bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel treatment for ovarian cancer (OC): Anti-Müllerian inhibiting substance type II receptor (MISRII) humanized monoclonal antibody (mAb) 3C23K—Preclinical validation.
Authors: Gaucher Christine , Jacquet Alexandra , Kersual Nathalie , Garambois Veronique , Fontayne Alexandre , Fournier Nathalie , de Romeuf Christophe , Tosi Diego , Sadoun Alain , Brune Frederique , Prost Jean-Francois , Urbain Remi , Pelegrin Andre , Teulon-Navarro Isabelle
Published: March 2020

5069

Background: Expressed on most OC subtypes while displaying a restricted expression profile in adult normal tissues, MISRII represents a potentialtarget for OC immunotherapy. We present here the preclinical assessment of a humanized anti-MISRII EMABling mAb, 3C23K. Methods: Either quantitative RT-PCR or immunohistochemistry (IHC) studies were performed to confirm MISRII expression profile in Granulosa Cell Tumor (GCT) or Epithelial OC (EOC) patient samples and to evaluate tissue cross-reactivity. For in vitro and in vivo experiments, we have generated 4 patient-derived MISRII expressing EOC cell lines. Xenograft studies were conducted in swiss nude mice on established tumors (100 mm3). Mice received 2 to 3 weekly i.p. injections (10 mg/kg/inj) for 4 to 6 wks and tumor volumes were compared with control groups. Comparison of i.p. vs i.v. injections were assessed as well as combination with carboplatin (once a week for 4 weeks, 60 mg/kg/inj). In addition, 3C23K plasma level was monitored to determine half-life. Results: 1) Target validation: we confirmed by IHC the expression of MISRII in most OC tissue sections (4/4 GCT and 13/14 EOC), meanwhile, MISRII mRNA was only detected in 7/48 normal tissues. 2) In vitro assessment: tested in vitro 3C23K displayed both cytotoxic (ADCC) and anti-proliferative activities. 3) In vivo assessment: in the mouse xenograft models 3C23K exhibited a strong anti-tumoral activity as measured by tumor volume, with T/C ratios reaching values below 0.42 shortly after the initiation of treatment. No differences in efficacy were noticed between i.p. and i.v. injections or between thrice vs twice a week administrations. In addition, similar half lives were observed for 3C23K injected either i.v. (96.9 h) or i.p (113.5 h). Finally, the combination of 3C23K with carboplatin (CP), a standard of care in OC, exhibited an even stronger anti-tumor activity with T/C values at D22 of 0.06 (3C23K+CP), 0.18 (3C23K) and 0.69 (CP) vs vehicle. Conclusions: 3C23K represents a promising candidate for OC targeted therapy and a dose-escalation phase I study is planned in patients with OC.
Tumor PIK3CA mutations, lymphocyte infiltration, and recurrence-free survival (RFS) in early breast cancer (BC): Results from the FinHER trial.
Authors: Loi Sherene , Michiels Stefan , Lambrechts Diether , Salgado Roberto , Sirtaine Nicolas , Fumagalli Debora , Claes Bart , Kellokumpu-Lehtinen Pirkko-Liisa , Bono Petri , Kataja Vesa V , Larsimont Denis , Piccart-Gebhart Martine J. , Joensuu Heikki , Sotiriou Christos
Published: March 2020

