bluuebunny/crossref_metadata_2025 huggingface dataset:
Intermittent (IAD) versus continuous androgen deprivation (CAD) in hormone sensitive metastatic prostate cancer (HSM1PC) patients (pts): Results of S9346 (INT-0162), an international phase III trial.
Authors: Hussain Maha , Tangen Catherine M. , Higano Celestia S. , Crawford E. David , Liu Glenn , Wilding George , Prescott Stephen , Akdas Atif , Small Eric Jay , Dawson Nancy Ann , Donnelly Bryan J , Venner Peter , Vaishampayan Ulka N. , Schellhammer Paul F. , Quinn David I. , Raghavan Derek , Vogelzang Nicholas J. , Thompson Ian Murchie
Published: February 2017

4

Background: Castration resistance occurs in the vast majority of HSM1PC pts treated with AD, with a median survival of 2.5 years (y). It is in part an adaptive process with activation of genes resulting in the production of autocrine/paracrine growth factors that contribute to maintaining the viability of PC cells. Replacing androgens before castration resistance is hypothesized to maintain PC androgen-dependence. Preclinically IAD prolonged time to castration resistance and early clinical data indicated feasibility and potential for better quality of life. Methods: HSM1PC pts with performance status (PS) 0-2, PSA ≥ 5 ng/ml were treated with 7 months (m) of goserelin + bicalutamide. Pts achieving PSA ≤4 ng/ml on m 6 and 7 were stratified by prior neoadjuvant AD/finasteride, PS and disease extent (minimal, extensive) and randomized to CAD or IAD. Primary objective: To assess if overall survival (OS) with IAD is noninferior to CAD using a one-sided test with an upper bound hazard ratio=1.20, adjusting for stratification factors. Sample size: 756 pts/arm, type I and II error rates of 0.05 and 0.10. Results: 3,040 pts were accrued by SWOG, CALGB, ECOG, NCIC, and EORTC (5/95- 9/08). After 7 m of CAD, 1535 eligible pts achieved PSA ≤4.0 (median age 70 yrs, 4% PS 2, 48% extensive disease, 12% prior neoadjuvant AD) and were randomized to CAD (759 pts) or IAD (770 pts). Grade 3/4 related adverse events: IAD 30.3%, CAD 32.6%. Median follow-up was 9.2 yrs. Median and 10 yr OS: All eligible pts from study entry: 3.6 yrs, 17%; from randomization CAD: 5.8 yrs, 29%; IAD: 5.1 yrs, 23%, HR (IAD/CAD) = 1.09 (95% CI 0.95, 1.24). No interaction with therapy was significant (p>0.25) except suggestion with disease extent (p=0.08): extensive disease HR=0.96 (95% CI 0.79, 1.15, p=0.64); minimal disease: HR=1.23 (95% CI 1.02, 1.48, p=0.035). PC was cause of death in 56% of CAD and 64% IAD pts. OSby race was not different (p=0.44). Conclusions: In HSM1PC, IAD is not proven to be noninferior to CAD. For extensive disease pts IAD was noninferior; however, IAD was statistically inferior in minimal disease pts suggesting that CAD is the preferred treatment in this group.
Bevacizumab (BEV) plus chemotherapy (CT) continued beyond first progression in patients with metastatic colorectal cancer (mCRC) previously treated with BEV plus CT: Results of a randomized phase III intergroup study (TML study).
Authors: Arnold Dirk , Andre Thierry , Bennouna Jaafar , Sastre Javier , Osterlund Pia J. , Greil Richard , Van Cutsem Eric , Von Moos Roger , Reyes-Rivera Irmarie , Bendahmane Belguendouz , Kubicka Stefan
Published: February 2017

CRA3503

Background: BEV in combination with fluoropyrimidine-based CT is standard treatment for mCRC in the first-line (1L) and BEV-naïve second-line (2L) settings. This is the first randomized study evaluating the benefit of continuing BEV in combination with standard CT as 2L treatment for patients with mCRC who progressed after receiving a standard BEV-containing regimen in the 1L setting. Methods: Patients with unresectable, histologically confirmed mCRC who progressed within 3 months after discontinuation of 1L BEV + CT were randomised to 2L fluoropyrimidine-based CT ± BEV (2.5 mg/kg/wk equivalent). Choice of oxaliplatin- or irinotecan-based 2L CT was dependent on the regimen used in 1L (crossover) and included as a stratification variable. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), response rate and safety. Results: 820 patients were randomized from February 2006 to June 2010 (409 to BEV + CT and 411 to CT alone). Baseline patient and disease characteristics were well balanced between arms. The study met its primary endpoint; median OS was 11.2 months for BEV + CT and 9.8 months for CT (HR=0.81; 95% CI 0.69–0.94; unstratified log-rank test, p=0.0062). Median PFS was 5.7 months for BEV + CT and 4.1 months for CT (HR=0.68; 95% CI 0.59–0.78; unstratified log-rank test, p<0.0001). The response rate was 5.4% for BEV + CT and 3.9% for CT (unstratified Chi-Square Test, p=0.3113). The adverse event profile was consistent with previously reported data for BEV + CT. Compared with historical data from BEV treatment in 1L or 2L mCRC, BEV-related adverse events were not increased when continuing BEV beyond progression. Conclusions: This is the first randomized study to prospectively investigate the impact of continuing BEV treatment in 2L mCRC for patients who progressed after receiving a BEV-containing regimen in 1L. Our findings demonstrate that BEV + CT (crossed over from 1L regimen) continued beyond progression significantly prolongs OS and PFS in 2L mCRC. Additional analysis (including biomarker evaluation) is ongoing.
CALGB 170601: A phase III double blind trial of duloxetine to treat painful chemotherapy-induced peripheral neuropathy (CIPN).
Authors: Smith Ellen M. Lavoie , Pang Herbert , Cirrincione Constance , Fleishman Stewart Barry , Paskett Electra D. , Fadul Camilo E. , Knox Chetaye , Shapiro Charles L. , Gilman Paul ,   Cancer and Leukemia Group B
Published: February 2017

