influence the development of lung cancer. These genetic factors may lead to biologically distinct subsets of cancers that have different outcomes. We evaluated whether GSVs associated with lung cancer risk are also associated with overall survival (OS) and progress free survival (PFS) in platinum-treated stage-IV NSCLC patients. We chose this subset of patients with lung cancer because they are uniformly treated and followed up at our institute (Princess Margaret Hospital). Methods: A total of 32 candidate GSVs in 21 genes previously reported to be associated with lung cancer risk were genotyped in 188 platinum-treated NSCLC stage-IV patients. Illumina Custom GoldenGate Genotyping Panel was used for the genotyping assay platform. Multivariate Cox proportional hazard models adjusted for the potential clinical prognostic factors were generated for OS and PFS. Results: Median age is 60 yr (range: 31-81); 73% with adenocarcinoma. Median follow-up time is 27 mo; median OS is 16 mo and PFS is 8 mo. The top significant GSV was rs4975616 (g.1315660G>A) in telomerase reverse transcriptase (TERT) and cleft lip and palate transmembrane 1-like (CLPTM1L) gene on chromosome 5p15.33. The adjusted hazard ratio (aHR) for OS was 0.76 (95% CI: 0.58-0.99; p=0.04) and for PFS aHR was 0.70 (95% CI: 0.55-0.90; p=0.005) for each protective allele, respectively. This GSV has previously been associated with lung cancer risk in genome-wide association study (PMID: 19654303). Conclusions: The TERT-CLPTM1L:rs4975616 GSV is not only a risk factor for lung cancer but also is associated with survival in patients with stage-IV NSCLC treated with platinum based chemotherapy. GSVs may be able to define subsets of patients with different risk and prognosis of NSCLC. Future studies should evaluate whether this GSV is predictive or prognostic.
Analysis of mutations in formalin-fixed paraffin-embedded (FFPE) tumor samples from two phase II clinical trials using a Sequenom-based approach.
Authors: Orr Maria , Sherwood James , McWalter Gael , Donald Emma
Published: March 2020

1548

Background: Analysis of tumour samples for biomarker discovery, personalised health care and disease stratification is becoming increasingly important. Methods to detect somatic mutations are often limited by the requirement for a significant amount of input DNA, low sensitivity or low sample throughput. The aim of this work was to obtain a comprehensive mutation profile of tumour samples taken from patients enrolled on two Phase II clinical trials. A Sequenom based approach was used to determine mutation profiles for the samples so that these could be correlated with response at some future date. Methods: After successfully piloting the Sequenom MassArray 4 platform on formalin fixed paraffin embedded (FFPE) tumour samples and tumour cell line admixes, we ran an exploratory analysis of 177 melanoma and 230 non small cell lung cancer (NSCLC) FFPE samples collected from two phase II clinical trials. DNA was extracted from the FFPE samples using the QIAmp DNA FFPE Tissue Kit (Qiagen). We designed a panel of 86 assays in 14 genes covering approximately 160+ mutations. Mutations were chosen based on mutation frequency and biological significance in these tumour types. Results: Using this approach we were able to detect concomitant mutation profiles in a significant percentage of samples using only approximately 20uL of FFPE DNA (500 copies/µL average). Mutation status concordance was over 97% in BRAF and KRAS when compared to data generated via other approaches (sequencing, ARMS). Conclusions: Using Sequenom to screen tumour material, collected during clinical trials, is a feasible, rapid and comprehensive approach. Such an approach can be used to identify mutation profiles which correlate with patient response, potentially identify further patient stratification and help generate new hypotheses for further exploration.
NAD(P)H: Quinone oxidoreductase 1 (NQO1) C609T polymorphism and lung cancer risk: A meta-analysis.
Authors: Lou Yuqing , Li Rong , Xiong Liwen , Han Baohui
Published: March 2020

1551

Background: No clear consensus has been reached on the NAD(P)H: quinone oxidoreductase 1 (NQO1) gene C609T polymorphism and lung cancer risk. We performed a meta-analysis to summarize the possible association. Methods: We conducted a computer retrieval of PUBMED and EMBASE databases prior to January 2012. References of retrieved articles were also screened. According to the inclusion criteria, 24 articles (31 studies) were finally included. The fixed-effects model and the random-effects model were applied for dichotomous outcomes to combine the results of the individual studies. Results: There was no statistical association between C609T polymorphism and lung cancer risk in overall, East Asians, African-Americans or Hispanics. In Caucasians, significant association was found in allele comparison model (T vs. C) (P=0.04, OR=1.09, 95%CI [1.00–1.19], Pheterogeneity=0.24, fixed-effects model). In Hawaiians, significant association could be found in dominant genetic model ((TT+CT) vs. CC) (P=0.04, OR=0.52, 95%CI [0.28–0.96], fixed-effects model). In the subgroup of squamous cell carcinoma, a borderline significance could be found in the dominant genetic model ((TT+CT) vs. CC) (P=0.05, OR=1.20, 95%CI [1.00–1.43], Pheterogeneity=0.65, fixed-effects model). Significant association could also be found in allele comparison (T vs. C) (P=0.03, OR=1.21, 95%CI [1.01–1.44], Pheterogeneity=0.68, fixed-effects model). In the subgroup of small cell lung cancer risk, significant association were found in allele comparison (T vs. C) (P=0.03, OR=1.68, 95%CI [1.05–2.68], Pheterogeneity=0.10, random-effects model) and in the homozygote comparison (TT vs. CC) (P=0.02, OR=2.79, 95%CI[1.14–6.85], Pheterogeneity=0.72, fixed-effects model). No association was observed in adenocarcinoma subgroup. Conclusions: NQO1 C609T polymorphism might associate with lung cancer risk in Caucasians and Hawaiians. NQO1 C609T polymorphism might also associate with squamous cell carcinoma and small cell lung cancer risk.
Differential effects of light at night and shift rotation pattern on the circadian system in night workers.
Authors: Razavi Pedram , Schernhammer Eva S ,   Nurses' Health Study II (NHS2) Group
Published: March 2020