507

Background: Tumor PIK3CA mutations (mts) and lymphocyte infiltration (LI) are prognostic in BC, but their importance is unknown in HER2-positive (HER2+) BC treated with adjuvant trastuzumab (T). Methods: The FinHER trial randomized 1010 patients (pts) with pN+ or high-risk pN- BC to 3 cycles of docetaxel (D) or vinorelbine, followed by 3 cycles of FEC. Pts with HER2+ BC were further randomized to 9 weeks of T or no T (n=232). Pts treated with D and T had superior outcome in prior analyses. BC samples were subjected to somatic hotspot mt profiling (Sequenom) and quantification of percentage tumor LI using full-face H&E sections. RFS and interactions with T were explored with Kaplan-Meier and Cox regression analyses. Results: The median FU time was 62 months. 935 (92.6%) and 687 (68.1%) tumors underwent LI and mt analysis, respectively. Correlation of LI assessment between 2 pathologists was 0.78 (p<0.001). 54 mts detected in 13 genes were evaluated. PIK3CA mts (exons 1,2,9,13,18,20) was present in 25.3% (n=174) and ERBB2 mt in 4.5% (n=31) BCs. Only 1 AKT mt was found and none in KRAS, BRAF, NRAS or PTEN. In ER+/HER2-, HER2+ and ER-/HER2- subtypes the prevalence of PIK3CA mts was 30.2%, 19.5% and 9.2%; ERBB2 mt 6.3%, 1.9% and 2.6%, respectively (both p<0.05). Neither PIK3CA nor ERBB2 mts were associated with RFS overall or within BC subgroups. No interaction was found for the benefit with T and presence of PIK3CA mt in HER2+ BC (interaction p=0.17 T vs no T). Increasing LI was associated with favorable RFS in ER-/HER2- BC (continuous score adjusted p=0.032); 3-y RFS was 90% with extensive LI (>30% infiltrated) vs 66% with non-extensive LI (p=0.007). In HER2+ BC, whilst there was no association with prognosis overall, there was a significant interaction with the benefit from T vs. no T and increasing LI (continuous score interaction p=0.042) with 3-yr RFS 96% vs 78% for extensive and non-extensive LI treated with T respectively (p=0.014). Conclusions: We report 3 clinically relevant findings from this large clinical trial dataset: 1) PIK3CA mts were not prognostic; 2) LI is a strong prognostic factor in ER-/HER2- BC and 3) for the first time that extensive LI predicts benefit from adjuvant T.
BRCA1 methylation status in high-grade serous ovarian cancer (HGSOC) patients (pts).
Authors: Ruscito Ilary , Braicu Elena Ioana , Benedetti Panici Pierluigi , Chekerov Radoslav , Dimitrova Desislava , Ganapathi Ram N. , Vasconcelos Ines , Bellati Filippo , Fotopoulou Christina , Lichtenegger Werner , Olek Sven , Sehouli Jalid
Published: March 2020

5070

Background: Mutations in BRCA1/2 genes contribute to increase risk for breast and ovarian cancer (OC).Hypermethylation of CpG islands in gene promoter regions is considered a frequent mechanism associated with inactivation of tumor suppressor genes which contributes to oncogenic transformation. Studies identified methylation changes in OC pts. Most of the studies analyzed a small cohort and combined different histological subtypes. HGSOC is a special entity of OC associated with poorer OS. Aim of this study was to analyze the clinical impact of BRCA1 promoter gene methylation status in HGSOC. Methods: The cohort comprised 127 HGSOC treated by cytoreduction followed by platinum-based chemotherapy at Department of Gynecology, Charité Medical University Berlin, Germany. Fresh frozen OC tissues provided by TOC were examined to access the tumoral tissue quality. Samples presenting at least 50% of tumour area were included within this study. DNA was extracted followed by sodium bisulfite conversion, and assessment of BRCA1 gene promoter methylation rate was determined by PCR. Statistical analisys has been carried out using SPSS software. Results: In our study, 14.2% of the pts presented a hypermethylation of the BRCA1 promoter gene. The hypermethylation of BRCA1 promoter gene was significantly more frequently encountered in the younger pts (<59 yrs: 77.8% in the Hypermethylation Group vs 47.7% in the Hypomethylation Group, p=0.022). No differences in methylation status between primary and metastatic tissue from OC pts could be observed. Also no correlation with FIGO stage was observed. Optimal tumor debulking could be reached in most of the pts (57.5%), without significant differences between both groups. Platinum response rates were similar between both groups. No differences in PFS and OS could be observed. Conclusions: The study shows that HGSOC pts presenting the BRCA1 gene promoter in the methylated status, developed the disease significantly earlier with respect to OC patients with unmethylated BRCA1 gene promoter. The clinical outcome was similar in HGSOC independently from BRCA1 methylation status.
BRCA mutations and outcome in epithelial ovarian cancer (EOC): Experience in ethnically diverse groups.
Authors: Safra Tamar , Lai Wei-Chu V , Berman Tara , Borgato Lucia , Reich Elsa , Alvear Maria , Muggia Franco , Pelles-Avraham Sharon
Published: March 2020