CRA9013

Background: CALGB 170601 was a randomized, placebo-controlled phase III trial to determine whether duloxetine reduces painful chemotherapy-induced peripheral neuropathy (CIPN). The secondary study endpoint was treatment-related adverse events. Methods: The study used a double-blinded placebo-controlled crossover design with equally weighted randomization to one of two arms. Arm A participants received duloxetine followed by placebo. Arm B participants received placebo followed by duloxetine. The initial and crossover periods each consisted of six weeks of drug/placebo followed by one week of washout. Randomization was stratified by neurotoxic agent and high risk for developing painful CIPN. Eligible patients were 18 years or older with an average CIPN pain score > 4/10 attributed to prior single agent taxane or platinum treatment. Participants took one capsule daily (30mg) for one week, and then two capsules (60mg) daily for four additional weeks. Participants completed the Brief Pain Inventory-Short Form (BPI-SF) at baseline and then weekly. The primary study endpoint was the change in BPI-SF scores within the initial treatment period. Analysis of covariance with an intent-to-treat approach was used to test the effect of treatment on change in pain score. Results: The target accrual goal (N = 231) was met, of which 185 (80%) completed the initial treatment period. Oxaliplatin was the most commonly received neurotoxic agent (59%). Individuals receiving duloxetine over the initial treatment period had a larger average decrease in pain score (mean change score = -1.09; S.E. = 0.19) than those receiving placebo (mean change score = -0.33; S.E. = 0.18) (p = 0.004). There was no difference in duloxetine efficacy based on the specific neurotoxic agent received. Severe (Grade 3) non-hematologic toxicity was reported by 11%, and 41% reported moderate (Grade 2) toxicities. The incidence of Grade 2+ fatigue, the most commonly reported side effect, was significantly higher in the duloxetine arm as compared to placebo (11% vs. 3%, p = 0.029). Conclusions: Duloxetine 60mg daily is an efficacious and well-tolerated intervention for the treatment of taxane or platinum-related painful CIPN.
New insights into the risk of breast cancer in childhood cancer survivors treated with chest radiation: A report from the Childhood Cancer Survivor Study (CCSS) and the Women's Environmental Cancer and Radiation Epidemiology(WECARE) Study.
Authors: Moskowitz Chaya S. , Chou Joanne F. , Wolden Suzanne L. , Bernstein Jonine L. , Malhotra Jyoti , Friedman Danielle Novetsky , Mubdi Nidha Z. , Henderson Tara O. , Leisenring Wendy M. , Stovall Marilyn , Hammond Sue , Boice John D. , Hudson Melissa M. , Diller Lisa , Bhatia Smita , Neglia Joseph Philip , Begg Colin B. , Robison Leslie L. , Oeffinger Kevin C. ,   WECARE Study Collaborative
Published: February 2017

CRA9513

Background: The risk of breast cancer (BC) by age 50 among women treated for childhood cancer with chest radiation therapy (RT) and how this risk compares with that of BRCA1 and BRCA2 (BRCA1/2) mutation carriers is unknown. Methods: We evaluated the risk of BC in a cohort of 1268 female 5-yr childhood cancer survivors treated with chest RT and estimated the cumulative incidence of BC non-parametrically treating death as a competing risk. The cumulative incidence of BC in BRCA1/2 mutation carriers was estimated with the kin-cohort method using data from 4570 female first-degree relatives of women diagnosed with unilateral BC (probands) participating in the WECARE Study. Absolute Excess Risks (AERs) were estimated using population-based data from the SEER program. Results: With a median follow-up of 26 yrs (range 5-39) for the CCSS cohort, 175 women were diagnosed with BC at a median age of 38 yrs (range 24-53) and a median latency of 23 yrs (range 7-38); the overall cumulative incidence of BC by age 50 was 24% (95% confidence interval [CI] 20-28%) and among Hodgkin lymphoma survivors was 30% (95% CI 25-35%). In comparison, among first-degree relatives of WECARE Study probands 324 were diagnosed with BC (median age at diagnosis, 55 yrs (range 26-90)). The estimated cumulative incidence by age 50 was 31% (95% CI 16-47%) and 10% (95% CI 2-23%) in carriers of BRCA1 and BRCA2 mutations, respectively. The population cumulative incidence of BC is 4% by age 50. Among the childhood cancer survivors, AERs for BCs diagnosed per 10,000 person-years of observation were respectively 34 (95% CI 18-52), 27 (95% CI 11-45), and 95 (95% CI 78-112) among women treated with 10-19 Gy (23%), 20-29 Gy (17%), and 30+ Gy (56%) of chest RT. Conclusions: Women treated for childhood cancer with chest RT have a substantial risk of BC comparable to BRCA1/2 mutation carriers and considerably greater than that of the general population. Women treated with 10-19 Gy RT had an increased excess risk warranting consideration of breast cancer surveillance strategies similar to the current recommendations for women treated with > 20 Gy.
A randomized multicenter trial of epirubicin, oxaliplatin, and capecitabine (EOC) plus panitumumab in advanced esophagogastric cancer (REAL3).
Authors: Waddell Tom Samuel , Chau Ian , Barbachano Yolanda , Gonzalez de Castro David , Wotherspoon Andrew , Saffery Claire , Middleton Gary William , Wadsley Jonathan , Ferry David Raymond , Mansoor Wasat , Crosby Tom David Lewis , Coxon Fareeda Y , Smith David , Waters Justin S. , Iveson Timothy , Falk Stephen , Slater Sarah , Okines Alicia Frances Clare , Cunningham David
Published: February 2017

