bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I/IB dose-escalation study of BEZ235 in combination with trastuzumab in patients with PI3-kinase or PTEN altered HER2+ metastatic breast cancer.
Authors: Krop Ian E. , Saura Cristina , Rodon Ahnert Jordi , Becerra Carlos , Britten Carolyn D. , Isakoff Steven J. , Demanse David , Hackl Wolfgang , Quadt Cornelia , Silva Antonio P. , Burris Howard A. , Abu-Khalaf Maysa M. , Baselga José 
Published: March 2020

508 Background: Alterations in the PI3K/AKT/mTOR pathway have been implicated in resistance to trastuzumab (T) in HER2+ breast cancer. BEZ235, a potent oral dual PI3K/mTORC1/2 inhibitor, has demonstrated growth inhibition and apoptosis in HER2+ breast cancer models, including those harboring PI3K pathway alterations, and with T resistance. In a Phase I study, BEZ235 was well tolerated as a single agent in pts with advanced solid tumors. The aim of this study was to determine the MTD of BEZ235 in combination with T in pts with T-resistant HER2+ metastatic breast cancer (mBC) with alterations of the PI3K pathway. Methods: Pts with T-resistant HER2+ mBC (i.e. disease progression during adjuvant therapy or metastatic disease on therapy with T) received oral BEZ235 daily, with weekly T (2 mg/kg). Pts were eligible for enrollment if a tumor sample was demonstrated to contain a molecular alteration of PIK3CA and/or PTEN. Dose escalation was guided by a Bayesian logistic regression model with overdose control. Results: As of 23 Sep 2011, 15 of the 19 enrolled pts were evaluable for dose escalation analysis. BEZ235 was evaluated at 3 dose levels: (1) 400 mg/day (3 pts); (2) 600 mg/day (6 pts); (3) 800 mg/day (10 pts), administered either in capsule form (400 mg) or in sachet form (600 mg and 800 mg). The MTD of BEZ235 in combination with T was estimated to be 600 mg/day. Observed DLTs were G3 nausea at 600 mg/day (1 pt), and G3 nausea, G3 fatigue and G3 skin rash (1 pt each) at 800 mg/day. The most frequent G3/4 adverse events (CTCAE v3.0) suspected to be related to study treatment were diarrhea (4 pts) and nausea (2 pts). No deaths related to study treatment occurred. 1 pt with lung and brain metastases had a partial response. 4 pts had disease stabilization for ≥4 cycles (16 weeks), including 1 pt with liver metastases, in whom BEZ235/T treatment resulted in disease stabilization for more than 21 cycles (84 weeks). Conclusions: BEZ235in combination with T demonstrated an acceptable safety profile in pts with HER2+ mBC and PI3K pathway alterations. Following the Bayesian model recommendation, the MTD for BEZ235 in combination with T was estimated to be 600 mg/day. The safety expansion arm is ongoing at the MTD.
How is the current clinical management of endometrial cancer worldwide? An international survey by the North-Eastern German Society of Gynaecological Oncology (NOGGO).