5078

Background: EOC patients with BRCA mutations have been reported to have better prognosis than non-hereditary (NH) matched cases, an advantage shown especially in the Ashkenazi-Jewish (AJ) population. We have analyzed our experience in our ethnically diverse patient cohort from NYC, Israel and Italy. Methods: A retrospective chart review of patients diagnosed with Stage IC-IV EOC between 1995-2008 at the NYU Cancer Institute, Tel Aviv Sourasky MC and Padova Clinical Cancer Centers. Out of >700 patients, 183 were tested for BRCA mutations and evaluated. Results: Median age was 55.5 (range 31–83 years). Out of 183, 86 are carriers of BRCA1/2 mutations and 97 tested negative, 67 and 19 are carriers of BRCA1 and BRCA2 mutation respectively. Carrier frequency in EOC population is 46% (45/97) in AJ's and 48% (41/86) in non-AJ's. AJ patients had the following BRCA1 mutations: 185delAG (29), 5382insC (5), unknown (UK) (2) and BRCA2 mutations: 6174delT (8), UK (1). Non-AJ's were divided by ethnicities into non-AJ, Caucasian, African-American, Hispanic, Middle Eastern or unknown. Non-AJ Jewish patients had BRCA1 mutations in 185delAG (7) and BRCA2 in 6174delT (1), UK (1). Non-Jewish Caucasians exhibited the widest variation of mutation types, with the following BRCA1 sites: 185delAG, K1702X (5223A>T), E1373X, 3829delT, 185delAT, IVS11+1G>A, 5385insC, 5083del19>stop1670, 1720delAF>stop536, 1806C/T>Igu536Ter, del ex1a-2, cod1486ex14:4575delAstop1504, 5563G7A;Trp1815stop, 5181delGTT(Val1688del) and UK and the following BRCA2 sites: 6174delT (2), 5301insA (1), 802delAT (1), cod2960ex22:9106C/t (1), cod68ex3:432delAstop79 (1), 7408A/T;Arg2394stop (1). One African-American patient with BRCA1 at 1294del40, 1 Hispanic BRCA1 at 185delAG. OS was significantly prolonged for BRCA carriers at 93.6 months versus 63.2 months [95% CI: 44.5-91.7] (p=0.0016) for NH. Conclusions: Our data reports a wide variety of BRCA mutations in an ethnically diverse EOC population and confirms that BRCA mutations carriers have a better prognosis with a longer median survival compared to NH population. A larger cohort might manifest prognostic differences between the different types of mutations.
Serum IGFBP4 levels in combination with miliary disease: A candidate predictor of ovarian cancer progression-free survival.
Authors: Cohen Samantha
Published: March 2020

5079

Background: Insulin-like growth factor binding protein, IGFBP4, was shown to be highly expressed across all stages of epithelial ovarian cancer (EOC) and serum levels are elevated in EOC. Moreover, IGFBP4 levels are ~3x greater in women with malignant pelvic masses. We investigated whether ascites volume and the presence of miliary disease in combination with serum levels of IGFBP4 are independent predictors of survival. Methods: A prospective and retrospective analysis was performed. Patients were enrolled at the time of cytoreductive surgery. Ascites volume was either absent, <500 cc (low), or >= 500 cc (high), and the presence of miliary disease was recorded. The IGFBP4 cutoff was 1064.5 ug/ml based upon previous results. The Kaplan-Meier product limit method was used to estimate PFS probabilities. The Cox proportional hazards model was used to estimate hazard ratios (HR) and corresponding 95% CI. Results: 57 cases were included in the analysis of ascites volume and miliary disease. Cytoreductive outcomes were complete gross resection (44.8%), optimal (<=1cm residual disease; 44.8%), and suboptimal ( >1cm residual disease; 10.3%). Histologic subtypes: papillary serous (n=35; 61.4%), mucinous (n=15; 26.3%), endometrioid (n=4; 7.0%), and clear cell (n=3; 5.3%). Stage distribution was 21.1% I/II, and 78.9% III/IV. PFS was unaffected by ascites volume (p=0.341) or miliary disease. Among this cohort, 29 had IGFBP4 levels available for a separate analysis. Patients with high IGFBP4 and miliary disease were 5.5 times as likely to recur compared with patients with miliary disease and low IGFBP4 (HR=5.55 [0.77, 39.82]), and the statistical significance was borderline (p<0.088). No statistically significant differences were detected between rates of recurrence among patients with high and low IGFBP4 values in combination with ascites volume. Conclusions: These exploratory studies suggest that patients with high IGFBP4 serum levels and miliary disease were > 5 times as likely to recur compared to women with miliary disease and low IGFBP4 levels. Future studies examining these variables using a larger population and examining the biologic basis of this relationship are planned.
Prognosic value of lower uterine segment involvement in high-grade endometrial cancers.
Authors: Gehrig Paola A. , Clark Leslie Horn , Franasiak Jason , Bae-Jump Victoria Lin , Ko Emily
Published: March 2020