LBA4000

Background: EGFR overexpression occurs in 27-50% of esophagogastric adenocarcinomas (OGA), and correlates with poor prognosis. The REAL3 trial evaluated the addition of the anti-EGFR antibody panitumumab (P) to epirubicin, oxaliplatin and capecitabine (EOC) in advanced OGA. Methods: Patients with untreated, metastatic or locally advanced OGA were randomised to EOC (E 50mg/m2, O 130mg/m2, C 1250mg/m2/day) or mEOC+P (E 50mg/m2, O 100mg/m2, C 1000mg/m2/day, P 9mg/kg). Primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), response rate (RR), toxicity, and biomarker evaluation. Response was evaluated by RECIST after 4 and 8 cycles. Following IDMC review in October 2011 trial recruitment was halted and panitumumab withdrawn. Data for patients on treatment were censored at this timepoint. Results: 553 patients were recruited (EOC 275, mEOC+P 278), with median follow-up 5.0 and 5.2 months respectively. Median OS was 11.3 months with EOC compared to 8.8 months with mEOC+P (HR 1.37: 95% CI 1.07-1.76, p=0.013). Median PFS was 7.4 and 6.0 months respectively (HR 1.22: 95% CI 0.98-1.52, p=0.068), with RR being 42% compared to 46% (odds ratio 1.16: 95% CI 0.81-1.57, p=0.467). mEOC+P was associated with ↑ G3/4 diarrhoea (17% vs 11%), skin rash (14% vs 1%) and thrombotic events (12% vs 7%), but ↓ haem toxicity (>G3 neutropenia 14% vs 31%). In the mEOC+P arm, OS was significantly improved in patients with G1-3 rash (77%, n=209) on treatment compared to those without (23%, n=63); median OS 10.2 vs 4.3 months (p<0.001), with similar significant improvements seen in RR and PFS. Biomarker analysis in the first 200 patients has not identified other predictive markers associated with P therapy. Multivariate analysis for OS in these patients demonstrated a negatively prognostic role for KRAS mutation (HR 2.1: 95% CI 1.10-4.05, p=0.025) and PIK3CA mutation (HR 3.2: 95% CI 1.01-10.40, p=0.048). Conclusions: Addition of P to EOC chemotherapy was associated with worsening of OS in an unselected advanced OGA population. This may be in part due to lowered doses of O and C in the mEOC+P regimen. Outcomes in patients treated with P varied by grade of skin toxicity.
Interim analysis (IA) results of COU-AA-302, a randomized, phase III study of abiraterone acetate (AA) in chemotherapy-naive patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Ryan Charles J. , Smith Matthew Raymond , De Bono Johann Sebastian , Molina Arturo , Logothetis Christopher , De Souza Paul L. , Fizazi Karim , Mainwaring Paul N. , Piulats Rodriguez Jose Maria , Ng Siobhan , Carles Joan , Mulders Peter , Kheoh Thian San , Griffin Thomas W. , Small Eric Jay , Scher Howard I. , Rathkopf Dana E. ,   on behalf of the COU-AA-302 Investigators
Published: February 2017

LBA4518

Background: AA is an androgen biosynthesis inhibitor that inhibits CYP17 and improves overall survival (OS) in post-docetaxel mCRPC. The primary objective of COU-AA-302 was to compare clinical benefit of AA + prednisone (P) vs placebo (PL) + P in chemo-naive, asymptomatic/mildly symptomatic mCRPC pts. Methods: 1088 pts (151 centers; 12 countries) were randomized 1:1 to AA (1 g) + P (5 mg BID) or PL + P. Co-primary endpoints: radiographic progression-free survival (rPFS) and OS. Median times estimated using K-M method including LR statistic for inference. The Lan-DeMets α-spending function was used for OS. Results:The Independent Data Monitoring Committee concluded that the OS, rPFS and secondary endpoints (Table) all favored the AA arm and unanimously recommended unblinding the study and crossing pts from PL to AA at IA (43% of total events). Median follow up = 22.2 mos. Grade 3/4 AEs (AA + P, PL + P) (%): hypertension 3.9 vs 3.0; hypokalemia 2.4 vs 1.9; ALT↑ 5.4 vs 0.7; AST↑ 3.0 vs 0.9. Conclusions:AA + P produced a statistically significant improvement in rPFS and a strong trend for increased OS at this IA. AA resulted in clinically and statistically significant effects on all secondary endpoints. IA results confirmed the acceptable tolerability/safety profile of AA. This is the first randomized trial to demonstrate both OS and rPFS benefits in chemo-naive mCRPC and that inhibition of persistent extragonadal androgen synthesis significantly delays initiation of cytotoxic chemo. While median OS (AA arm) has not been reached, median PL arm OS (27.2 mos) is the longest measured in any phase III mCRPC study. [Table: see text]
PARAMOUNT: Final overall survival (OS) results of the phase III study of maintenance pemetrexed (pem) plus best supportive care (BSC) versus placebo (plb) plus BSC immediately following induction treatment with pem plus cisplatin (cis) for advanced nonsquamous (NS) non-small cell lung cancer (NSCLC).
Authors: Paz-Ares Luis , De Marinis Filippo , Dediu Mircea , Thomas Michael , Pujol Jean-Louis , Bidoli Paolo , Molinier Oliver , Sahoo Tarini Prasad , Laack Eckart , Reck Martin , Corral Jaime Jesus , Melemed Symantha , John William J. , Chouaki Nadia , Zimmermann Annamaria , Visseren-Grul Carla , Gridelli Cesare
Published: February 2017