Authors: Kraetschell Robert W. , Fotopoulou Christina , Dowdy Sean Christopher , Fujiwara Keiichi , Yaegashi Nobuo , Lorusso Domenica , Casado Antonio , Mahner Sven , Herzog Thomas J. , Vergote Ignace B. , Miller David Scott , Marth Christian , Battista Marco Johannes , Lichtenegger Werner , Sehouli Jalid ,   North-Eastern German Society of Gynaecological Oncology
Published: March 2020

5087 Background: Indication, technique and extent of lymph-node-dissection (LND) in endometrial cancer (EC) remains controversial and is strongly debated in cancer community. We conducted a national- and at a second step an international-survey evaluating the current status-quo of the surgical and medical management of EC. Methods: A validated 15-item-questionnaire regarding surgical and adjuvant procedures of EC was sent to all major gynaecological cancer societies and study groups worldwide. The questionnaire could also be answered online. Results: In a phase-I-national trial, the questionnaire was validated on basis of 316 German institutions. On the phase-II-international survey a total of 302 questionnaires were answered from 24 countries, mainly from Japan (38.7%), Spain (8.3%), Austria (7%), United-Kingdom (6.3%), Italy (6%), USA (4.3%) and Canada (4%). The vast majority of the participating clinics were academic (62.8%), while 75.2% of them belonged to gynaecology. Only 0.7% of the clinics internationally reported never performing LND in EC. 62.3% of the clinics perform both a pelvic and paraaortic lymph node dissection. 59.1% of the participants performed a systematic lymph node dissection with the intention of both adequate staging and for therapeutic value. 15.05% of the clinics perform LND up to the common-iliac-arteries, 9.03% up to the inferior-mesenteric-artery and 70.6% up to the renal-veins. The most common risk-factors to indicate LND were: high-grading (93%), non-endometrioid-histology (90.1%), lymphovascular-invasion (55.3%), blood-vessel invasion (45.4%) and tumor-diameter >2cm (38.4%). For advanced stage III&IV disease the vast majority (60% and 80%, respectively) of the physicians indicated systemic chemotherapy alone. Conclusions: This study presents the large variety in clinical management of EC worldwide, underlining so the high need of future prospective randomised trials which will establish standard and evidence based treatment guidelines for EC- disease.
Clinicopathologic characteristics of endometrial cancer in Lynch syndrome.
Authors: Lecuru Fabrice , Bouquier Julie , le Frere-Belda marie-Aude , Bensaid Cherazade , Nos Claude , Laurent-Puig Pierre , Bats Anne-Sophie 
Published: March 2020

5098 Background: Poor data exist on clinico-pathological description of endometrial cancer (EC) in Lynch syndrome (LS) compared with sporadic ones. To evaluate the clinico-pathological findings of Lynch-related EC to establish histological criteria to discriminate familial and sporadic EC and to decide the optimal management of patients. Methods: Retrospective study of prospective cohort of patients with LS in our institution from 1999 to 2011. We identified and described all cases of endometrial cancers. Management and follow-up were detailed. Results: Of a cohort of 126 patients with LS, 10 women developed endometrial carcinoma. The median age at diagnosis was 51 years (41-58). Five patients had an identified mutation (2 hMLH1, 2 hMSH2 and 1 hMSH6). In 9 cases, EC was the first Lynch-related tumor to occur. No patient developed ovarian cancer. All, except 2 patients (1 serous carcinoma and 1 clear cell carcinoma), had endometrioid adenocarcinoma (80%). Tumor grade was grade 1 in 3 patients, grade 2 in 5 and grade 3 in 2 patients. Forty per cent of patients had lymphovascular space involvement (LVSI). The FIGO stages were as follows: stage IA (n=7), stage IB (n=2) and stage IIIC (n=1). Four in ten patients had tumor located in the lower uterine segment. With a median follow-up of 14 months (range 9 – 40 months), recurrence occurred in one patient with a stage IB grade 2 endometrioid adenocarcinoma with LVSI. Conclusions: EC in LS is characterized by early age at onset, localization in lower uterine segment, and high rate of LVSI. Other data on histology and survival do not differ from sporadic cancers. These results suggest that we can consider conservative treatment in patients with good prognosis tumors. Further studies are required.
The effects of age on treatment and outcomes in women with stage IB-IIB cervical cancer.
Authors: Roque Dario R. , Cronin Beth , Robison Katina , Lopes Vrishali , Rizack Tina , Dizon Don S. 
