bluuebunny/crossref_metadata_2025 huggingface dataset:
p53 mutations in advanced cancers: Clinical characteristics and outcomes in a phase I setting.
Authors: Said Rabih , Hong David S. , Wheler Jennifer J. , Naing Aung , Falchook Gerald Steven , Fu Siqing , Janku Filip , Zinner Ralph , Piha-Paul Sarina Anne , Warneke Carla L , Tsimberidou Apostolia Maria , Kurzrock Razelle
Published: March 2020

10607

Background: p53 mutation is one of the most common mutations in human tumors and plays an important role in apoptosis, genomic stability and inhibition of angiogenesis. Methods: We retrospectively reviewed 121 consecutive patients (pts) with solid tumors referred to the Clinical Center for Targeted Therapy (Phase I program) who were tested for p53 mutation, and compared clinical characteristics and outcomes in p53 positive vs. wild-type (wt) pts. Results: Of the 121 tested pts, 65 (53.7%) were p53 mutation-positive. The presence of p53 mutation was not associated with sex and race. Tumors with p53 mutation metastasized more often to the liver (44 pts (67.7%) with mutated p53 vs. 26 pts (46.4%) with wt p53, p=0.0264); there was no difference in metastasis to the bones, lungs, brain, soft tissues and adrenals. p53 mutation also showed a trend toward an association with PTEN-loss (13 out of 43 (30%) with p53 mutated vs. 4 out of 37 (11%) with wt p53, p=0.053). Among pts with the p53 mutation, the best median progression-free survival (PFS) prior to phase I trial entry was 10.97 months (range 0.85–29.04 months) when the treatment regimen included bevacizumab and 4.37 months (range 0.92–14.98 months) when the treatment did not include bevacizumab (P=0.0046). Among patients with wt p53, there was no significant difference in PFS between bavacizumab-containing regimens and regimens without bevacizumab. The median OS from diagnosis was 7.7 years (95% CI 6.32–9.84 years) vs. 11.8 years (95% CI 10.37 years, not attained) for p53 mutant vs. wild-type disease (p = 0.03). Univariate analysis for OS from diagnosis showed that mutated p53, Hispanic race (vs. Caucasians) and the shorter time from diagnosis to metastasis were associated with a worse prognosis. Conclusions: Tumors with p53 mutation have a more aggressive clinical behavior, metastasize more to the liver and may have a higher rate of PTEN loss compared to tumors with wt p53; In addition, anti-angiogenic agents may be of therapeutic value in p53-mutated pts.
Serum activinA and TGF-β as biomarkers of breast cancer bone metastasis behavior.
Authors: Addison Christina L. , Bouganim Nathaniel , Zhao Huijun , Vandermeer Lisa , Mazzarello Sasha , Mallick Ranjeeta , Berghout Koralee , Goss Glenwood D. , Clemons Mark
Published: March 2020

10620

Background: Bisphosphonates (BP) are prescribed to pts with metastatic bone disease every 3-4 weeks regardless of individual risk for skeletal related events (SREs). In an era of personalized medicine this “one size fits all” approach is not appropriate and novel markers of SRE risk are required. TRIUMPH is an ongoing clinical trial evaluating 12 weekly IV BP therapy for 1 year in women with low risk bone metastases from breast cancer (BC) as defined by the bone resorption marker C-telopeptide (CTx,) levels <600 ng/L. This sub-study evaluated the utility of novel biomarkers in better predicting the risk of developing SREs. Methods: Serum obtained from pts at baseline and 6 weeks post-entry were analyzed for tumor growth factor-β (TGF-β) and activinA levels by ELISA (sensitivity ~15-30 pg/ml). Levels were correlated with pt parameters including time to development of bone metastasis, and number of previous SREs using linear regression analysis. Changes in levels of biomarkers from baseline to 6 weeks were used to calculate odds ratios using logistic regression analysis. Results: Baseline activinA correlated with baseline CTx and bone specific alkaline phosphatase (p=0.004 and p<0.0001 respectively). Baseline activinA also correlated with weight (p=0.02), BMI (p=0.007) and trended towards total number of prior SREs (p=0.07). Baseline TGF-β correlated with pt age (p=0.02), weight (0.006), BMI (p=0.0005) and duration of metastatic bone disease (p=0.004), but did not correlate with any other biomarker. Change in activinA (baseline to week 6) was the only biomarker that trended to predict coming off study early (p=0.053) as per protocol (i.e. CTx>600 ng/ml, SREs or pt/physician choice). Conclusions: Baseline levels of activinA trended to predict incidence of SREs in patients with bone metastases, and changes in levels from baseline to 6 weeks trended to predict coming off study early. These findings warrant future studies in BC pts assessing activinA as a predictor of risk associated with breast cancer bone metastases. This study was conducted with the support of the Ontario Institute for Cancer Research through funding provided by the Government of Ontario, and with funding from the Ontario Chapter of the Canadian Breast Cancer Foundation.
Diurnal proteomics and biomarker discovery in indolent versus aggressive chronic lymphocytic leukemia patients.
Authors: Bjarnason Georg A. , Spaner David , Ackloo Suzanne , Li Jieran , Zhu Pei Hong , Nuin Paulo S , Geraci Joseph , Dharsee Moyez , Martino Tami , Wang Cathy , Evans Kenneth R.
Published: March 2020