1556

Background: Light at night as in shift work suppresses nocturnal secretion of melatonin, a pineal hormone with oncostatic properties. Several studies have associated night shift work with higher risk of cancer, leading WHO in 2007 to classify rotating night shift work as “probably carcinogenic”. We conducted one of the most comprehensive studies, to date, to evaluate the effects of light and night shift work on melatonin measurements in the field. Methods: Study participants were 130 active nurses (84 current rotating night shift workers and 46 day shift workers) participating in NHS2. Each nurse wore a head-mounted light- and accelerometer for a 3-day study period, during which each spontaneous urine was collected for repeated urinary 6-sulfatoxymelatonin (melatonin) measurements. In addition, nurses were asked to fill out paper questionnaires and diaries. We used mixed models to evaluate the influence of light, activity and night shift work on urinary melatonin level adjusting, for age, lifestyle, and occupational history. We log-transformed main variables and report geometric means (GM [standard deviation]). Results: Greater levels of light were associated with lower melatonin (P < 0.0001), independent of activity level. An increase in light intensity from 10 to 100 lux was associated with a 12% decrease in geometric mean of melatonin level; however, this inverse association was only significant at night (Ptrend = 0.01). At night, each hour increase in exposure to ≥ 20 lux light lowered melatonin level by 5.7% (Ptrend < 0.0001). A single night shift affected the circadian system by lowering melatonin peak by 22% (day shift: GM = 17.57 [2.73]; night shift: GM = 13.64 [2.54]) and induced a phase shift (PS) of 0.9 hours, -changes that reset to normal by the next day. Two consecutive night shifts had a similar effect as a single shift. However, the effect was worse after three consecutive night shifts (GM = 10.11 [2.77]; PS = 2.2 hours). Conclusions: We found significant inverse associations of intensity and duration of exposure to light at night with urinary melatonin, independent of activity level. Three consecutive night shifts affected the circadian system more strongly than two consecutive, or a single night shift.
Clinical and genetic predictors of weight gain in patients diagnosed with breast cancer.
Authors: Reddy Sangeetha Meda , Sadim Maureen , Helenowski Irene B. , Li Jun , Yi Nengjun , Kaklamani Virginia G.
Published: March 2020

1561

Background: Obesity and weight gain in breast cancer patients has been associated with decreased quality of life, decreased response to chemotherapy, increased cancer recurrence, and higher all-cause mortality. Our study was designed to identify factors that contribute to this weight gain. Methods: Chart review was conducted on 565 breast cancer patients to obtain weights and BMIs over an 18 month period from diagnosis, tumor characteristics (ER/PR/Her2 status, grade, presence of LN metastases, stage), demographics (age, race), clinical factors (menopausal status), and treatment regimens (chemotherapy, hormone therapy, radiation). Blood samples were genotyped for polymorphisms in FTO (fat mass and obesity-associated protein) and the adiponectin pathway, two pathways found to be associated with obesity and breast cancer risk. Results: See table. For genetic analysis, one statistically significant epistatic and three gene x environmental interactions were detected for adiponectin SNPs: rs822396d x BMI at diagnosis (effect size 8.65), rs2232853a x age (2.75), rs1501299a x BMI at diagnosis (3.63), and rs266729d x rs7539542d (6.40). Conclusions: We have identified multiple clinical and genetic variables that are likely predictors of weight gain in breast cancer patients. We are conducting a prospective study of 200 breast cancer patients to validate the findings of this retrospective study. By identifying a high risk patient population, we hope to target them for aggressive lifestyle interventions to prevent weight gain and thereby improve their mortality and morbidity. [Table: see text]
Risk perception and knowledge of breast and colon cancers in a diverse population.
Authors: Lang Katherine , Gyure Maria , Rodriguez Vivian , Corona Rosalie , McClish Donna , Bowen Deborah , Krist Alex , Borzelleca Joseph , Bodurtha Joann , Quillin John
Published: March 2020