Published: March 2020

5100 Background: Advanced age may affect the treatment choice and subsequent outcome in elderly patients with cervical cancer. Given the potential for cure with either surgery or chemoradiation in early stage disease, we aimed to determine whether a patient’s age influenced the treatment received and the outcome. Methods: Our retrospective cohort identified a total of 303 patients diagnosed with Stage IB1 through IIB cervical carcinoma who were treated at our institution between 2000 and 2010. The eligible patients were divided into two groups based on age at the time of diagnosis: <65 and > 65 years. Adjusted odd ratios were calculated to determine variables associated with treatment received (chemoradiation or surgery). Single and multivariate Cox proportional hazards modeling were used to estimate hazard ratios for variables associated with disease specific survival. Results: Of the patients meeting inclusion criteria, 253 were <65 years and 50 were > 65 years. The distribution of tumor histology, stage and grade was not different between the two groups. After adjusting for histology, stage and a validated comorbidity score, the odds ratio of receiving chemoradiation vs. surgery for the cohort > 65 years was 1.69 (OR 95% CI: 0.68-4.17). There was no significant difference in the type of primary treatment received between the two groups (P = 0.16). Persistent disease was seen in 46 (18%) of the younger patients and in 19 (38%) of the older patients (P = 0.02). In the elderly cohort the treatment received did not influence disease-specific or all-cause mortality. However, compared to women under 65, older women treated surgically had increased disease specific (HR 3.18, 95% CI: 0.98-10.3) and all-cause mortality (HR 6.53, 95% CI: 2.57-16.6). Conclusions: Age does not appear to be a factor influencing the treatment received by patients with Stage IB1-IIB cervical cancer. The type of treatment received does not seem to affect disease-specific mortality among older versus younger women. However, surgery was associated with a 6.5-fold increased risk of all cause mortality among older women when compared to women under 65 years.
Cervical cancer treatment for operable lesions in a low-resource contemporary setting.
Authors: Lynch Caroline Dorothy , Omenge Elkanah , Itsura Peter , Muliro Hellen , DelPriore Guiseppe , Rosen Barry , Washington Sierra , Strother Robert Matthew 
Published: March 2020

5107 Background: To compare HIV+ and HIV- women with operable cervical cancer in a low resource contemporary setting. Methods: A retrospective study using well-matched controls from a Kenyan teaching and referral hospital. Results: 183 women were treated for cervical cancer between October 2007 and June 2011. The histologic subtype was squamous cell in all but one case. At presentation, 28 had operable lesions (Stage IA1–IIB1); 7 more received neoadjuvant chemotherapy prior to surgery. HIV seroprevalence was 54% (18/33) among initial operative cases and 57% among the neoadjuvant group (p=ns). Mean age was 42 (HIV+), and 43 (HIV-), (range 25-64). HIV- vs. HIV+ cervical cancer patients (mean CD4 count 373, 50%<200) were detected by visual inspection with acetic acid (VIA) (18% (2/11)vs 68% (15/22) p=.099), symptoms (27%(3/11) vs 14%(3/22) p=.43), or Pap smear (45% (5/11) vs .09% (2/22) p=.06), respectively.HIV+ patients (two Stage IB1, two Stage IB2) did not require more downstaging than HIV- patients (two stage IIB, one stage IIIA) before surgery (18% (4/22) vs 27% (3/11) p=.63). Surgical treatments were not statistically different in either group and included radical hysterectomy(25), total abdominal hysterectomy(2), cesarean hysterectomy(1), and total vaginal hysterectomy(5). Postoperative complications included fever, dehiscence, DVT, ileus, fistula, and infectious complications (chest, urinary tract, wound). One HIV- patient suffered postoperative fever, vesicovaginal fistula, and wound dehiscence (overall complications .06%).Lymph node involvement was noted in 7 HIV+ and 3 HIV- patients who underwent full staging procedures (p=.004). Conclusions: In patients with operable cervical cancer, HIV serostatus does not affect complication rate or influence need for downstaging prior to surgery compared to a well-matched control group. HIV+ patients were not more likely to receive neoadjuvant chemotherapy but were more likely to have positive lymph nodes. VIA detected the majority of cervical cancers HIV+ patients.
Preoperative geriatric assessment (GA) and surgical outcomes in older women with gynecological (gyn) cancer.
Authors: Li Daneng , Korc-Grodzicki Beatriz , Zhou Qin , Iasonos Alexia , Chi Dennis , Gardner Ginger J. , Lichtman Stuart M. , Tew William P. 