10622

Background: In rodents, 10-20% of the genome has a 24-hour (h) rhythm in RNA expression. A molecular clock consisting of transcription / translation feedback loops of clock-genes controls this rhythmicity. In a microarray study (Affymetrix HG_U133_Plus2 chip) on RNA extracted from CLL cells sampled every 4 hours over 24 hours (6 samples) from 3 male (M) and 6 female (F) patients (pts) with chronic lymphocytic leukemia (CLL) we found 15,094 and 13,415 rhythmic transcripts (Cosinor analysis) in M and F respectively, only 6,629 of which were common to both M and F. We hypothesized that these gender differences in rhythmic RNA expression might have clinical implication for biomarker discovery with some important biomarkers only found at a certain times of day and with gender differences. Methods: Sampling was performed again at 6 time points in M and F CLL patients with indolent CLL (10pts, 5 M, 5F) and aggressive CLL (10 pts, 5M, 5F). An 8-plex iTRAQ kit was employed for mass spectrometry (MS) based relative quantification. Each iTRAQ block comprised all time-points for a single patient including a universal control. Results: At least 300 proteins were identified at a 95% confidence level in each iTRAQ experiment. Of these, 74 proteins displayed significant change between aggressive and indolent pts in 24-hour average or single time point normalized expression based on a non-parametric U-test (p<0.05). The JTK_CYCLE algorithm was used to detect 24-hour rhythmic patterns in the proteomic datasets. Significant rhythmic expression was found for 44 proteins (p<0.10) identified by iTRAQ. Data for each time point were independently analyzed using an in-house Butterfly clustering algorithm based on discrete dynamical systems. The 4 PM time point was found to be optimal for stratifying aggressive and indolent disease. Cellular pathways with significant association to differentially expressed proteins included PPAR signaling, fatty acid metabolism, and granzyme-A signaling. Confirmation by selected reaction monitoring (SRM) MS is ongoing. Conclusions: Rhythmic protein expression may have clinical implications for biomarker discovery.
Early changes in angiogenesis and hypoxia following bevacizumab therapy in primary breast cancer.
Authors: Mehta Shaveta , Hughes Nicholas Peter , Jubb Adrian M. , Turley Helen , Han Chen , Li Sonia Patricia , Taylor N Jane , Padhani Anwar R. , Adams Rosemary Frances , Makris Andreas , Harris Adrian L.
Published: March 2020

1066

Background: Bevacizumab (BV), a monoclonal antibody directed against vascular endothelial growth factor (VEGF), is an approved anti-angiogenic agent, but despite its widespread use, little is known about how tumours develop resistance to BV. We have conducted a window-of-opportunity study in which BV is administered as a short-term first-line treatment for primary breast cancer (PBC) patients, and assessed histological markers of tumour angiogenesis and hypoxia before and after therapy. Methods: 47 patients with locally advanced breast cancer were prospectively enrolled. Informed consent was obtained from all patients. A single infusion of BV (15 mg/kg) was given 2 weeks before starting neoadjuvant chemotherapy. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and core biopsies for immunohistochemistry (IHC) analysis were performed immediately prior to and 2 weeks after BV. 36 patients with invasive ductal carcinoma and good quality MRI scans and core biopsies were included in this analysis. Wilcoxon rank test and Spearman’s correlation test were used for statistical analysis. Results: IHC revealed a significant upregulation of carbonic anhydrase 9 (P = 0.04) and hypoxia inducible factor-1a (P = 0.001) following BV therapy along with a significant reduction in plasmalemma vesicle associated protein (PLVAP) (p=0.01) and Ki67 (p= 0.006). DCE-MRI analysis revealed a significant reduction in vessel permeability and blood flow following BV, as measured by a decrease in the forward transfer constant Ktrans (P < 0.0001) and the reverse rate constant kep (P < 0.0001). In addition, we found a significant negative correlation between CA9 levels and median Ktrans at baseline (Spearman’s rho = -0.46; P = 0.01). Conclusions: Using combined DCE-MRI and IHC analysis, we found that PBC patients treated with single-agent BV showed a decrease in markers of tumour angiogenesis, together with a corresponding increase in tumour hypoxia. Our results suggest that tumour hypoxia may be a key mechanism governing the early onset of resistance to BV therapy, and argue for the use of suitable combination therapies to overcome the resistance and ultimately improve patient survival.
Outcomes of 47 patients with human immunodeficiency virus infection treated for breast cancer: A 20-year experience.
Authors: Ochoa Roberto Enrique , Kyriakopoulos Christos , Hurley Judith
Published: March 2020

1071

Background: Patients (pts) with Human Immunodeficiency Virus (HIV) are living longer and non-AIDS defining malignancies have been increasingly reported in these patients. Methods: Retrospective review identified 47 pts with breast cancer (BC) and HIV who were seen at the University of Miami Sylvester Comprehensive Cancer Center/Jackson Memorial Hospital between January 1999 and June 2011. Results: Pt characteristics: 46 female, 1 male, mean age 46 years (range 31-65). Race: African American 79%, Caucasian 21%. Ethnic: Hispanics 14%, non-Hispanics 86%. Premenopausal 68% postmenopausal 32%. Tumor characteristics: Stage: Tis 4%, Stage I: 6 % , Stage II: 38%, Stage III: 38%, Stage IV: 9%. ER positive (50%) her-2 positive (15%), Triple negative (21%). HIV characteristics: 36 pts with HIV before or concurrent with the diagnosis of BC. 6 pts diagnosed with HIV within 1 year of BC diagnosis. HIV dx date unavailable in 5 pts. 27% had AIDS. CD4 counts (in cells/µL)were: > 500 (23%); 201-500 (37%), 51 – 200 (20%) < 50 (20%). 15 pts were diagnosed with BC in preHAART era. Of those dx with BC after 1996, 60% were on HAART. BC treatment: 43 pts had localized disease. 32 underwent modified radical mastectomy, 8 breast conservation and 3 pts refused surgery. 26 pts received curative or palliative chemotherapy. Complications of BC treatment: serious side effects were reported in 11 (42%) including neutropenic fever/sepsis (10 pts), ARDS (1 pt). Zoster infection was reported in 12% of the pts. 3 patients developed rapidly progressive and fatal AIDS within 6 months of completion of chemotherapy. Survival: See Table. Conclusions: BC in patients with HIV infection spans the spectrum of BC presentations. Hormonal therapy, surgery and radiation therapy were well tolerated. Infectious complications were common in patients treated with chemotherapy and routine use of growth factors and prophylactic acyclovir should be considered. [Table: see text]
Comparing the outcome between multifocal, multicentric, and bilateral breast cancer and the impact of guideline-adherent adjuvant treatment: A retrospective multicenter cohort study of 5,308 patients.
Authors: Schwentner Lukas , Wolters Regine , Novopashenny Igor , Wischnewsky Manfred , Kreienberg Rolf , Wöckel Achim ,   BRENDA Study Group
Published: March 2020