1563

Background: The accuracy of cancer risk perception has implications for preventive behaviors. Studies show that despite receiving personalized breast and colon cancer risk information, people continue to overestimate their numeric risks. It is still not fully understood why this occurs. Breast cancer, especially, is highly visible in the media so an individual may hear more about breast cancer, increasing general knowledge but potentially inflating risk perceptions. This study explores relationships between general knowledge and numeric risk perceptions for breast cancer (BC) and colon cancer (CC) among women. We hypothesize that general knowledge of BC will be high relative to CC, but risk perception for BC will be less accurate. Methods: Data was obtained from the first 369 (final N=490) patients recruited for the Kin Fact study from a Women’s Health Clinic. Kin Fact is a randomized controlled trial examining effects of an intervention to increase cancer risk communication in families. Women complete baseline surveys including knowledge and numeric risk perception measures for BC and CC. We use CA Gene software to calculate actual lifetime risk for BC and CC. Correlations, t-tests and linear regressions were used for the analysis. Results: Women averaged 33 years old, and 58% were African American. Average lifetime risk was 3% for CC and 11% for BC. Women overestimated their numeric risk for both BC and CC, but the mean overestimation for BC (24%) was significantly larger than for CC (19%) (p<0.001). Average scores for BC knowledge were also significantly higher than for CC (p<0.001). Compared to knowledge about CC, women who had greater knowledge of BC also were more inaccurate in terms of their perceived numeric risk (r= -0.131, p=0.016). This finding remained significant controlling for age, race and genetic literacy. Conclusions: Results endorse an apparently paradoxical effect that compared with CC, women with increased knowledge of BC have less accurate risk perception for BC. Inaccuracies in perceived risk can affect psychosocial well-being and adherence to screening and prevention recommendations. Findings reveal a need for increasing knowledge about cancer without adversely impacting the accuracy of risk perceptions.
Esophageal cancer incidence gender disparity.
Authors: Mathieu Luckson Noe , Hooker Craig , Kanarek Norma , Rudin Charles M. , Brock Malcolm
Published: March 2020

1573

Background: Over the past 30 years, esophageal cancer incidence has been increasing more rapidly than any other solid neoplasm in the Western world. Globally, there is a large male predominance in both esophageal squamous and adenocarcinoma. The reasons for this gender difference and the possible role of estrogen are unclear. The objective of this study is to determine if estrogen exposure is consistent with the male predominance observed in esophageal cancer incidence. Methods: A database assessment of esophageal cancer incidence rates (age-adjusted) from 1975 to 2008 was conducted in the National SEER 9 Database and the Maryland Cancer Registry. Rates by gender and age were calculated. Gender-specific incidence rate ratios were compared across age groups. Annual percentage change (APC) was compared for each gender-age group. Results: In both national and state, male and female, adeno and squamous cell histologies, incidence rates increase with patient age. SEER data trends revealed the 50-64 aged female cohort as the only gender-age cohort APC decreasing between 1975-2008. Furthermore, a significant increase in incidence for females is observed in the 65+ age groups; whereas among males, the rates are rising in all age groups. Conclusions: Using age as a proxy for estrogen exposure, our findings suggest a hormonal component in the declining male: female esophageal cancer incidence rate ratios with increasing age and confirm gender differences in incidence long observed in esophageal cancer. Histological features may be predictive of a lower rate ratio. (Bodelon et al. 2011) Estrogen exposure may play a protective role in esophageal cancer which dissipates with time after age 60-69. Our data suggest possible future roles of estrogen as a chemopreventive agent in esophageal cancer (Barone et al. 2011). [Table: see text] [Table: see text]
Age, race/ethnicity, and the ER/PR/HER2 subtypes in breast cancer.
Authors: Parise Carol , Caggiano Vincent
Published: March 2020

1582

Background: The association of age and ER/PR/HER2 subtype in African-American (AA) and Hispanic women with breast cancer has been reported. This study examines the association of age and subtype among 12 self-reported race/ethnicity categories. Methods: Using the California Cancer Registry 2000-2010, we examined 136,175 cases of first primary female invasive breast cancer. Race/ethnicity was stratified into 12 categories. The distribution of age and race/ethnicity among the 8 ER/PR/HER2 subtypes was examined. Age was stratified into <40, 40-69, and 70+ years. For each age strata, odds ratios (OR) and 95% confidence intervals (CI) were computed to assess the association of race/ethnicity with ER-/PR-/HER2+, ER-/PR-/HER2- (TN), and ER+/PR+/HER2+ (TP) when compared with the ER+/PR+/HER2- subtype. Results: The % of each race was: White 66.8; AA 6.0; Hispanic 15.9; Pacific Islander (PI) 0.3; Southeast Asian (SEA) 2.5; Indian Continent (IC) 0.7; American Indian; 0.2; Chinese 2.5; Japanese 1.2; Filipino 3.1; Korean 0.7; Hispanic/non-white 0.3. All AA women had increased ORs of the ER-/PR-/HER2+, TN and TP. Hispanic women mimicked the AA population except for young women with TP. Chinese (OR=0.53; 95%CI=0.37-0.76) Japanese (OR=0.51; 95%CI=0.28-0.96), and Filipino (OR=0.45; 95%CI=0.31-0.67) women <40 were less likely to have TN subtype. For women 40-69, SEA, Chinese, Filipino, and Korean women had increased ORs for TP, and ER-/PR-/HER2+. The Japanese had increased ORs for the TP (OR=1.23; 95%CI=1.00-1.49) but decreased odds for the TN (OR=0.72; 95%CI=0.57-0.90). IC women had increased odds for the TN (OR=1.38; 95%CI=1.10-1.72). Korean women 70+ were more likely to have the TP and ER-/PR-/HER2+. SEA had increased ORs for ER-/PR-/HER2+ and TN, IC only had increased ORs for TN (OR=2.03; 95%CI=1.26-3.27). Chinese and Filipino women only had increased ORs for the ER-/PR-/HER2+. Conclusions: AA and Hispanic women of all ages are at increased risk of the TN, and ER-/PR-/HER2+ subtypes. AA women of all ages and Hispanic women over age 40 are at increased risk of the TP subtype. The diversity of Asian women with regard to breast cancer necessitates accurately defining this population.
Correlation of high body mass index and circulating tumor cell positivity in patients with early-stage breast cancer.
Authors: Ortmann Uta , Janni Wolfgang , Andergassen Ulrich , Beck Thomas , Beckmann Matthias W. , Lichtenegger Werner , Neugebauer Julia Katharina , Salmen Jessica , Schindlbeck Christian , Schneeweiss Andreas , Scholz Christoph , Schreier Jörg , Spickhoff Frank , Zwingers Thomas , Rack Brigitte Kathrin
Published: March 2020