Published: March 2020

5108 Background: GA can predict surgical outcomes in older patients (pts); however, pre-surgical evaluation for older pts with gyn malignancies has not been well-described. This study will determine the association between GA variables with post-operative morbidity and mortality. Methods: Women 75yrs or older who had geriatric evaluation before any gyn surgery at Memorial Sloan Kettering Cancer Center (MSKCC) between 1/2010-6/2011 were identified. Pre-operative GA included: Mini-Cog Test (cognition), fall history, medication list, nutritional status (weight loss >10lbs, albumin), functional status (activities of daily living (ADL), instrumental I-ADL), and Charlson comorbidity index. Outcomes included: delirium, length of hospital stay (LOS), 30-day surgical adverse events (AE, grade 1-5, via prospective-MSKCC surgical database), 30-day hospital readmission and 6-month mortality. Utilizing bivariate analyses, associations between GA measures and post-operative outcomes were evaluated. Results: 72 pts (median age 79yrs, range 75-92) with gyn cancer (54% uterine, 36% ovarian/peritoneal/tubal, 10% cervical/vaginal/vulvar) had gyn surgery. 34 pts (47%) had stage III/IV disease. 21pts (30%) had secondary cancer history. Pt’s baseline GA measures: ADL-dependent (13%), IADL-dependent (19%), weight loss (18%), fall history (18%), mini cog score (median 4, range 0-5), Charlson score (median 2, range 0-9). 24pts (33%) had surgical AE; no significant association with age or GA. Median LOS was 2 days (range 0-20); 11pts (15%) required 30-day readmission. Delirium (p=0.01), nutrition (weight loss p=0.04, albumin p=0.04), anemia (p=0.003) and high comorbidity index (p=0.013) were associated with longer LOS. Six-month mortality was 8%; older age (p=0.02), poor functional status (lower ADL and IADL, p<0.001 and p=0.007), number of medications (p=0.05) and poor cognition (p<0.001) were associated with shorter survival. Conclusions: Surgical morbidity is common in older pts. Although AE’s were not associated with GA variables, GA can detect high-risk features for longer LOS and shorter survival. Further prospective studies with pre-operative GA and interventions are warranted.
Impact of body mass index (BMI) on the efficacy of zoledronic acid in premenopausal patients with hormone receptor positive breast cancer: An analysis of the ABCSG-12 trial.
Authors: Pfeiler Georg , Konigsberg Robert , Fesl Christian , Mlineritsch Brigitte , Stoger Herbert , Singer Christian F. , Poestlberger Sabine , Steger Guenther G. , Seifert Michael , Dubsky Peter Christian , Jakesz Raimund , Samonigg Hellmut , Bjelic-Radisic Vesna , Greil Richard , Marth Christian , Gnant Michael 
Published: March 2020

514 Background: Zoledronic acid (ZOL) improves disease outcome in premenopausal patients with breast cancer (BC), especially in those with low estrogen environment. Obesity is associated with increased estrogen serum levels, which might influence the efficacy of ZOL. We investigated the impact of BMI on the efficacy of ZOL in premenopausal patients with BC. Methods: ABCSG-12 examined the efficacy of ovarian suppression using goserelin (3.6 mg q28d SC) in combination with anastrozole (ANA) or tamoxifen (TAM) ± ZOL 4 mg IV q6mo) in premenopausal women with endocrine-responsive BC. BMI was calculated using the prospectively collected data on patients’ height and weight at study entry. BMI definitions of the WHO were used: normal 18.5-24.9 kg/m2, overweight: BMI 25-29.9 kg/m2, obese BMI ≥ 30 kg/m2). Disease-free survival (DFS) and overall survival (OS) were calculated by Kaplan-Meier method and results were compared by using the log-rank test and Cox proportional hazard modeling. Results: Two thirds of the patients were normal weight (1,111) and one third was overweight (391) or obese (182). Normal weight patients treated with ZOL experienced the same benefit as overweight/obese patients treated with ZOL compared to patients without ZOL regarding disease free survival (HR 0.75, 95%CI 0.53 1.05 p = 0.09 and HR 0.71, 95%CI 0.46 1.1, p=0.12, respectively) as well as overall survival (HR 0.67, 95% CI 0.37 1.22, p=0.19 and HR 0.64, 95%CI 0.32 1.28, p=0.19, respectively). No difference regarding DFS and OS could be detected between normal weight and overweight/ obese patients treated with ZOL (HR 1.05, 95%CI 0.69 1.59, p=0.83 and HR 1.27, 95%CI 0.62 2.61, p= 0.51). Comparing normal weight patients with ZOL to obese patients with ZOL, again no difference could be observed. Conclusions: The significant outcome benefit of adjuvant zoledronic acid in ABCSG-12 can be demonstrated both in normal weight and overweight/obese premenopausal patients with early breast cancer, indicating that the bone marrow microenvironment changing impact of adjuvant bisphopshonate treatment does not correlate with patients’ BMI.