1078

Background: Beside unifocal-unilateral (UU) breast cancer (BC) there are several subtypes including multifocal, multicentric and bilateral BC. This study tries to answer the following questions:(1) Does localization (multifocal/multicentric/bilateral) influence outcome concerning BC mortality? (2) Is there an impact of guideline-adherent adjuvant treatment in these BC subtypes? Methods: This German multi-center retrospective cohort study called BRENDA included 5277 patients obtained from 1992 until 2005. The definition of guideline adherence was based on the German national S3 breast cancer guideline (2004). Results: 4085 (77.4%) were UU, 698 (13.2%) multifocal, 282 (5.3%) multicentric and 212 (4.0%) bilateral BC. RFS in multifocal [p=0.003; HR=1.35 (95% CI: 1.11-1.65)], multicentric [p<0.001; HR=1.76 (95% CI: 1.31-2.34)] and bilateral [p<0.001; HR=2.28 (95% CI: 1.76-2.97)] BC was significantly lower compared to unilateral-unifocal BC. Concerning OAS we found only a borderline difference between UU and unilateral-multifocal [p=0.057; HR=1.22 (95% CI: 0.99-1.48)], but a significant difference between multicentric [p= 0.018; HR=1.42 (95% CI: 1.06-1.90)] resp. bilateral [p<0.001; HR=2.87 (95% CI: 2.21-3.74)] and UU-BC. There was a significant impact by guideline adherent adjuvant therapy [UU: p<0.001, HR=2.76,95%C.I.:2.25-3.38], [unilateral-multifocal: p=0.001, HR=2.04,95%C.I.:1.33-3.14], [unilateral-multicentric: p=0.020, HR=2.13,95%C.I.:1.13-4.01] and [bilateral: p=0.042, HR=2.10,95%C.I.:1.03-4.31]. After stratifying for 100% guideline adherent treatment and adjusting for age, tumor size, nodal status and grading there was no significant difference in RFS/OAS in patients with multifocal [p=0.282/p=0.610], multicentric [p=0.829/p=0.609] or bilateral BC [p=0.457/p=0.773] compared to patients with UU-BC. Conclusions: Patients with multicentric and bilateral BC have primarily a worse prognosis in terms of RFS and OAS. However if guideline adherent adjuvant treatment was applied it was no more possible to demonstrate significant differences in survival.
Bevacizumab, etoposide, and cisplatin (BEEP) in brain metastases of breast cancer progressing from radiotherapy: Results of the first stage of a multicenter phase II study.
Authors: Lu Yen-Shen , Chen Wei-Wu , Lin Ching-Hung , Tseng Ling-Ming , Yeh Dah-Cherng , Wu Pei-Fang , Chen Bang-Bin , Chao Ta-Chung , Tsai Yi-Fang , Huang Shu-Min , Shih Tiffany Ting-Fang , Cheng Ann-Lii
Published: March 2020

1079

Background: With a general prolongation of survival, brain metastasis (BM) has become a common complication of breast cancer. However, management of BM remains a severe challenge. We hypothesized that bevacizumab (BE) could significantly enhance drug delivery of etoposide (E) and cisplatin (P), two of the cytotoxic agents that have moderate activity in BM of breast cancer, to brain tumors and thereby improve the efficacy. Methods: Breast cancer patients (pts) with BM progression after whole brain radiotherapy (WBRT) were enrolled. Pts received BE 15 mg/kg day 1, and E 70 mg/m2/day, days 2-4, P 70 mg/m2/day, day 2, every 21 days for a maximum of 6 cycles. The primary endpoint was a centrally assessed CNS objective response (CNS-OR) defined as a ≥50% reduction in the volumetric sum of all measurable CNS lesions in the absence of increasing steroid use, development of new CNS lesion, or progressive neurologic symptoms. Using a Simon’s optimal two-stage design with 15% as a minimum interest in CNS-OR rate (by intent to treat analysis), 11 pts were needed at the first stage; and a total of 31 evaluable for the whole study. Results: Among 16 pts enrolled from Jan 2011 to Jan 2012, 12 pts were evaluable for treatment response at the time of abstract submission. Median age was 55 (range 34-66); 1 pt was ER+HER2-, 5 pts were HER2+, and 6 pts were ER-HER2-. The median treatment cycles were 4.5 (range 1-6). Nine of 12 pts (75%; 95%CI 42.8-94.5) achieved CNS-OR including 6 pts (50%) with ≥80% and 3 pts (25%) with 50-80% CNS volumetric reduction, respectively. Two pts had non-CNS disease progression while CNS tumors remained under control. The median CNS progression free survival was 6.6 months (95% CI 0.8-12.4). Grade 3 /4 toxicities included neutropenia, leukopenia, anemia, and platelet in 13 (25.5%), 6 (11.8%), 2 (3.9%), and 2 (3.9%) cycles, respectively. Seven pts (58.3%) had received dose reduction to E 60 mg/m2 and P 60 mg/m2. Early reporting of this study was approved by Data and Safety Monitoring Committeedue to an extremely promising result. Conclusions: BEEP regimen has a significant anti-tumor effect for BM of breast cancer which progresses after WBRT.
Validation of NAD(P)H quinone oxidoreductase (NQO1) expression as a predictive factor for adjuvant chemotherapy benefit in patients with early breast cancer.
Authors: Arnedos Monica , Goubar Aicha , Sprott Kam M. , Jiang Chunsheng , Suschak Jessica , Weaver David T. , Delaloge Suzette , Conforti Rosa , Andre Fabrice
Published: March 2020