1600^

Background: The prognostic relevance of both body mass index (BMI) and circulating tumor cells (CTC) has been confirmed in different trials for patients with early breast cancer. This analysis evaluates the correlation between high BMI and CTC positivity as risk factors for reduced disease free and overall survival. Methods: Data of 3658 patients of the SUCCESS A trial have been analyzed. CTC count and BMI were documented before (N = 2026) and after (N = 1504) chemotherapy. Within this trial patients with early breast cancer were randomized to two chemotherapy regimens and received either 3 cycles of fluorouracil, epirubicin and cyclophosphamide followed by 3 cycles of docetaxel (FE100C-Doc) or 3 cycles of fluorouracil, epirubicin and cyclophosphamide followed by 3 cycles of docetaxel and gemcitabine(FE100C-DG). In addition, patients were randomized to zoledronic acid either for 2 or 5 years. CTC were analyzed using the CellSearch System (Veridex, USA). Different groups of bodyweight were classified according to the WHO’s international definition: Underweight (BMI < 18,5 kg/m2), normal range (BMI > 18,5- < 25), overweight (BMI >25- < 30), obesity (BMI > 30). Correlation between CTC count and BMI was analyzed using frequency-table methods. Results: At study entry 24 (1.2%) patients were underweight, 952 (47%) patients were normal weight, 658 (32.5%) patients were overweight and 392 (19.4%) patients were obese. Before the start of chemotherapy, CTC were detected in 435 (21.5%) patients. We did not find a correlation between CTC positivity and BMI (p=0.94). After chemotherapy CTC were detected in 330 (16,3%) patients. Again, there was no statistically significant correlation between BMI and CTC positivity (p=0.86). In particular, CTC positivity was not observed more frequently in obese patients neither before (p=0.70) nor after chemotherapy (p=0.95) compared to patients with a BMI < 30 kg/m2. Conclusions: As compared to patients with normal BMI, there was no significant difference in the prevalence of CTC in underweight, overweight and obese patients, respectively, neither before nor after chemotherapy. The risk factors obesity and prevalence of CTC seem to be independent prognostic factors.
Correlation of BMI with tumor stage in early breast cancer patients (pts): Pooled analysis of the German SUCCESS A, B, and C trials.
Authors: Melcher Carola Anna , Ortmann Uta , Scholz Christoph , Zwingers Thomas , Schneeweiss Andreas , Lichtenegger Werner , Lorenz Ralf , Hagenbeck Carsten , Forstbauer Helmut , Ulmer Hans Ulrich , Kasprowicz Nikola S. , Heinrich Georg , Jaeger Bernadette Anna Sophia , Fehm Tanja N. , Beckmann Matthias W. , Janni Wolfgang , Rack Brigitte Kathrin
Published: March 2020

1602

Background: Independent from known prognostic factors, e.g., tumor size and nodal status, obesity is a risk factor for poor disease free, distant disease free, and overall survival in breast cancer. The aim of this analysis was to examine the correlation of the body mass index (BMI) with tumor characteristics in early breast cancer. Methods: We analyzed the data of 7,997 pts with early, node positive or high risk node negative primary breast cancer treated with adjuvant taxan-based chemotherapy within the German multicenter phase III SUCCESS A, B, or C trials. The pts’ tumor stage at primary diagnosis was classified according to the UICC tumor-node-metastasis (TNM) classification. Additionally, the tumor’s hormone-receptor status and HER2/neu status were determined. Before enrollment into the study each patient was grouped according to the WHO global database on BMI. Contingency table methods were used to analyze the correlation of BMI and tumor characteristics. Results: Among the 7,997 pts 100 (1.3%) pts were underweight, 3,556 (44.5%) pts were normal weight, 2,569 (32.1%) pts were overweight and 1,772 (22.2%) were obese. Of all pts 4,508 pts (56.4%) suffered from a pT2-4 tumor, 4830 (60.4%) showed lymph node involvement (pN1-3) and 7509 (93.9%) had G2-3 tumors. 5839 pts (73.0%) showed positivity for ER or PR and 935 (11.7%) for HER2/neu. Overweight and obese pts had significantly larger tumors compared to pts with normal BMI (p<0.0001; p<0.0001). Furthermore, overweight and obesity were associated with a significantly higher rate of lymph node involvement (p=0.0001; p=0.0003) respectively. In contrast neither grading, tumor histology, ER/PR-status nor HER2/neu-overexpression were correlated with BMI. Conclusions: These data are the first to show in a large number of pts that both obese and overweight women suffering from primary breast cancer have significantly larger tumors and more often positive axillary lymph nodes. As there are no differences in tumor biology, the advanced tumor stage might be due to more difficult and delayed detection of breast cancer and lymph node lesions in these women.
Health and quality of life (QOL) issues in four groups of lung cancer patients: Low-dose computed tomography (LDCT) screened, chest x-ray detected, incidentally found, and routinely diagnosed.
Authors: Yang Ping , Yost Kathleen J. , Clark Matthew M. , de Andrade Mariza , Piderman Katherine M. , Wampfler Jason A. , Sloan Jeff A. , Midthun David E.
Published: March 2020