LBA7507

Background: The PARAMOUNT trial showed that pem continuation maintenance therapy significantly reduced the risk of disease progression over plb (HR=0.62; 95% CI: 0.49-0.79; p <0.0001) in patients (pts) with advanced NS NSCLC who had not progressed during pem-cis induction. Here we present the final OS data. Methods: In a double-blind, plb-controlled study, alpha-controlled for OS, 939 pts received induction (4 cycles of pem 500 mg/m2 and cis 75 mg/m2 on d1 of 21d cycles), and 539 pts who had not progressed and had an ECOG performance status (PS) of 0/1 were randomized (2:1) to maintenance pem (500 mg/m2, on day 1 of 21-day cycles) plus BSC or plb plus BSC until disease progression. All received B12, folic acid, and dexamethasone. After 397 deaths, a log-rank test compared OS between arms using anominal α level of 0.0498. Results: Pt characteristics were balanced between arms: median age 61 years; 58% men; 32% PS 0; 95% Caucasian; 86% adenocarcinoma; 45% complete/partial response (CR/PR) to induction. Pem resulted in a statistically significant 22% reduction in risk of death (HR=0.78). The HR was the same when measured from the beginning of induction. Survival improvement was similar for pts with an induction outcome of CR/PR versus stable disease. Conclusions: Pem continuation maintenance therapy offers superior OS compared with plb. These final results confirm that pem-cis induction followed by continuation pem further benefits pts compared with induction therapy alone, offering a change in the treatment paradigm for advanced NS NSCLC. [Table: see text]
Phase II study of pertuzumab, trastuzumab, and weekly paclitaxel in patients with HER2-overexpressing metastatic breast cancer (MBC).
Authors: Datko Farrah Mikhail , D'Andrea Gabriella , Dickler Maura N. , Theodoulou Maria , Goldfarb Shari Beth , Lake Diana , Fornier Monica Nancy , Modi Shanu , Sklarin Nancy T. , Comen Elizabeth Anne , Fasano Julie , Gajria Devika , Drullinsky Pamela , Murphy Conleth G. , Syldor Angemael , Patil Sujata , Liu Jennifer , Chandarlapaty Sarat , Hudis Clifford , Dang Chau T.
Published: February 2017

134

Background: Pertuzumab (P) is a monoclonal antibody which binds to extracellular domain II of HER2 distally from trastuzumab (H), disrupting HER2 dimerization and signaling. The CLEOPATRA phase III trial showed that HP + docetaxel in HER2+ MBC prolonged progression-free survival (PFS) compared to placebo + H + docetaxel. We report preliminary results of a phase II study to evaluate the safety and efficacy of weekly paclitaxel (T) with HP (THP). Methods: Patients (pts) with HER2+ MBC with 0-1 prior treatment (Rx) are eligible. Pts receive weekly (w) paclitaxel (80mg/m2), q3w trastuzumab (loading dose 8mg/kg → 6mg/kg), and q3w pertuzumab (flat loading dose 840mg → flat dose 420mg). The primary endpoint is PFS at 6 months (mo). Secondary endpoints include response, safety (including cardiac events), and tolerability. Evaluable pts are those who have started study Rx and are assessed at 6 mo for PFS. Left ventricular ejection fraction (LVEF) is monitored by echocardiogram every 3 mo. Cardiac events are defined as symptomatic LV systolic dysfunction (LVSD), non-LVSD cardiac death, or probable cardiac death. Results: As of 5-1-12, 33 of the planned 69 pts were enrolled; 16 were evaluable at 6 mo. Of the 16 pts, G 3/4 toxicities included sepsis (1pt, 6%), cholecystitis (1pt, 6%), fatigue (1pt, 6%), skin ulceration (1pt, 6%) and cystic macular degeneration (1 pt with prior prolonged Rx with paclitaxel, 6%). G 1/2 toxicities included alopecia (16 pts, 100%), fatigue (15 pts, 94%), ALT/AST elevation (14 pts, 88%), neuropathy (14 pts, 88%), diarrhea (12 pts, 75%), rash (9 pts, 56%), nail changes (8 pts, 50%), nausea (7 pts, 44%), mucositis (7 pts, 44%), and dry skin (6 pts, 38%). Median LVEF was 63% at baseline, 60% at 3 mo and 58% at 6 mo. There were no cardiac events. At 6 mo, 12/16 pts (75%) were progression-free (2 CR, 7 PR and 3 SD); 4 pts progressed. Conclusions: Our single-center phase II study continues to accrue, with no significant diarrhea or signal of increased cardiac toxicity to date. If the estimate of activity is similar to results with docetaxel in CLEOPATRA, this will provide support for THP as an alternative option in this setting.
Sarcopenia to predict tolerance of adjuvant breast cancer chemotherapy.
Authors: Sabel Michael S. , Conlon Anna S.C. , Griffith Kent A. , Englesbe Michael , Wang Stewart
Published: February 2017

138

Background: Despite improved survival with adjuvant chemotherapy among older women, it is less often recommended for fear they cannot complete therapy or will have excessive toxicity. Analytic morphometrics uses objective imaging measurements such as muscle size, bone mineral density (BMD) and body composition to improve risk stratification. We examined whether morphometrics might help predict toxicity of chemotherapy in breast cancer patients. Methods: Our prospective IRB-approved breast cancer database was queried for all patients who underwent adjuvant or neoadjuvant chemotherapy and had CT scans of the chest, abdomen and pelvis prior to chemo. Complications of chemotherapy were graded according to the NCI-CTC. CT scans were processed using semi-automated algorithms (MATLAB v13.0) to measure psoas area (PA) and density (PD), BMD and subcutaneous fat (SF), visceral fat (VF), and total body area (TBA. Outcome (DFS and OS) was assessed by K-M, and logistic regression models and ANOVA were used for toxicity events. Results: We identified 129 patients, ranging in age from 24 to 83 (median 52). 105 (81%) received AC/T while 19% received alternate regimens, all full weight based. T-stage, nodal status and HER2 expression were significantly associated with measures of obesity, except BMI, but not sarcopenia. After adjusting for stage and Her-2, BMI remained a significant predictor of DFS (OR 1.07 (95%CI 1.01, 1.13)) and OS (OR 1.06 (95% CI 1.00, 1.12)).After controlling for age, PD and VF were predictors of chemotherapy completion. The OR for completing chemotherapy decreased 0.95 (95% CI: 0.90, 1.01, p=0.08) for every increase of 1000 in VF and increased 1.08 (95% CI: 1.01, 1.15, p=0.03) for every unit increase in PD. Sarcopenia was associated with an increased risk of pulmonary complications (p=0.01) and anemia (p=0.06). Conclusions: Although age is a significant predictor of increased toxicity and inability to complete chemotherapy, sarcopenia is an objective, independent predictor of chemotherapy completion. Psoas density, easily obtainable from a pre-treatment CT scan, can help the clinician older breast cancer patients for adjuvant chemotherapy.
Assessing the use of routine abdominal CT in staging evaluation of patients with primary breast cancer.
Authors: Staley Stuart-Allison Moffat
Published: February 2017