1091

Background: NAD(P)H:quinone oxidoreductase-1 (NQO1) has important antioxidant functions by stabilizing p53 from proteasomal degradation. NQO1 knockdown is associated with higher susceptibility to oxidative stress. Polymorphisms suppressing NQO1 are predictors of poor survival in patients with breast cancer (BC) treated with anthracyclines. BC cell lines with impaired NQO1 function showed resistance to epirubicin chemotherapy (CT) independently of p53 status suggesting NQO1 as predictive factor for anthracycline benefit. In this study we hypothesized that lack of NQO1 could predict resistance to anthracycline-containing CT in patients with early breast cancer (EBC). Methods: Patients were identified from two French multicentric trials that randomized patients with EBC to adjuvant anthracycline-based CT vs no CT between 1988 and 1995. NQO1 was determined in TMAs by automated quantitative assessment of immunofluorescence (On-Q-ity Inc, Waltham). Cut-off for positivity was the median value of NQO1 expression. Univariate and multivariate Cox regression models were performed. Treatment effect was assessed on long term overall survival (OS). Results: NQO1 expression was assessed in 600 patients. 75% were postmenopausal, had more often grade II (62%), LN-negative (58%) and ER-positive (67%) BC. Higher NQO1 expression was observed in postmenopausal (P=0.02) patients. No relation with other clinicopathological factors (grade, LN or ER) was observed. Effect of adjuvant CT on death rates was dependant on NQO1 level. Hazard ratio (HR) for treatment efficacy at the four quartiles of NQO1 were 1.07 (95%CI: 0.69-1.7), 0.87 (0.64-1.19), 0.66 (0.45-0.97), 0.46 (0.22-0.95) (interaction test: 0.1). Interaction test was statistically significant (0.02) when NQO1 expression was considered as binary variable with median value taken as cut-off. NQO1 remained predictive among ER+ patients only. HR for OS was 0.61 (0.36-1.02) and 1.25 (0.79-1.99) in patients with high and low NQO1 respectively. Conclusions: This study adds to the existing data suggesting NQO1 expression as an independent predictor of efficacy for adjuvant anthracycline-containing CT.
Analysis of pretreatment nonpharmacologic, pharmacologic factors, and yoga intervention on CINV outcomes in breast cancer patients undergoing adjuvant chemotherapy.
Authors: Usharani Malur R. , Raghavendra Rao M. , Gopinath Kodaganur Srinivasachar , S Ramesh Bilimagga , Diwakar Ravi B , Rao Nalini K , Ajaikumar Basavalinga S. , Nandini P K
Published: March 2020

1093

Background: Chemotherapy induced nausea and vomiting (CINV) is affected by both pretreatment patient factors, chemotherapy and antiemetic regimen and psychological interventions. In this study we evaluated the effects of mind body intervention such as yoga in modulating CINV outcomes controlled for the above factors. Methods: Chemotherapy naïve breast cancer patients with stage II and III disease participating in a randomized controlled trial comparing yoga (n=45) vs. supportive therapy (n=53) were assessed for CINV outcomes during adjuvant chemotherapy. Morrows Assessment of nausea and emesis was used to asses CINV symptoms including their frequency, severity and anticipatory nature. We developed a multiple regression analyses to test the role of intervention on CINV beyond that explained by the independent prognostic factors [age (<50/≥50 years), stage of disease (II vs III), menopausal status (pre vs post), antiemetic regimen (5HT3 antagonists vs. antidopaminergics), administration of anxiolytics (yes/ no) and type of chemotherapy regimen (FAC vs. CMF)] that were included in model A. Model B includes these six variables plus intervention (yoga vs. supportive therapy) in predicting nausea and vomiting outcomes. Results: Intervention emerged as a primary predictor for nausea frequency (β= -0.38, p=0.002), intensity (β= -0.44, p=0.001 ), anticipatory nausea frequency (β=-0.26 , p= 0.04) and intensity (β=-0.38 , p=0.004 ). Age group emerged as a primary predictor for anticipatory vomiting frequency (β=-0.39 , p=0.01 ) and secondary predictor for nausea frequency (β=-0.41, p= 0.006). Administration of anxiolytics emerged as a primary predictor for vomiting intensity (β=-0.40, p= 0.001) and secondary predictor for anticipatory nausea frequency (β=-0.26 , p= 0.05). Conclusions: Yoga intervention influences CINV outcomes when controlled for pretreatment and pharmacological factors during chemotherapy in breast cancer patients poorly controlled for nausea and vomiting.
Prevention of chemotherapy-induced damage to ovarian reserve by sphingosine-1-phosphate
Authors: LI Fang , Ozkaya Enis , Akula Komala , Desutter Petra , Oktay Kutluk
Published: March 2020