5092

Background: To determine the relationship of lower uterine segment (LUS) involvement and clinical-pathologic outcomes in high grade endometrial cancers (EC). Although LUS and prognosis has been previously reported in the literature, the results have been conflicting and limited to early stage cases without focus upon the highest risk histologies. Methods: A single-institution retrospective cohort analysis of all grade 3 EC from Jan 2005- Sept 2010 was performed. Clinical-pathologic data were abstracted. LUS status was determined based on permanent-section pathology. Statistical analyses were performed using univariate and bivariate analyses with t-tests, X2, and log-rank tests. Multivariate regressions were performed by cox modeling. Two sided p-values<0.05 were considered significant. Results: Of 329 cases, 52% were LUS+. Mean age was 66.1(SD 10.8) and BMI 31.7(SD 8.3). The majority were Caucasian (63.2%) and 30.1% were African-American (AA). Most women (80.2%) were overweight or obese, 58.7% had hypertension, and 22.5% were diabetic. Most women had stage I disease (54.8%), but 8.6% had stage II disease, and 36.6% had stage III-IV disease. Histologic subtypes included 32.2% endometrioid, 47.4% serous/clear cell, and 17% carcinosarcoma. Thirty-nine percent had > 50% myometrial invasion (MI) and 43.2% had LVSI. Most of the women (80.8%) underwent retroperitoneal node dissection (77.9% pelvic, 70.0% periaortic). Mean follow-up time was 24.5 months (range 0.13, 73.3). Age, HTN, and DM did not differ by LUS status. Statistically significant factors associated with LUS positivity included race AA (38.3 v 26.5%), obesity (57.5 v 46.7%), serous/clear cell (65.7 v 53.8%), LVSI (56.2 v 30.5%), deep MI (52.1 v 25.3%), and positive nodes (42.4 v 12.7%). LUS+ was significantly associated with an increased rate of recurrence (HR 2.3, CI 1.16-4.47, p =0.02) after adjusting for obesity, deep MI, LVSI, nodal status, stage, serous/clear cell histology, and adjuvant therapy. Conclusions: Lower uterine segment was independently associated with an increased rate of recurrence in high grade EC. This should be confirmed in prospective endometrial trials to see if this remains an independent predictor of recurrence.
Phase II trial of robotic stereotactic radiosurgery (SBRT) in patients with recurrent gynecologic malignancies.
Authors: Kunos Charles , Brindle James , Adams Ramon , DeBernardo Robert
Published: March 2020

5102

Background: Ablative radiation dose delivered by a robotic SBRT platform has shown progression-free survival benefit in two limited case series among patients with recurrent gynecological malignancies. The therapeutic impact of SBRT on disease progression (PD) was evaluated in the recurrent setting in this phase II trial. Methods: Fifty patients with recurrent and measurable gynecologic malignancy were treated with SBRT. The cohort included patients with recurrent ovarian (n =25), endometrial (n =14), cervical (n =9), or vulvar (n =2) cancer, 1 prior chemotherapy or radiation regimen, and GOG performance status 0, 1, 2. Patients underwent image-guided SBRT in 3 daily doses of 800 cGy = 2400 cGy. SBRT planning target volumes were determined by both the radiation and gynecologic oncologist using non-contrasted CT and 18F-FDG PET/CT overlays. The primary endpoints were 6-month clinical benefit rate (# complete response + # partial response + # stable disease without PD [by RECIST v1.0] / 50), and less than 30-day posttherapy toxicity. Results: Between July 2009 and September 2011, 50 patients were enrolled and have a median posttherapy follow-up of 9 months. At 3 months, 50% (n=25) had complete response, 46% (n=23) had partial response, and 4% (n=2) had stable disease in SBRT-targeted lesions. Twenty-six patients (52%) have had non-SBRT target PD and 18 (36%) have died of PD. Of the 50 patients, 33 had a PD-free interval of at least 6 months, for an overall clinical benefit rate of 66%. Less than 30-day posttherapy SBRT-related toxicities were grade 2 fatigue (n =9 [18%]), grade 2 nausea (n =3[6%], grade 3 nephropathy (n =2[4%]), and grade 4 hyperbilirubinemia (n =1[2%]). Conclusions: This is the first phase II clinical trial of SBRT showing a clinically relevant benefit of ablative radiation in the setting of recurrent gynecological disease. Despite excellent control of targeted lesions with minimal toxicity, non-SBRT target PD rates are high, spurring interest for future SBRT-chemotherapy clinical trials.
Validation of the predictive value of modeled HCG residual production “P” in low-risk gestational trophoblastic neoplasia (GTN) patients treated in GOG-174 phase III trial.
Authors: You Benoit , Deng Wei , Oza Amit M. , Osborne Raymond
Published: March 2020