3

Background: The purpose of this study was to determine the utility of routine abdominal CT in the staging evaluation of women with newly diagnosed primary breast cancer given no detectable disease beyond the ipsilateral axillary nodes on chest CT. Methods: The chest and abdominal CT scans from 440 patients over a 10-year period were reviewed. The presence of definite or possible metastatic disease in the axillary nodes, chest wall, internal mammary nodes, mediastinal nodes, lungs, liver and adrenals were recorded for each patient. Cross tabulation bivariate analysis as well as a chi-square test were performed to characterize the relationship between detection of disease in the chest and disease in the abdomen. Results: Of the 440 patients reviewed, the following were found to have detectable metastatic disease by CT scan: axillary nodes 258 of 440 (56.46%), chest wall 40 of 440 (9.10%), internalmammary nodes 8 of 440 (1.82%), mediastinal nodes 29 of 440 (6.59%), lung 25 of 440 (5.68%), liver 12 of 437 (2.73%), and adrenals 8 of 440 (1.82%). In total, 81 patients had disease detectable in the chest beyond the ipsilateral axillary nodes, and only 12 patients had detectable disease spread in the abdomen. Of the 359 patients who had a negative chest CT, only 1 patient had detectable or possible metastatic disease spread on abdominal CT, resulting in a 99.70% negative predictive value (p < 0.001). Conclusions: The routine use of abdominal CT in women with newly diagnosed primary breast cancer and no detectable disease beyond the ipsilateral axillary nodes on staging chest CT scan has little value with a 99.70% negative predictive value. We recommend that if a negative CT scan of the patient’s chest yields no detectable disease beyond the axillary nodes, then further CT imaging of the abdomen is of no additional benefit to the patient. [Table: see text]
Comparison of molecular (BluePrint and MammaPrint) and pathological subtypes for breast cancer among the first 800 patients from the EORTC 10041/BIG 3-04 (MINDACT) trial.
Authors: Viale Giuseppe , Slaets Leen , De Snoo Femke , van 't Veer Laura J. , Rutgers Emiel J. , Bogaerts Jan , Stork-Sloots Lisette , Engelen Kristel , Russo Leila , Dell'Orto Patrizia , Cardoso Fatima , Piccart-Gebhart Martine J.
Published: February 2017

32

Background: Biology has become the main driver of breast cancer therapy. Intrinsic biological subtypes by gene expression profiling have been identified. Pathology can be used to define surrogates of these subtypes but these are not always concordant, which may lead to different treatment plans. We investigated the concordance between BluePrint (BP) + MammaPrint (MP) (micro array based) breast cancer subtypes and pathological surrogates (based on ER, PR, HER2 and Ki67). Contrary to the Perou gene set (evolved into PAM50), BluePrint was trained using pathological data. Methods: Using available data (centrally assessed pathology and genomic) from the MINDACT pilot phase (Rutgers et al 2011) 621 tumors were analyzed. Two pathology classifications were used: one with 4 categories and one with 5 categories (Goldhirsch et al 2011). Based on BP 3 subtypes are formed: Luminal, HER2 and Basal. The Luminal subtype is further split into Luminal A (MP low risk) and Luminal B (MP high risk). Results: See table. Conclusions: All pathological Basal cases are BP Basal, apart from 1 BP HER2 case. Of the BP Basal cases, 15 are not pathological Basal: 1 is Luminal A, 11 are Luminal B (of which 8 are IHC ER/PR borderline (≥1% and < 10%)) and 3 are HER2. All pathological Luminal (A & B) that are BP HER2 are HER2- by TargetPrint. 25 of the 26 pathological HER2+ that are BP Luminal A are ER+. Most discordant cases are seen within the Luminal subtype, indicating that Ki67 discriminates Luminal A vs. B differently than MammaPrint does. The observed subtype discrepancies reveal potential important impact for treatment-decision making. MINDACT will provide important information. [Table: see text]
Clinical outcome of preoperative breast MRI for early-stage breast cancer.
Authors: Hamdan Shadi E. , Martin Leslie A. , Sunkara Rajitha
Published: February 2017