1097

Background: Chemotherapy agents such as cyclophosphamide (Cy) and doxorubicin (D) are known to compromise ovarian function. We have previously shown that these agents alter ovarian function by causing apoptotic death of primordial follicles and thereby causing diminishment of ovarian reserve (Cancer Research 2007; Aging 2011). While assisted reproduction techniques exist to preserve fertility there has been no proven approach to pharmacologic preservation of ovarian function. Sphingosine-1-Phosphate (S1P) is a naturally occurring ceramide-induced death pathway inhibitor. Here we investigated whether S1P can prevent Cy or D-induced apoptotic follicle death in mouse ovaries. Methods: Eight wk old NOD mice (n=23) were treated with Cy (75 mg/kg), Cy+S1P (200 μM), D (10 mg/kg), D+S1P or vehicle only (Control). S1P was administered via continuous infusion using a mini-osmotic pump beginning 3 hours prior to single dose chemotherapy injection for 72 hours. Ovaries were removed 72h later and serially sectioned, and stained with anti-caspase 3 (AC-3) antibody for the detection of apoptosis in primordial follicles. The ratio of apoptotic to total follicles was expressed as percentage in each group. Results: Both Cy and D resulted in significant increase in apoptotic follicle death compared to controls (48.2±11.6 vs. 28.2±8.9, p=0.016 and 46.4±5.4 vs. 24.8±5.2, p=0.004, respectively). Percentages of apoptotic follicles were similar between Cy and D-treated groups (48.2±11.6 vs. 46.4±5.4, P=NS) indicating that these agents were equally gonadotoxic. S1P treatment resulted in a significant decrease in the percentage of apoptotic follicles both in the Cy (25.6±3.5, P<0.011) and the D group (32.2±10.8, P< 0.013) compared to controls. In the S1P-treated groups, the percentages of apoptotic follicles were similar to those in untreated controls indicating that S1P completely blocked Cy and D-induced apoptotic follicle death. Conclusions: S1P can block apoptotic follicle death induced by highly cytotoxics agents. In addition, we showed that S1P can block follicle death by chemotherapy agents that act through different molecular mechanisms. If targeted delivery systems can be developed, S1P may hold significant promise in preserving fertility by pharmacological means.
Receipt of locoregional therapy among young women with breast cancer.
Authors: Freedman Rachel A. , Virgo Katherine S. , Labadie Julia , Partridge Ann H. , Keating Nancy Lynn
Published: March 2020

1100

Background: Although younger women with breast cancer have the most to gain from receipt of optimal care, few data are available regarding their receipt of locoregional breast cancer treatments. Methods: We identified 318,083 women aged 18-64 who were diagnosed with invasive breast cancer at hospitals reporting to the National Cancer Data Base, a large national cancer registry, during 2004-2008. We used multivariable logistic regression to assess the association of patient age with mastectomy vs. breast-conserving surgery (BCS), radiation with BCS, and post-mastectomy radiation (PMRT) with varying indications, adjusting for patient and tumor characteristics, area-level socioeconomic status, and insurance. Results: Overall, 4% of women were aged ≤35 and 7% were aged 36-40. Women aged ≤35 were significantly more likely to have mastectomy than BCS compared with women aged 56-60 (57% vs. 35%, adjusted odds ratio [OR] 1.97; 95% Confidence Interval [CI] 1.87-2.07) but were less likely to receive radiation if BCS was performed (69% vs. 80%, OR 0.77; 95% CI 0.73-0.82). For those who underwent mastectomy, although overall rates of PMRT receipt were low, women aged ≤35 were more likely to receive postmastectomy radiation (PMRT) despite the presence or absence of clinical indications for PMRT (OR 1.11; 95% CI 1.01-1.22 for strong indications, OR 1.71; 95% CI 1.53-1.91 for borderline indications, and OR 1.49; 95% CI 1.28-1.73 for no indications [all vs. ages 56-60]). Conclusions: Young women with breast cancer may not be receiving optimal locoregional therapy. We observed lower odds of radiation after BCS but higher odds of PMRT for young women regardless of indications for PMRT. Efforts are needed to further understand and improve the receipt of appropriate adjuvant radiation therapy among young women to improve their disease-free and overall survival.
Primary tumor resection to improve survival and local disease control in stage IV inflammatory breast cancer.
Authors: Akay Catherine Liebig , Ueno Naoto T. , Chisholm Gary B. , Hortobagyi Gabriel N. , Woodward Wendy A. , Alvarez Ricardo H. , Lucci Anthony , Bedrosian Isabelle , Kuerer Henry Mark , Hunt Kelly , Huo Lei , Babiera Gildy
Published: March 2020

1102

Background: Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer typically presenting with early metastasis. Optimal outcomes are achieved with multimodality treatment strategies in the non-metastatic setting. Data is limited, however, on the benefit of surgery in patients with metastatic IBC. We evaluated the effect of primary tumor resection on outcomes in patients with newly diagnosed stage IV IBC. Methods: We reviewed records of 172 patients with metastatic IBC treated at our institution from 1994 - 2009. All patients received systemic therapy with or without locoregional therapy (LRT). Patient demographics, receptor (ER) and HER2-neu status, grade, histology, presence of lymphovascular invasion, margin status, number of distant disease sites, pathologic response of primary tumor and clinical response to systemic therapy (CRS) at distant disease sites were recorded. Overall survival (OS), distant progression-free survival (DPFS), and chest/skin involvement at last follow-up were evaluated. Kaplan-Meier survival analyses, univariate (UV) and multivariate (MV) logistic regression models were used. Chest/skin involvement was compared between groups using Kruskal-Wallis test. Results: Seventy-nine (45%) patients underwent primary tumor resection. Average age was 51 (22-78). Median live-patient follow-up was 33 months. OS and DPFS were significantly better for patients who underwent LRT versus none (p<0.0001). Factors associated significantly for improved DPFS on MV analysis were ER and HER2-neu status (HR 0.61,0.60 p=0.02,0.05 ,respectively), LRT (HR .38, p=0.002) and CRS (HR 0.62, p=0.03). ER status (HR .45, p<0.001), LRT (HR .30, p<0.001) and CRS (HR 0.54, p=0.02) were significant predictors for higher OS on MV analysis. At last follow up, chest/skin involvement was moderate/severe in 11% of patients in LRT group versus 35% of patients in no LRT group (p<0.0001). Conclusions: This latest retrospective study demonstrates metastatic IBC patients who undergo LRT in addition to systemic therapy may have improved survival and local control outcomes. CRS may be used to guide LRT. A prospective randomized trial is needed to validate these findings.
Can primary tumor markers of cancer-initiating cells predict lymph node positivity in breast cancer patients?
Authors: Chagpar Anees B. , Neumeister Veronique , Lannin Donald R. , Rimm David
Published: March 2020