5110

Background: In low-risk GTN, chemotherapy is changed according to serum hCG levels. We previously showed mathematical modeling of hCG kinetics provides a parameter production “P”, a useful early predictor of methotrexate (MTX) resistance (You et al; Ann Oncol 2010; ASCO and ISSTD 2011). We applied this approach to patient cohort of GOG-174 trial, in which weekly MTX (Arm 1) was compared to dactinomycin (Arm 2). Methods: Database (210 patients, including 78 with resistance) was split into 2 sets. A 126 patient Model Set was initially used to adjust model parameters. Patient hCG kinetics from day7 to day50 were fit with NONMEM™ program to: “[hCG(time)] = hCG0i * exp(–k*time) + P”; where P is residual hCG tumor production, hCG0i is the initial hCG level, and k is the rate constant. Three putative P-based classifiers of resistance were assessed using ROC analyses. Then an 84 patient Test Set with blinded-resistance status was used to assess the validity of predictions. The primary endpoint was treatment resistance defined as relapse and/or lack of hCG normalization. Results: Due to initial surge in 14% patients, hCG kinetic modeling was started on day7. Individual hCG decline profiles of Model Set patients were modeled. There was no impact of treatment arm on variability of kinetic parameter estimates. The best P cut-offs to discriminate resistant vs. sensitive patients were 7.7 in Arm 1 and 74.0 in Arm 2. They were combined to define 2 predictive groups with low vs. high risks of resistance (ROC AUC = 0.82; Se = 93.8%; Sp = 70.5%). The model was then applied to Test Set patient cohort. The predictive value of P-based predictive groups regarding resistance was reproducible (ROC AUC = 0.81; Se = 88.9% (95% CI: 70.8%-97.7%); Sp = 73.1% (95% CI: 60.0%-84.4%)). Both P and treatment arm were associated with resistance using multivariate logistic regression tests. Predictive value of P was less accurate in dactinomycin arm. Conclusions: The early predictive value of the modeled kinetic parameter P regarding resistance appears promising in GOG-174 study, especially in MTX arm. This is the second positive evaluation of this procedure study. Prospective validation is warranted.
Reduction in Ki-67 in benign breast tissue of high-risk premenopausal women with the SERM acolbifene.
Authors: Fabian Carol J. , Kimler Bruce F. , Zalles Carola M. , Petroff Brian K. , Metheny Trina , Phillips Teresa A. , Echalier Ben R. , Bailey Howard Harry , Cornelison Terri L
Published: March 2020