42

Background: Preoperative breast magnetic resonance imaging MRI is used in clinical practice to improve oncologic outcome of breast cancer. Concerns over increased rate of unnecessary mastectomies and additional biopsies have been raised. The purpose of our study is to review the outcome of preoperative breast MRI at our institution. Methods: The current study is a retrospective review of 215 patients with early stage breast cancer who underwent definitive surgery. Breast MRI is being used at our institution within the context of multidisciplinary approach. Patients who had complete clinical, radiologic, and pathological data available were identified and formed the basis of this analysis. Results: 215 patients were diagnosed with breast cancer stage I-II in the period of 2006-2012 and had complete data for review. 92 patients out of 215 (43%) had breast MRI prior to definitive surgery. both groups were different in regard of age. Rate of breast conservative surgery, mastectomies, and re-excision for positive margins was similar in both groups. 6 patients out of 12 patients who had breast MRI and underwent bilateral mastectomies were found to have abnormal pathological findings (DCIS 3, LCIS 1, invasive ductal carcinoma 1, and focal epithelial atypia 1). Time from first diagnostic procedure to definitive surgery was similar in both groups (29 days vs. 27.5 days). 38 (41%) patients out of 92 who had breast MRI underwent additional breast biopsies for suspicious lesions with only 8 (21%) patients found to have abnormal pathological findings. Conclusions: Use of breast MRI prior to definitive surgery for early stage breast cancer was associated with increased rate of additional biopsies for suspicious lesions with no favorable effect on re-excision rate. [Table: see text]
A program to increase use of chemoprevention for women with high-risk breast lesions.
Authors: Roche Constance A. , Hughes Kevin S.
Published: February 2017

46

Background: Tamoxifen, raloxifene, and exemestane have been demonstrated to reduce risk of breast cancer in high-risk women, bututilization is very low.Among the reasons cited are lack of awareness and reluctance of physicians to prescribe. Women with high-risk breast lesions are generally candidates for chemoprevention and can be evaluated and counseled in a high-risk breast clinic. Knowledge about drugs that can prevent breast cancer may increase uptake among high-risk women. Methods: In a single practice, women with a diagnosis of atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), lobular carcinoma in situ (LCIS), or severe atypical ductal hyperplasia/borderline ductal carcinoma in situ are offered an extended visit with a nurse practitioner in the Breast and Ovarian Cancer Risk and Prevention Clinic. The visit includes data collection, patient interview about relevant history and personal preferences, risk assessment, including use of relevant models (via HughesRiskApps.com), and recommendations for surveillance and prevention. Emphasis is placed on understanding of individual risk as well as risks and benefits and appropriateness of chemoprevention and surveillance modalities. Based on personal and family history, women are advised if chemoprevention is appropriate to consider, their choice is made, and they are encouraged to have surveillance in the Breast Clinic. Results: Since January 2001, 487 women with a diagnosis of ADH, ALH or LCIS, or severe ADH have been evaluated and counseled in the Breast and Ovarian Cancer Risk and Prevention Clinic. 132/487 (27%) were advised against taking chemoprevention and 355/487 (73%) were appropriate for chemoprevention. Of those for whom chemoprevention was clinically appropriate, 188/355 (53%) took one of the medications, or participated in a chemoprevention trial. 53/188 (28%) did not complete therapy (discontinued at 2 weeks to 54 months) due to preference or side effects. 75 women have completed five years of therapy and 60 are currently on therapy. Conclusions: When provided with personalized information about breast cancer risk and the pros and cons of chemoprevention, many women will choose to take medication to reduce breast cancer risk.
Determination of breast density by bioimpedance.
Authors: Bukhanov Karina , Ironstone Joel S. , Basso Cindy , Bilodeau Tina
Published: February 2017

56

Background: Mammographic breast density is a significant risk factor for breast cancer. Women with extremely dense breasts are at 4-to-6 times the risk of developing breast cancer than women with primarily fatty breast tissue. Electrical Breast Densitometry (EBD) is a new technique that assesses breast density. EBD is non-ionizing, fast, has low cost per test ($20-$30) and may help in breast cancer risk assessment in the primary care setting. Methods: This study evaluated the feasibility of the EBD in an IRB-approved pilot study of 20 patients. The study used a custom-made self-adhesive electrode (SenoSENSE Medical Systems, Toronto, Canada) interfaced to an off-the-shelf impedance meter (Bodystat 1500, Bodystat, Isle of Man, UK) with a customized cable. On the same day as the subject’s scheduled mammogram, impedance measurements were acquired for each breast. Mammogram densities were scored by a trained radiologist using standard BiRADS breast density categories 1 to 4. Results: A high correlation coefficient was observed (Pearson correlation coefficient >0.80) between breast density determined by the EBD and the BiRADS breast density score. In addition a statistically significant difference was observed between dense categories (BiRADS 3,4) and fatty categories (BiRADS 1,2) (p<0.01), as well as between extremely dense breasts (BiRADS 4) and all other categories (p<0.01). Very high correlation (Pearson correlation coefficient >0.95) was observed between EBD measurements on the left and right breasts. Previous studies have reported a left/right correlation of 0.89 for blinded mammography readers. Conclusions: These results suggests that the EBD measure may be less variable than mammographic estimates of density. The results of the study suggest that Electrical Breast Densitometry is a promising technique for the assessment of breast density and the ability to aid in evaluation of breast cancer risk. It can be reasonably deployed at primary care facilities.
Everolimus for postmenopausal women with advanced breast cancer: Updated results of the BOLERO-2 phase III trial.
Authors: Arena Francis P. , Noguchi Shinzaburo , Pritchard Kathleen I. , Burris Howard A. , Rugo Hope S. , Gnant Michael , Hortobagyi Gabriel N. , Latini Luciano , Yardley Denise Aysel , Melichar Bohuslav , Petrakova Katarina , Harb Wael , Feng Wentao , Cahana Ayelet , Taran Tanya , Campone Mario , Baselga José , Sahmoud Tarek , Lebwohl David Edward , Piccart-Gebhart Martine J.
Published: February 2017