1121

Background: Cancer initiating cells, characterized by ALDH1 positivity and/or colocalization of ALDH1 and CD44, have been shown to be associated with poor prognosis in breast cancer patients. The prognostic value of these tumor markers with respect to prediction of lymph node (LN) status remains unclear. Methods: Tissue microarrays from a cohort of 223 breast cancer patients diagnosed between 2003 and 2007 were evaluated using the AQUA method for quantitative immunofluorescence for CD44 and ALDH1. These data, along with other clinicopathologic data, were correlated with LN positivity. Results: The median patient age of the cohort was 56 (range; 26-89), with a median tumor size of 1.5 cm. 72 (32.0%) patients were LN positive. The median number of LNs excised was 3 (range; 1-27). Of the LN positive patients, the median number of positive LNs was 1.5 (range; 1-24). Levels of CD44, ALDH1, and ALDH1 colocalizing with CD44 did not correlate with number of positive LNs (Spearman rho coefficients: -0.042, 0.131, and 0.058, respectively), nor overall LN status. Tumor size and lymphovascular invasion (LVI) were the only factors found to be significantly correlated with LN status. Conclusions: While ALDH1 colocalized with CD44 has been found to be associated with poor prognosis in breast cancer patients, these markers do not predict LN status. Given that the only factors that reliably predict LN status are tumor size and LVI, further work is required to find primary tumor markers that may predict LN status in order to spare patients axillary surgery. [Table: see text]
Clinical findings and outcomes from MRI staging of breast cancers in women.
Authors: Raghavendra Akshara , Ricker Charite Nicolette , Ji Lingyun , Church Terry , Tang Sujie , Larsen Linda , Sheth Pulin , Tripathy Debu
Published: March 2020

1124

Background: For patients diagnosed with breast cancer, case series have shown that staging MRI can detect occult breast cancers in 1-10% of cases. Prevalence and risk factors in underserved populations remain unclear. Methods: We performed a retrospective analysis of all patients, newly diagnosed, with breast cancer who had a preoperative staging MRI seen at Norris Comprehensive Cancer Center and LAC +USC, that cares for an underserved and minority population, from 2006 to 2011. Demographic, clinicopathologic and imaging data were obtained through a review of electronic records. Non index lesions were defined as those not known to be malignant, not presenting with clinical, mammographic or ultrasound findings, in a different quadrant and given an MRI BIRADS score of 4 or 5. Results: A total of 718 patients were analyzed and 148 patients (21%) had a total of 187 non index lesions; 63% were ipsilateral, 26% contralateral and 11% bilateral. As initial evaluation of non-index ipsilateral lesions, 71 (38%) had biopsy, 24 (13%) had excision and 34 (18%) had mastectomy. For contralateral non-index lesions, 41 (22%) had contralateral biopsy, 6 (3%) had excision and 11(6%) had mastectomy. Among all non index lesions, 111 (59%) were benign, 14 (7%) DCIS and 62 (33%) invasive cancer. Occult ipsilateral cancer was detected in 50 (6.9%) of patients and contralateral in 10 (1.4%) and bilateral in 6 (0.8%). Conclusions: The occult cancer detection rate with staging MRI was in this 9.2% of this diverse population. No clear risk factors were identified, with detailed factors, including BRCA status to be updated and reanalyzed. [Table: see text]
Changes in glucose, insulin, and insulin resistance from presurgery to post adjuvant treatment for breast cancer.
Authors: Guinan Emer M. , Hussey Juliette M. , Healy Laura , Carroll Paul A. , Kennedy John , Connolly E. M.
Published: March 2020

1511

Background: Elevated fasting insulin levels at breast cancer diagnosis are associated with increased risk of recurrence and reduced survival. (Goodwin PJ, et al. JCO. 2012;30:164-171) Weight gain related to adjuvant treatment coupled with sedentary activity habits may further alter insulin-related measures for breast cancer survivors. We present results from a prospective longitudinal study examining changes in insulin-related markers from pre breast cancer surgery to post adjuvant treatment. Methods: Subjects were recruited from St. James’s hospital, Dublin, Ireland at the time of breast cancer diagnosis (stage I-III). Fasting pre-surgery blood samples were drawn to measure insulin, glucose and glycosylated haemoglobin A1c (HBA1C). Insulin resistance was calculated using the homeostatic model assessment (HOMA). Subjects with no evidence of active cancer completed the same measurements 2-5 years later. Paired sample t-tests were used to measure changes from pre-surgery to post-adjuvant treatment. Statistical significance was set at P = .05. Results: Forty-four subjects (n = 22 postmenopausal) completed both measurements (mean ± SD age 54.1±8.6 years). Mean time since diagnosis to follow-up measures was 3.4±0.8 years. Adjuvant therapy included chemotherapy (n=37), radiotherapy (n=36), biological therapy (n=8) and concurrent hormonal therapy (n=37). There was a statistically significant increase in insulin (mean ± SD change 2.8±4.1mU/L, P=.000), insulin resistance (0.54±1.0, P=.001) and HBA1C (0.1±0.2 %, P= .003). Fasting glucose levels did not change (P = .06). Conclusions: Results indicate that patients with breast cancer experience significant increases in insulin, insulin resistance and HBA1C from pre-surgery to post adjuvant treatment. Elevated post-treatment insulin levels may further contribute to risk of breast cancer recurrence and mortality, while also predisposing to the development of cardiovascular disease and type 2 diabetes mellitus. Exercise and diet interventions are warranted in this population to improve markers of insulin resistance as a surrogate for improving breast cancer and overall health outcomes.
An alternative approach to identify women at risk for colorectal cancer.
Authors: Bruegl Amanda S. , Djordjevic Bojana , Westin Shannon Neville , Soliman Pamela T. , Brandt Amanda C. , Daniels Molly S , Lu Karen H. , Broaddus Russell
Published: March 2020