Mammostrat as an immunohistochemical multigene assay for prediction of early relapse risk in the TEAM pathology study.
Authors: Bartlett John M. S. , Bloom Kenneth J. , Robson Tammy , Lawton Thomas J. , Van De Velde Cornelis J. H. , Ross Douglas T. , Seitz Robert S. , Beck Rodney A. , Hasenburg Annette , Kieback Dirk Guenter , Putter Hein , Markopoulos Christos , Dirix Luc Yves , Seynaeve Caroline M. , Rea Daniel 
Published: March 2020

516 Background: Some postmenopausal patients with hormone sensitive early breast cancer remain at high risk of relapse despite endocrine therapy, and might benefit additionally from adjuvant chemotherapy. The challenge is to prospectively identify such patients. The Mammostrat test uses five immunohistochemical markers to stratify patients regarding recurrence risk, and may inform treatment decisions. We tested the efficacy of this panel in the TEAM trial. Methods: Pathology blocks from 4598 TEAM patients were collected and TMAs constructed. The cohort was 47% node positive and 36% were also treated with adjuvant chemotherapy. Triplicate 0.6mm2 TMA cores were stained and positivity for p53, HTF9C, CEACAM5, NDRG1, SLC7A5 assessed. Cases were assigned a Mammostrat risk score, and distant relapse free (DRFS) and disease free survival (DFS) analysed. Results: In multivariate regression analyses, corrected for conventional clinicopathological markers, Mammostrat provided significant additional information on DRFS after endocrine therapy in ER positive node negative patients (N=1226) not receiving chemotherapy (p=0.004). Further analyses in all patients not exposed to chemotherapy, irrespective of nodal status (N=2559) and in the entire cohort (N=3837) showed Mammostrat scores provide additional information on DRFS in these groups (p=0.001 and p<0.0001 respectively; multivariate analyses). No differences were seen between the two endocrine treatment regimens. Conclusions: The Mammostrat score predicts DRFS for both exemestane and tamoxifen-exemestane treated patients irrespective of nodal status and chemotherapy. The ability of this test to provide additional outcome data following treatment provides further evidence for its’ utility in risk stratification of ER positive postmenopausal breast cancer patients.
Validation of IHC4 algorithms for prediction of risk of recurrence in early breast cancer using both conventional and quantitative IHC approaches.