1610

Background: Low dose computed tomography (LDCT) scans have reduced lung cancer deaths by 20.3% in high risk populations, although there is an unknown balance between the benefits and harms of LDCT scans as a screening tool. Our purpose was to compare health-related QOL issues among lung cancer patients who were initially detected by LDCT scans; 4 comparison groups included: lung cancer diagnosed by a screening chest X-ray, as an incidental finding from procedures taken for other medical reasons, or based on symptoms indicative for lung cancer and routinely diagnosed, and individuals who were LDCT screened but found no lung cancer (controls who participated in Mayo’s lung cancer CT screening trial). Methods: A total of 1,658 lung cancer patients (cared at Mayo Clinic) in the 4 groups (37, 151, 389, and 1081 respectively) and 488 controls were compared on following patient-reported outcomes (collected via validated tools): overall QOL, four symptoms (cough, pain, dyspnea, fatigue), mental/ physical/ emotional/ social/ spiritual QOL, and other concerns (e.g., family/ friends/ financial/ legal). A clinically significant deficit was defined as at least 10-points in difference (or <50 points) on a 0-100 scale. The rates of deficits were compared via Fisher’s exact tests and average QOL values via Kruskal-Wallis tests. Results: Overall QOL and individual symptoms were significantly worse (p<0.05) in all lung cancer groups than in controls, except for pain. LDCT-screened patients reported the greatest deficit among the 4 lung cancer groups in physical (41%), emotional (24%), social (38%), and spiritual QOL (24%); whereas chest X-ray detected patients had the least deficit in overall QOL (22%) and pain (32%). All 4 lung cancer groups experienced much worse fatigue (52-64%) than the controls (32%). Conclusions: Our preliminary results suggest that LDCT-screening detected lung cancer patients reported a different QOL profile from other lung cancer patients and non-lung cancer controls. The clinical course, smoking behavior, and QOL related health issues associated with LDCT screening for lung cancer warrant thorough investigation.
Randomized phase II 8-arm factorial study of adjuvant dose-dense (dd) temozolomide (TMZ) with permutations of thalidomide (Thal), isotretinoin (CRA), and/or celecoxib (Cel) for newly diagnosed glioblastoma (GBM).
Authors: Gilbert Mark R. , Hess Kenneth R. , Lagrone Lore , Groves Morris D. , Levin Victor A. , De Groot John Frederick , Loghin Monica Elena , Puduvalli Vinay K. , Fisch Michael , Giglio Pierre , Colman Howard , Conrad Charles A. , Aldape Kenneth D. , Yung W. K. Alfred ,   M. D. Anderson CCOP, Brain Tumor Trials Collaborative
Published: March 2020

2003

Background: Concurrent radiation and TMZ followed by 6-12 months of adjuvant TMZ (d 1-5 of a 28d cycle) is the current standard of care for patients with newly diagnosed GBM. The addition of cytostatic or signal transduction agents may enhance efficacy without a significant increase in toxicity. A phase I trial (Neuro-oncology 2009) established the safety of ddTMZ with 2 or 3 of the cytostatic agents. Methods: This randomized phase II study was conducted by the Brain Tumor Trials Collaborative (BTTC) and the MDACC CCOP. The primary objectives: determine if specific cytostatic agents added to ddTMZ alters outcomes (PFS, OS) and compare triplet with doublet therapy. Eligibility criteria: centrally confirmed newly diagnosed GBM, age ≥18, KPS≥60, stable or improved after chemoradiation (pseudoprogression allowed), adequate hematologic, renal and hepatic function. Pts were randomly assigned to 12 treatment cycles (28 d/cycle) in 8 arms: ddTMZ alone (150 mg/m2/day, 7-d on, 7-d off) or TMZ-containing doublet, triplet and quadruplet combinations with Thal, CRA, or Cel. Results: The study enrolled 155 eligible patients from 11/2005 to 9/2010 to the 8 arms of the factorial design. Median age was 53 (18-84) and median KPS, 90 (60-100). Compared with TMZ alone, the TMZ+CRA doublet had worse PFS (10.5, 6.5 mo; p=0.043) and OS (21.2, 11.7 mo; p=0.037). Trends were also seen for worse outcome (PFS, OS) for CRA-containing regimens, improved OS for Cel containing arms and no impact of Thal. A strong trend for OS improvement was seen for triplet compared with doublet regimens (20.1, 17.0 mo; p=0.15), but no difference for PFS. Treatment was well tolerated with expected high rates of grade 3/4 lymphopenia, and overall a modest toxicity rate. Conclusions: The results indicate that the addition of CRA to ddTMZ may be detrimental in patients with newly diagnosed GBM. This study demonstrated the utility of the factorial design in efficiently testing drug combinations, the impact of individual agents in these combinations as well as doublet vs. triplet regimens and supports its utility in testing combinations of targeted agents.
Intraventricular (IVe) topotecan for women with neoplastic meningitis (NM) associated with "responsive" malignancies.
Authors: Jaeckle Kurt A. , Anderson S. Keith , Willson Anna , Colon-Otero Gerardo , Patel Tejal Amar , Perez Edith A.
Published: March 2020