1513

Background: Hereditary colorectal cancer (CRC) is preventable; however, identification of individuals at sufficiently high risk to warrant heightened surveillance is difficult. Lynch Syndrome (LS) is an inherited cancer syndrome due to germline mutation in a DNA mismatch repair gene. For women with LS, the lifetime risk of endometrial cancer (EC) is 64% and CRC is 54%. Fifty percent of women with LS will present with EC or ovarian cancer prior to CRC. Therefore, women with LS associated EC represent an ideal group for CRC prevention. The optimal method to identify women with LS associated EC is not known. The purpose of this study was to determine the utility of Amsterdam II and Society of Gynecologic Oncology (SGO) Criteria (modified Bethesda criteria that use EC as the sentinel cancer) in identifying women with LS associated EC. Our ultimate goal is to identify women at increased risk of CRC. Methods: Immunohistochemistry (IHC) for DNA mismatch repair proteins and MLH1 methylation analyses were used to identify LS associated EC among 388 women. EC was designated as LS if there was loss of mismatch repair protein expression. Absence of MLH1 methylation was required to confirm LS in tumors with MLH1 protein loss. Results: Fifty-nine (15.2%) of the EC patients tested had LS. These patients are summarized in the table. Conclusions: Clinical criteria to detect LS identify 17/59 (29%) - 44/59 (74%) of women who present with EC first. EC with MSH2 loss is most likely to occur in younger women and women with positive family history of EC and CRC, features classically associated with LS. In general, the MSH6 mutation is associated with older age at diagnosis and fewer familial CRCs, however, we found a large number of MLH1 (50%) and PMS2 (86%) cases diagnosed at greater than 50 years with no family history of CRC. Our data suggest that classic clinical screening criteria are inadequate to detect patients with LS who present with EC, potentially missing up to 25% of these patients. [Table: see text]
Risk-reducing salpingo-oophorectomy and prophylactic mastectomy among BRCA mutation “previvors.”
Authors: Holman Laura L. , Daniels Molly S , Brandt Amanda C. , Arun Banu , Keeler Elizabeth , Gershenson David Marc , Sun Charlotte C. , Lu Karen H.
Published: March 2020

1518

Background: We prospectively evaluated the timing and uptake of risk-reducing surgery in a cohort of female BRCA mutation carriers that have no personal cancer history (“previvors”). Methods: Patients at high risk of breast and ovarian cancer were enrolled between 2007 and 2011 and followed in a high-risk ovarian cancer screening clinic. Women were offered risk-reducing salpingo-oophorectomy (RRSO) and/or prophylactic mastectomy (PM) per guidelines. Their clinical data were recorded and analyzed using descriptive statistics. Results: Of 260 BRCA mutation carriers enrolled, 73 have no personal history of cancer and are “previvors.” Patients have been followed for a median of 26.5 months (1-50 months). The median age is 38 years, 81.1% are white, 16.2% are Ashkenazi Jewish, and 79.7% are premenopausal. BRCA1 carriers account for 43.2% of participants and 55.4% have a BRCA2 mutation. The majority of patients (77.6%) presented for ovarian cancer screening <1 year after their BRCA testing. In all, 60.8% of women underwent prophylactic surgery: 28.4% chose RRSO, 18.9% chose PM, and 13.5% chose both procedures. Postmenopausal women were more likely to choose RRSO, while uptake for both procedures was common for premenopausal women (Table, p=0.04). RRSO was also more likely in parous than nulliparous premenopausal women (35.2% vs 9% p=0.001). PM was not associated with parity (p=0.79). Of women that had both surgeries, 20% had them concurrently and 20% had PM first. Of the 60% that underwent RRSO first, all had their second surgery within 14 months. Conclusions: BRCA mutation “previvors” have a high overall uptake of prophylactic surgery. Premenopausal women are more likely to choose PM than postmenopausal women; reasons for this are unclear. “Previvors” that choose RRSO and PM typically have both surgeries within a fairly short timeframe. With the growing population of “previvors” in the US, further study of patient preferences regarding preventative surgery and long-term consequences is needed. [Table: see text]
Breast cancer intrinsic subtypes by PAM50 in older women.
Authors: Jenkins Emily Oldham , Deal Allison Mary , Anders Carey K. , Prat Aleix , Perou Charles M. , Carey Lisa A. , Muss Hyman Bernard
Published: March 2020