Authors: Christiansen Jason , Bartlett John M. S. , Gustavson Mark , Rimm David , Robson Tammy , Van De Velde Cornelis J. H. , Hasenburg Annette , Kieback Dirk Guenter , Putter Hein , Markopoulos Christos , Dirix Luc Yves , Seynaeve Caroline M. , Rea Daniel 
Published: March 2020

517 Background: Hormone receptors, HER2 and Ki67 are residual risk markers in early breast cancer. Combining these markers into a unified algorithm (IHC4) provides information on residual recurrence risk of patients treated with hormone therapies. This study aimed to independently investigate the validity of the IHC4 algorithm for residual risk prediction using both conventional (DAB)-IHC and quantitative immunofluorescence (QIF-AQUA). Methods: The TEAM pathology study recruited >4500 samples from patients treated in the TEAM trial. TMAs were stained for ER, PgR, HER2 and Ki67 using QIF-AQUA technology or DAB-based immunohistochemistry (DAB-IHC). Central HER2 FISH was performed. Quantitative image analysis was used to generate expression scores that were normalized to produce “IHC4 algorithm” as well as novel algorithm scores. Algorithm scores were compared with disease recurrence in univariate and multivariate Cox Proportional Hazards models. Results: Both DAB-IHC and QIF-AQUA IHC4 continuous models were significant (P<0.0001) for prediction of disease recurrence with a continuous Hazard Ratio (HR) of 1.011 (1.010 – 1.013) for QIF-AQUA IHC4 versus 1.008 (1.007 – 1.010) for the DAB-IHC IHC4 model using the published IHC4 algorithm (Cuzick et al 2011). Binning continuous model scores (4 bins) by Kaplan-Meier survival analysis was used to graphically illustrate these effects. De novo models for both DAB-IHC and QIF-AQUA were also significantly (P<0.0001) predictive of residual risk in early breast cancer. Additionally, all 4 models were independent predictors of recurrence (P<0.0001) with other recognized clinical prognostic factors in multivariate analysis. Although results from DAB and QIF-AQUA were modestly correlated, the QIF-AQUA model showed enhanced prediction of recurrence in both Cox Proportional Hazards Modeling and C-index calculations. Conclusions: Either conventional DAB or QIF-AQUA methods of IHC provided evidence supporting the clinical utility of IHC4 algorithms in the context of the TEAM study. With careful standardization, either of these IHC4 assays should be considered for prediction of residual risk in early breast cancer.
Aspirin use and mortality in women with stage I-III breast cancer: A population-based study.
Authors: Barron Thomas Ian , Sharp Linda , Bennett Kathleen , Visvanathan Kala 
Published: March 2020

521 Background: Recent observational studies have associated aspirin (ASP) use with large reductions in breast cancer (BC) mortality. However, these studies have provided limited information on dose or duration of ASP use, key issues relevant to translation of the results into clinical practice. Methods: Linked National Cancer Registry Ireland and prescription refill data (General Medical Services Ireland, GMS) were used to identify women aged 50-80 with incident stage I-III BC (2001-2006). ASP use was defined as high or low by the median number of ASP days’ supply (85 days) in the 90 days pre-diagnosis. Full capture of ASP use is expected as the GMS provides all medications, including ASP, without charge. Hazard ratios (HR) with 95% confidence intervals (CI) for ASP use and (i) all-cause and (ii) BC-specific mortality were estimated using Cox proportional hazards models adjusted for age, stage, grade, ER, PR, HER-2 status, comorbidity and other drug exposures. Analyses were stratified by tumor stage and nodal status. Results: 2714 women with stage I-III BC were identified (median follow-up = 3.3 years), of whom 642 (23.7%) used ASP in the 90 days pre diagnosis. High and low ASP exposure groups were strongly predictive of post-diagnosis ASP exposure levels (High: mean post diagnosis exposure duration – 83% of follow-up; dose – 75mg/day in 91% of women. Low: mean post-diagnosis exposure duration – 58% of follow-up; dose – 75mg/day in 80% of women). Women with any ASP use had a non-significant reduction in all-cause (HR 0.85 95%CI 0.68, 1.06) and BC-specific (HR 0.86 95%CI 0.65, 1.15) mortality, compared to ASP unexposed women. However, in the dose response analysis high ASP exposure was associated with a significant reduction in all-cause (HR 0.70 95% CI 0.51, 0.95) and BC-specific (HR 0.63 95% CI 0.42, 0.96) mortality. No reduction was observed for low ASP exposure. The benefits of ASP exposure were greater in early stage, node negative disease. Conclusions: Only high ASP exposure was associated with a significant reduction in all cause and BC-specific mortality. These findings may explain inconsistent results from previous studies. Our findings can inform future clinical trials.