2015

Background: A prior study of intra-CSF topotecan (TOPO) for unselected pts w/ NM reported PFS 6 mo of 19%, and OS of 15 wks (Groves, NeuroOncol 2008;10:208). We postulated that greater activity might occur in pts w/ malignancies considered sensitive to topoisomerase inhibitors. Methods: We reviewed outcome of women with NM and adenocarcinoma of the breast, ovary or lung receiving IVe TOPO (0.4 mg 2x/wk x 4wk, Q wk x 4, Q 2wk x 2, Q mo x 3, Q 2mo x 3, and Q 3mo x 4) until progression (PROG) or adverse events (AE). All had baseline CSF cytology, and MRI of brain and spine. CSF cytology was obtained at each treatment (Rx), and brain/spine MRI Q 3mo. Neuro-specific PROG was defined as recurrent + CSF cytology; PROG of NM on MRI; all-cause neurologic worsening; pt refusal; or death. PFS/OS were measured from 1st TOPO Rx. All pts signed consent; the study was IRB approved. Results: 17 women (breast -12; lung-3; ovary - 2) were treated via Ommaya reservoirs; 7 (41%) had VP shunts w/ valves, adjusted for Rx. Median (med) age was 53 (41-79), and KPS 70 (50-90). At presentation, 11(65%) had + CSF cytology and 14 (82%) had NM on MRI [brain-11 (65%); spine-10 (59%)]. 15 (88%) had no prior intrathecal Rx. 13 pts (76%) received focal RT for CNS disease, and 8 (47%), chemotherapy for extracranial disease. Med.number of Rx were 13/pt (range, 3-50); med. duration of TOPO Rx was 14 wks (range, 1-109). Med. neuro-specific PFS was 13 wks; PFS6 was 41%, and PFS12, 29 %. Med. OS was 33 wks (range, 5-180), w/ 4 alive at 13+, 30+, 33+, and 180+ wks. 4 pts (24%) lived > 95 wks. Of 11 w/ baseline + CSF cytology, 7 (64%) cleared CSF of malignant cells (med. duration clear = 47 wk (range, 9-104). AE included arachnoiditis (18%), leukoencephalopathy (18%), and Ommaya infections (12%). Rx was stopped for neuro PROG (29%); systemic PROG (23%); refusal (18%); AE (12%); or persistent negative CSF (6%); 12% are still on Rx. Conclusions: Promising activity of IVe TOPO was observed in women with NM from breast, lung and ovarian cancer. PFS 6 and 12, OS and cytologic response were twice that noted in prior studies of NM pts w/ unselected malignancies. This data supports our plan for a phase II study targeting this select cohort.
IDH1 status and survival benefit from surgical resection of enhancing and nonenhancing tumor in malignant astrocytomas.
Authors: Cahill Daniel P. , Beiko Jason , Suki Dima , Prabhu Sujit S. , Weinberg Jeffrey , Lang Frederick F. , Gilbert Mark R. , Rao Ganesh , McCutcheon Ian E. , Aldape Kenneth D. , Sawaya Raymond
Published: March 2020