1524

Background: Breast cancer (BC) incidence dramatically increases with age and the number of older BC patients (pts) in the U.S. is rising. Although immunohistochemical (IHC) data confirm that the incidence of luminal BC increases with age while the incidence of triple negative (TN) BC decreases, age-specific data on the frequency of BC subtypes defined by gene expression is limited. We characterized the incidence of BC intrinsic subtypes using gene microarrays according to age. Methods: Data from 2,150 pts were pooled from publicly available microarray datasets to determine the incidence of PAM50 breast cancer intrinsic subtypes (Luminal A [LumA], Luminal B [LumB], HER2-enriched [Her2E], Basal-like [Basal] and Normal-like [Norm]) by age. Adjuvant treatment data (none, chemotherapy, endocrine therapy or both) were available for 1,741 samples. Relapse-free (RFS) and overall survival (OS) differences were determined using the Kaplan-Meier method. Results: PAM50 intrinsic subtypes by age are tabulated below. The incidence of luminal (A, B, A+B) tumors increased with age (p<0.01, p<0.0001, p<0.0001, respectively), while the percentage of basal tumors decreased (p<0.0001). Basal tumors represented 13% of pts aged > 70 years (yrs); of the 70% with available IHC data, 74% were TNBC. Age as a continuous variable was not associated with RFS (p = 0.37). Subtype alone (n=2031), and after controlling for treatment (n=1645), was significantly associated with RFS (both p<0.0001). The addition of age to a multivariate analysis added no prognostic information. Conclusions: Though more favorable subtypes increase with age, older BC pts still have a substantial percentage of high-risk subtypes. Age alone was not a significant factor in outcome. Tumor biology as defined by intrinsic subtype is an important clinical predictor. [Table: see text]
Identification of new susceptibility genes in familial breast cancer by exome sequencing.
Authors: Lynch Henry T. , Wen Hongxiu , Kim Yeong , Snyder Carrie , Kinarsky Yulia , Chen Pei Xian , Cowan Kenneth H. , Goldgar David , Wang San Ming
Published: March 2020

1538

Background: Familial breast cancer was described in the early 1970s with its syndromy confirmed by the discovery of BRCA germline mutations in the 1990s. BRCA mutations account for less than 10% of affected families. Efforts made in the past two decades have resulted in limited results in identifying additional susceptibility genes for familial breast cancer. Methods: Using exome sequencing, we analyzed eight members in a BRCA1-, BRCA2-, p53- and PTEN-negative breast cancer family; five with breast cancer and three unaffected. Mutation candidates were idenified by bioinformatics analysis, experimentally validated by Sanger sequencing and their damaging effect was predicted by the SIFT program. Validated mutations were also tested in 42 additional breast cancer samples from BRCA-negative breast cancer families. Results: We identified 55 non-synonymous germline mutations affecting 49 genes in multiple members of this family, 20 of 22 selected mutations predicted to cause damaging effects were validated. As an exemplar, two mutations in the MYST4 gene were detected at the C terminal (p.D1516Y and p.R1577C), validated, and predicted to cause damaging consequences. MYST4 is a histone acetyltransferase (Champagne, N. et al. JBC. 274, 28528-28536,1999). It contains a C2HC-type finger and a PHD-type zinc finger. Its N-terminal is involved in transcriptional repression while its C-terminal is involved in transcriptional activation and interacts with important transcriptional regulators RUNX1 and RUNX2. MYST4 is involved in DNA replication, transcriptional regulation, and epigenetic modification of chromatin structure. A translocation t(10;16)(q22;p13) between CREBBP and MYST4 was identified in acute myeloid leukemia. The 20 validated germline mutations were tested by Sanger sequencing in 42 additional breast cancer cases from 26 BRCA-negative families. None of the 20 mutations were detected. Conclusions: Results show that remaining unknown susceptibility genes are likely family-specific and can be detected in each affected family using genome sequencing approaches. These results may be the first reported in an exome sequencing study of BRCA-negative breast cancer families.
Evaluation of genes associated with undescended testes as predictors of TGCT susceptibility.
Authors: Marshall Ariela , Ciosek Stephanie L. , Vardhanabhuti Saran , Mitra Nandita , Vaughn David J. , Kanetsky Peter A. , Nathanson Katharine
Published: March 2020

1539

Background: Testicular germ cell tumors (TGCTs) are highly heritable. Cryptorchidism (undescended testes; UDT) is a strong risk factor for TGCT, with increased risk to both the ipsilateral and contralateral testes. However, recent genome-wide association studies (GWAS) identifying genetic variants associated with TGCT susceptibility have not found differences in genotype carriage between TGCT patients with and without UDT. We investigated the role of potential risk variants for UDT as risk factors for TGCT. Methods: 1300 SNPs in and around 25 gene regions with published associations with UDT were evaluated in 474 TGCT cases (45 with UDT) and 919 controls. Genotype information was available from the Affymetrix Genome-Wide Human SNP Array 6.0. Statistical analysis was performed using PLINK, and statistical significance was assessed by Fisher's Exact test. Results: Comparing TGCT cases with and without UDT, variants in the region of four genes (EPHB2, ESR1, SEMA3C, TGFBR3) were suggestively associated with UDT. When TGCT cases with UDT were compared with unaffected controls, the associations all met the required level of significance (p < 4 x 10-5). Only variation at ESR1 approached significance (P=0.0004) when TGCT cases and unaffected controls were compared. Conclusions: We identified variants at three genetic loci - SEMA3C, TGFBR3 and EPHB2 - that were significantly associated with UDT, but not with TGCT. The association of variation in EPHB2 and SEMA3C with UDT are novel findings. While associated with UDT, variation at ESR1 is also potentially associated with TGCT risk. These data continue to suggest that genetic risk factors for UDT are largely independent of those for TGCT. Thus, screening for TGCT could be targeted in a UDT population to those with genetic risk factors. Further studies should be done to investigate the genetic link between UDT and TGCT.