99

Background: Current treatment options for postmenopausal patients with estrogen-receptor–positive breast cancer (BC) who relapse or progress on a nonsteroidal aromatase inhibitor (NSAI) are limited. The BOLERO-2 trial supports the activity of everolimus (EVE; an oral mammalian target of rapamycin [mTOR] inhibitor) added to the steroidal aromatase inhibitor exemestane (EXE) to prolong progression-free survival (PFS) in this patient population. Long-term PFS and survival data are awaited. Methods: BOLERO-2 is a phase 3, double-blind, randomized, international trial comparing EVE (10 mg once daily) + EXE (25 mg once daily) vs. placebo (PBO) + EXE in postmenopausal women with advanced estrogen-receptor–positive BC progressing or recurring after NSAIs (letrozole or anastrozole). Patients were randomized (2:1) to EVE + EXE or PBO + EXE. The primary endpoint was PFS by local investigator assessment. Main secondary endpoints included centrally assessed PFS, overall survival (OS), safety, bone turnover, and overall response rate. Results: Baseline disease characteristics including tumor burden and prior cancer therapy were well balanced between treatment arms (N = 724). Median PFS was doubled and response rates were consistently improved with EVE + EXE (n = 485) vs PBO + EXE (n = 239) in interim analyses. Median PFS by local assessment was ~3 mo with PBO + EXE vs 6.9 mo (hazard ratio [HR], 0.43; P < .0001) and 7.4 mo (HR, 0.44; P < .0001) with EVE + EXE at 7.5 mo and 12.5 mo follow-up, respectively. Fewer deaths were reported with EVE + EXE (17.2%) vs PBO + EXE (22.7%) at 12.5 mo follow-up. Safety profiles were consistent with previous reports for mTOR inhibitors. PFS data including 528 events (protocol-specified final analysis), and updated OS and safety data will be presented. Conclusions: Adding EVE to EXE markedly prolonged PFS in patients with NSAI-refractory advanced estrogen-receptor–positive BC. There were fewer deaths among patients receiving EVE, and further follow-up will evaluate the effect of EVE on OS.
Comparison of COBAS 4800 KRAS, PCR TaqMan, and PCR high-resolution melting assays for the detection of KRAS somatic mutations in formalin-fixed paraffin-embedded colorectal tumors.
Authors: Harle Alexandre , Merlin Jean-Louis
Published: February 2017

103

Background: Colorectal cancer (CRC) is the 2nd most common cancer with more than one million new cases diagnosed every year. From 2006 to 2008, several studies showed the importance of the KRAS oncogene in the treatment of metastatic CRC (mCRC) and response to anti-EGFR therapies like cetuximab or panitumumab. KRAS is a small G protein which can bear activating mutations in 40% cases of mCRC. Numerous methods have been described for the detection of KRAS mutations in FFPE tissues. Direct sequencing is the gold standard but the most sensitive methods are real time PCR assays based. The new COBAS4800 KRAS developed by Roche Diagnostics is a CE IVD validated assay using real time PCR and TaqMelt technology. This assay is validated for the detection of 19 KRAS somatic mutations on exon 2 (codons 12/13) and exon 3 (codon 61) in specimen containing at least 5% of mutated tumoral cells. Methods: We compared COBAS with previously validated PCR TaqMan and PCR High Resolution Melting (HRM) assays. The PCR TaqMan and HRM are a real time PCR based assays. TaqMan can detect accurately 0.5 to 1% of mutated tumoral DNA on codon 12 (G12A, G12C, G12D, G12R, G12S and G12V) and on codon 13 (G13D). HRM can detect 5 to 10% of tumoral DNA on codon 12 and 13. 80 FFPE samples of colorectal tumors resections or biopsies have been collected and processed with the 3 assays. Results have been compared using kappa statistics. Results: On 80 samples, 69 were interpretable with COBAS and TaqMan and 62 with COBAS and HRM. No statistically significant difference between COBAS and TaqMan was found (k=0.942 ; p<0.001). Only 2 discordant cases were found mainly regarding codon 61 mutations not detected with TaqMan. No statistically significant difference between COBAS and HRM was found (k=0.903 ; p<0.001). Three discordant cases were found two regarding codon 61, not detected with HRM and one G12S mutation (detected by COBAS and TaqMan). Conclusions: The 3 assays can detect accurately KRAS mutations. Less ininterpretable results were found with COBAS and TaqMan assays. A pre screening with COBAS and mutation characterization with TaqMan seem to be a good scheme for routine diagnostic of KRAS mutations.
Validation of galectin-7 using backscattering interferometry.
Authors: Olmsted Ian Roys , Massion Pierre P. , Bornhop Darryl J. , Hassanein Mohamed , Hoeksema Megan
Published: February 2017

15

Background: More than 60% of lung cancer patients are diagnosed with advanced disease due to a lack of early diagnosis tools. These patients are ineligible for surgical resection and have a poor prognosis. This situation could be avoided if we could quantify lung cancer specific biomarkers at sufficiently low concentrations, providing an indication of disease threat. Backscattering Inerferometry (BSI) is a label-free sensor with a simple optical train that is used to quantify biomarkers in complex matrices at picomolar to femtomolar levels. Here we demonstrate that BSI can enable lung cancer biomarker validation in complex, volume constrained samples and at detection limits significantly better than ELISA. Methods: A BSI dose response curve for Galectin-7 was constructed by incubating increasing concentrations (0-20 ng/mL) of recombinant galectin-7 with 100 ng/mL of polyclonal antibody. The samples were mixed at 300 RPM for 2 before being injected into the BSI instrument and measured in triplicate each day. All reagents used were obtained from a commercial ELISA kit. An ELISA dose response curve was similarly constructed using spiked serum and spiked plasma according to the manufacturer’s recommended procedure. Finally, 9 patient serum samples were quantified using BSI and ELISA for direct comparison of the two technologies. Results: BSI was used to quantify galectin-7 in spiked serum and patients samples. The lower limit of detection with standards was determined to be 0.5 ng/mL for ELISA in serum, 10 ng/mL for ELISA in plasma, and 0.04 ng/mL for BSI in serum. In the analysis of 9 patient serum samples, all were quantifiable using BSI, which enjoys low pg/mL detection limits, yet with ELISA only 5 samples contained a galectin-7 concentration high enough to be measured. In this small sample set there was a good correlation between disease state and galectin-7 concentration as measured by BSI. Conclusions: This study demonstrates that BSI is well-suited for biomarker detection and validation, having a greater dynamic operating range and much lower limits of detection than standard commercially available ELISA kits. Future work will focus on detecting other NSCLC biomarkers that are undetectable with currently available technology.
Do insulin-like growth factor associated proteins qualify as a tumor marker?
Authors: Matuschek Christiane , Peiper Matthias , Budach Wilfried , Gerber Peter Arne , Bojar Hans , Steinbach Gerald , Rudoy Michael , Knoefel Wolfram Trudo , Schauer Matthias
Published: February 2017