2019

Background: The value of maximal safe resection for malignant astrocytic gliomas (AA, WHO Grade III anaplastic astrocytoma and GBM, WHO Grade IV glioblastoma) has sometimes been controversial, because of confounding between measures of surgical resection and other prognostic factors. IDH1 gene mutations are associated with improved survival in glioma patients, and are thought to identify tumors with a distinct molecular evolutionary origin. We sought to determine the prognostic impact of surgical resection on survival after controlling for IDH1 status in malignant astrocytomas. Methods: Clinical parameters including preoperative and postoperative MRI-based tumor volume were recorded prospectively on 407 malignant astrocytoma patients – AA (n=157) and GBM (n=250). IDH1 status was assessed by sequencing and R132H-specific immunohistochemistry. Results: The measures of surgical resection associated with longer survival differed between IDH1 wild-type and mutant tumors. In multivariate analyses of IDH1 wild-type tumors (controlling for age, Karnofsky performance score, tumor location, and tumor grade), residual postoperative enhancement was associated with a median survival of 9.9 mo vs. 17.4 mo with no enhancement (HR=1.73, 95% CI, 1.19-2.52, p=.004). Residual non-enhancing disease, however, was not associated with survival (scored as continuous volumetric cc, 95% CI 0.99-1.01, p=.608). These results are consistent with prior studies of GBM, which are largely IDH1 wild-type lesions (Lacroix et al., J Neurosurg 95:190-8, 2001). In contrast, in IDH1 mutant tumors, both residual enhancing (HR=7.93, 95%CI 1.14-55.22, p=.037) and non-enhancing (HR=1.03, 95% CI 1.01-1.05, p=.005) postoperative tumor burden were associated with worse survival. Conclusions: These data suggest surgical resection in malignant astrocytic gliomas may be individualized based on IDH1 genotype. IDH1 mutant tumors have a better baseline overall prognosis, therefore more aggressive surgery and tolerance of temporary peri-operative neurologic deficits can be weighed in an attempt to gain the additional survival benefit that appears to be associated with reducing non-enhancing tumor burden.
Genomic characterization of meningiomas.
Authors: Brastianos Priscilla Kaliopi , Horowitz Peleg , Santagata Sandro , Jones Robert T. , McKenna Aaron , Ligon Keith , Palescandolo Emanuele , Van Hummelen Paul , Getz Gad , Hahn William C , Dunn Ian F. , Beroukhim Rameen
Published: March 2020

2020

Background: Understanding the genetic alterations in cancer has lead to groundbreaking discoveries in targeted therapies. Meningiomas are among the most common primary brain tumors, with approximately 18,000 new cases diagnosed annually. Though certain genes have been associated with the development of meningiomas, most notably the tumor suppressor gene neurofibromatosis 2 (NF2), the genetic changes that drive meningiomas remain poorly understood. Our objective was to comprehensively characterize the somatic genetic alterations of meningiomas to gain insight into the molecular pathways that drive this disease. Methods: Fresh frozen specimens and paired blood were collected from 16 consented patients. DNA was extracted from regions of high tumor purity determined by evaluation of H&E slides. Whole-genome sequencing from 10 tumor-normal pairs and whole-exome sequencing from 6 tumor-normal pairs was carried out. We performed an unbiased screen for point mutations, insertions-deletions, rearrangements and copy-number changes across the exomes and genomes. Recurrent (potential driver) events were then analyzed with additional algorithms for statistical significance. Results: Alterations in the NF2 gene were present in 9 of 16 patients. Multiple novel rearrangements and recurrent non-NF2 mutations were also identified in the cohort. Massive genomic rearrangement termed chromothripsis was observed in chromosome 1 in one sample, which has never previously been described in meningiomas, and represents a potentially new mechanism of malignant transformation in this tumor type. Conclusions: While NF2 mutations appear to drive a majority of these tumors, our analysis has uncovered additional potential driver genes in meningiomas, particularly in those tumors negative for NF2 alterations. To our knowledge, this is the first study to comprehensively characterize the totality of somatic genetic alterations in meningiomas, and brings us closer to the development of new therapeutic targets for this disease.
Pilocytic astrocytomas in adults: A retrospective study of 125 patients.
Authors: Theeler Brett James , Sadighi Zsila Sousan , Ellezam Benjamin , Puduvalli Vinay K.
Published: March 2020

2022

Background: Pilocytic astrocytomas (PAs) are rare primary brain tumors in adults. The natural history is poorly defined with the largest published series including only 30-40 patients. To better define clinical characteristics of adult PAs, we present an analysis of adult PAs at MD Anderson Cancer Center. Methods: We conducted an IRB-approved, retrospective chart review of patients ≥18 years diagnosed with PAs from 1990-2011 at our institution. Results: We identified 125 patients with a median age of 29 (range 18-72y), female to male ratio of 1.7:1, and median follow-up of 62 months. The most common anatomic locations were brainstem 22%, cerebellum 14%, intraventricular 14%, and cortical/lobar 14% (36% other locations). 21% of cases had an initial pathologic diagnosis discordant with neuropathologic review at our institution. Comorbidities included neurofibromatosis type 1 (5 pts) and a history of asthma or autoimmune disease (14%). 38 patients had a gross total (GTR), 55 a sub-total resection (STR) and the remainder a biopsy. 62 patients were treated with radiotherapy (RT): 45 as adjuvant (adj), 17 at recurrence; 2 received RT in both adj and recurrent settings. 73 (58%) patients were stable after initial treatment (surgery +/- adj RT). Median progression free survivals (mPFS) based on upfront treatment as follows: GTR only (n=30) - not been reached, STR only (n=32) 226.6 months, GTR plus adj RT (n=8) 13.2 months, STR plus adj RT (n=23) is 52.4 months (p=0.026, logrank test for trend). At last follow-up, 77% of all patients were stable and 13% were deceased. Conclusions: This is the largest series of adult PAs reported to date. Extracerebellar location, slight female predominance, and history of allergic/autoimmune disease were associations found in this cohort. Neuropathologic review is essential to avoid misdiagnosis. A significant subset of adult PAs behave more aggressively than expected for a grade I tumor with over 40% of patients experiencing recurrence after initial treatment. Adj RT following GTR or STR did not improve PFS, and a trend towards worse PFS with adj RT was observed although these analyzed subgroups were small. These results may help provide a framework for prospective studies in this tumor type.
Impact of adjuvant anti-VEGF therapy on treatment-related pseudoprogression in patients with newly diagnosed glioblastoma receiving chemoradiation with or without anti-VEGF therapy.
Authors: Pinho Marco C , Polaskova Pavlina , Jennings Dominique , Wen Patrick Y. , Jain Rakesh K. , Sorensen A. Gregory , Gerstner Elizabeth Robins , Batchelor Tracy
Published: March 2020

2025

Background: Chemoradiation (CRT) can significantly modify the appearance of glioblastoma (GBM) on MRI, especially within the 3-month window after CRT. Pseudoprogression (PsP) is an increasingly recognized phenomenon in this scenario, and is thought to be secondary to increased permeability of the tumor vessels from irradiation, possibly enhanced by temozolomide (TMZ). We sought to determine if the addition of a VEGF signaling inhibitor (cediranib) during and after CRT had an impact on the frequency of PsP, by comparing two groups of patients with newly diagnosed GBMs. Methods: Two groups of patients enrolled in IRB-approved trials underwent serial MRIs at baseline, weekly during CRT and monthly thereafter. The control group received radiation plus TMZ, while the other group (CED) also received cediranib until progression (which was defined by RANO criteria) or toxicity. Patients that progressed up to 3 months after CRT were considered to have apparent progression (AP) and kept on treatment. Lesions that subsequently stabilized/regressed were classified as PsP, while those that maintained growth despite treatment were classified as true early progression (EP). Results: Forty patients were enrolled in CED and 11 as controls. Ten patients from CED and three controls were excluded due to treatment discontinuation before 3 months (drug-related toxicity and enrollment in post-CRT trials respectively). Three patients in CED (6%) had AP (all confirmed as EP) and no patients fulfilled criteria for PsP. Six patients from control (54%) had AP; 3 (27%) were eventually classified as EP and 3 (27%) as PsP. The frequency of PsP was significantly higher in the control group (p=0.0086). Conclusions: The addition of a VEGF inhibitor as part of adjuvant treatment in this cohort of glioblastoma patients prevented the development of early treatment-related effects (PsP). Suppressing the edema and mass effect that accompanies PsP may improve the tolerability of treatment. Additionally, this effect may be exploited as a strategy to make chemoradiation feasible in patients with large, unresectable tumors and/or poor baseline performance status.
A single-institution phase II trial of radiation (RT), temozolomide (TMZ), erlotinib, and bevacizumab for initial treatment of glioblastoma (GBM).
Authors: Clarke Jennifer Leigh , Molinaro Annette M , Butowski Nicholas A. , Chang Susan Marina , Phillips Joanna J , Costa Bruno M , Costello Joseph F , Rabbitt Jane E , Kivett Valerie A , DeSilva Ashley A , Prados Michael
Published: March 2020

2026

Background: Standard treatment for GBM includes surgery followed by RT and TMZ, rarely a curative treatment. Both the EGFR and VEGF pathways are frequently overactive in GBM; we previously added erlotinib, an EGFR inhibitor, to RT and TMZ, with modest improvement in survival. The present study combined bevacizumab, a VEGF inhibitor, and erlotinib with RT and TMZ, with the goal of improving overall survival (OS). Methods: Treatment consisted of fractionated RT to 60 Gy with daily TMZ at 75 mg/m2/d and erlotinib 150-200 mg/d (or 500-600 mg/d for patients on enzyme-inducing antiepileptic drugs [EIAEDs]). Bevacizumab was given at 10 mg/kg every 2 wks, starting ≥ 4 wks after surgery. After RT, adjuvant TMZ was given at 200 mg/m2/d x 5d per 28d cycle, with unchanged erlotinib and bevacizumab doses. Treatment was continued until progression or for 12 mo, with an option to continue for up to 24 mo. OS and progression-free survival (PFS) from initial diagnosis were compared against institutional historical controls (recent prior up-front clinical trials including RT and TMZ). Results: 59 pts were enrolled; 12 were receiving EIAEDs. Median age was 54 yrs; median KPS was 90. 33% underwent gross total resection and 53% subtotal resection. 16 pts had tumors with methylated MGMT (mMGMT), 26 with unmethylated MGMT (umMGMT), and 17 with unknown status. The most frequent related grade 3/4 AEs were lymphopenia (68%) thrombocytopenia (24%), neutropenia (10%), diarrhea (14%), weight loss (14%), and fatigue (12%). 1 pt died of aspergillosis. Median OS and PFS were 19.8 mo and 13.5 mo, respectively, vs. 18 mo and 8.6 mo for the historical control. The hazard ratio (adj for age, KPS, and extent of surgery) for PFS was 0.7 (95% CI 0.49-0.99, p=0.04). Median OS in pts with mMGMT was 20.9 mo, vs. 17.5 mo in pts with umMGMT; median PFS was 14 mo vs. 12.4 mo, respectively. Conclusions: The combination of bevacizumab, erlotinib, TMZ, and RT showed improved PFS but not OS vs. historical controls. Though the numbers were small, PFS and OS for pts with umMGMT were not significantly different from pts with mMGMT, suggesting that this combination may be more effective than standard therapy alone for pts with unMGMT tumors.