18

Background: Insulin-like growth factor (IGF)-1, -2 and insulin-like growth factor binding proteins (IGFBP) are involved in the proliferation and differentiation of cells. It has never been evaluated if the IGF-system can serve as a tumor marker in neoplasms. Methods: In our prospective study, 163 patients with colorectal cancer (22), prostate cancer (21), glioblastoma (12), head and neck tumors (17), lymphomas (20), lung cancer (34), and other entities (37) were analysed for their IGF and IGFBP serum levels at the beginning and the end of radiotherapy and compared with 13 healthy people. Subgroups of patients with local tumor disease versus metastatic disease, primary and recurrent therapy and curative versus palliative therapy were compared. Results: The serum levels of IGF-2 were significantly elevated in patients with prostate and colorectal cancer. However, sensitivity and specificity were only 70%. IGFBP-2 serum levels were elevated in patients with head and neck tumors. Again, sensitivity and specificity were only 73%. A difference between local disease and metastatic disease could not be found. A difference between IGF serum levels before and after radiotherapy could not be detected. Conclusions: The IGF-system cannot serve as a new tumor marker. The detected differences are very small and sensitivity and specificity are too low. IGF measurement is not useful for the evaluation of the success of radiotherapy in malignancies.
Growth of tumorspheres from peripherally circulating tumor cells.
Authors: Zimon Dorothea , Pizon Monica , Pachmann Ulrich A. , Pachmann Katharina
Published: February 2017

2

Background: Even after the complete resection of a malignant tumor the menace remains, that cells that have dissociated from the tumor might resettle in distant organs and grow into life-threatening metastases. Therefore we have developed an approach (maintrac) to detect and monitor the circulating tumor suspect epithelial cells in blood. However, the question arises whether these cells have the potential to grow into metastases. Methods: Using a nondissipative approach with only one enrichment step of red blood cell lysis, the cells from the pellet, containing the white blood cells together with the putative tumor cells were cultured under conditions favoring the growth of epithelial cells. At 7, 14, and 21 days the cultured cells were stained with anti-EpCAM antibody and inspected for the appearance of epithelial antigen positive spheroids. Results: Peripherally circulating cells from patients with malignant tumors in different stages of disease were analyzed for the presence of circulating epithelial tumor suspect cells and the frequencies of tumorspheres. Tumorspheres could so far be grown from all of 20 patients in whom more than 2000/ml epithelial tumor suspect cells were detected. Fractions of tumorspheres varied from less than 1% of the epithelial tumor suspect cells in patients with primary breast cancer to up to 70% in a patient with an aggressively growing metastatic colon cancer. The size of the spheres increased from day 7 to day 21 but already had reached the size of day 21 colonies after seven days in the patient with the metastatic colon cancer. Conclusions: Here, we demonstrate that the tumor suspect cells, detected in our approach contain a subpopulation with stem cell-like properties capable of growing into tumorspheres. The frequency and growth potential of cells capable of forming spheres seems to be dependent from the properties of the primary tumor. The possibility to grow tumorspheres from peripherally circulating tumor cells may open up a new field, where the relevant cells with stem cell properties from individual patients can now be specifically analysed further for genetic endowment, transcriptional activity, heterogeneity, and stem cell markers.
PTPRF expression as prognostic/predictive marker for treatment with erlotinib in non-small cell lung cancer (NSCLC)?
Authors: Klughammer Barbara , Bordogna Walter , Delmar Paul
Published: February 2017

22

Background: Erlotinib is an EGFR TKI established as maintenance, second- and third-line treatment in unselected NSCLC patients and as first-line treatment in patients harboring EGFR mutations. Aberrations in the receptor type protein tyrosine phosphatase (PTP) gene family were described by Jacob and Motiwala (2005) as a hallmark of carcinogenesis. Recent research established the role of PTPRS, a member of the same gene family, as necessary for the dephosphorylation of EGFR in head and neck cancer (Morris and Bivona. 2011). The role of PTPRF as an interesting prognostic marker in NSCLC and potential predictive marker for treatment with erlotinib is reported here. Methods: MERIT was a single arm phase II clinical trial (Tan et al. 2010) where all patients had biopsies performed by bronchoscopy before starting treatment with erlotinib (150 mg/day p.o.). Biopsies were snap frozen and RNA was extracted using laser capture microdissection to enrich for tumor content. Affymetrix Human U133A microarrays were used to analyse gene expression profiles. Exploratory statistical methods identified several gene candidates by comparing benefitting and nonbenefitting patients including PTPRF. These findings were confirmed by qRT-PCR in both fresh and FFPE tissue. Here we describe analysis of PTPRF in FFPE tissue from the randomized phase III SATURN trial (Cappuzzo et al. 2010) Results: PTPRF expression was found to be greater in benefitting patients than in nonbenefitting patients in MERIT HR 0.50 (0.34 - 0.73), p = 0.0004 on a continuous log2 scale. Results from SATURN further suggested predictive characteristics for PTPRF, with a larger treatment effect observed in patients with high levels as defined above median. Conclusions: Data from MERIT and SATURN suggest PTPRF to be a possibly prognostic marker for OS in NSCLC and potential predictive marker for treatment with erlotinib. This gene family is very interesting and further research, especially MoA is warranted. [Table: see text]