520

Background: Selective Estrogen Receptor Modulators (SERMs) are approved for reduction of risk for breast cancer; however, uptake and use is limited. We conducted a pilot study of a 4th generation SERM to determine tolerability and effect on tissue biomarkers in healthy women at high risk for development of breast cancer. Methods: Premenopausal women at elevated risk for breast cancer were screened by random periareolar fine needle aspiration (RPFNA) performed during the follicular phase of the menstrual cycle. Women were eligible if breast epithelial cells exhibited evidence of cytologic hyperplasia with or without atypia, as well as Ki-67 ≥2% by immunocytochemistry. Following 6-8 months of open-label acolbifene (20 mg/d), the RPFNA was repeated. The primary endpoint was modulation of the proportion of cells that expressed Ki-67. Body composition (DEXA), pelvic sonography, mammographic breast density, and serum levels of IGF-1/IGFBP3 and several bioavailable hormones were assessed pre and post intervention. Results: 76 women were screened by RPFNA, with 25 eligible and enrolled in the intervention over a 9 month period. All 25 (7 on oral contraceptives) subjects completed the study, had a second RPFNA, and were evaluable. Median Ki-67 at baseline was 4.6% (range 2.4 – 21.9%) and off study 1.4% (range 0 – 6.6%); median change was a reduction of 3.0% (range -20.2% to +2.8%; decreased in 23, increased in 2) or a relative reduction of 77%. The end-of-study Ki-67 was significantly less than baseline (p<0.001, 2-tailed Wilcoxon test). There were no statistically significant changes in cytomorphology over this short intervention period. There was a marginal effect on breast density (16 decreased; 8 increased; p=0.067). Adverse events were minimal with greatest grade of 3 reported by 2 subjects, grade 2 by 7 subjects, and grade 1 by 11 subjects. No serious adverse event was reported and no subject discontinued the study due to an AE. Conclusions: Based on preliminary evaluation showing favorable modulation of proliferation and minimal adverse events, further investigation of acolbifene, a fourth generation SERM, as a breast cancer chemoprevention agent for premenopausal women appears warranted. Supported by NO1-CN-35135.
Mucin-1 protein and mRNA expression in breast cancer: Predictive value for therapy response and survival after neoadjuvant chemotherapy.
Authors: Sinn Bruno Valentin , Von Minckwitz Gunter , Denkert Carsten , Eidtmann Holger , Darb-Esfahani Silvia , Belau Antje , Kronenwett Ralf , Holzhausen Hans-Juergen , Mehta Keyur , Loibl Sibylle
Published: March 2020

522

Background: Mucin-1 (MUC1) is expressed in normal epithelial cells and in breast cancer. Immunotherapeutic agents targeting MUC1 are currently tested in clinical trials. Methods: We evaluated the frequency of MUC1 expression by immunohistochemistry (IHC; n = 691) and quantitative RT-PCR (qRT-PCR; n = 286) in formalin-fixed paraffin-embedded (FFPE) pre-treatment biopsies from patients of the GeparTrio trial (NCT 00544765). mRNA levels were analyzed as a continuous variable, a distribution-based cut-off was chosen for IHC data. The predictive value for therapy response and survival after neoadjuvant anthracycline/taxane-based chemotherapy (CTX) was evaluated. Results: MUC1 was detectable by IHC in 95%. qRT-PCR covered a dynamic range of 3 orders of magnitude. IHC and mRNA data were correlated (p < 0.001). MUC1 was detected in higher quantities in HR+ tumors (p < 0.001), the lowest levels were found in HR-/HER2- tumors (p < 0.001). High MUC1 protein and mRNA expression were associated with lower probability of pathologic complete response (pCR) in the overall population (p < 0.001) and in HR+ (p = 0.004 and < 0.001), HER2- (p < 0.001) and HR+/HER2- tumors (p < 0.001). In multivariable logistic regression, MUC1 was independently predictive (high MUC1 protein: odds ratio (OR) 0.464, 95% CI 0.300 – 0.719, p = 0.001; MUC1 mRNA (per 20-dCT unit): OR 0.673, CI 0.546 – 0.829, p < 0.001). MUC1 protein and mRNA expression were associated with longer patient survival in the overall population (p = 0.03 and < 0.001) and in HER2- tumors (p = 0.005 and < 0.001). MUC1 mRNA was also prognostic in HR+ (p < 0.001) and HR+/HER2- tumors (p = 0.001). In multivariable analysis, protein and mRNA expression were independently prognostic (high MUC1 protein: hazard ratio (HR) 0.388, CI 0.166 – 0.907, p = 0.029; MUC1 mRNA per 20-dCT unit: HR 0.763, CI 0.595 – 0.909, p = 0.005). Conclusions: MUC1 is frequently expressed in breast cancer and detectable by IHC and qRT-PCR from FFPE tissue. Despite its association with HR+ status, it provides independent predictive information for therapy response and survival after neoadjuvant CTX. In clinical immunotherapy trials, MUC1 expression may serve as a predictive marker.
ACE inhibitors and angiotensin receptor blockers use and breast cancer outcomes in patients treated with neoadjuvant systemic chemotherapy.
Authors: Chae Young Kwang , Brown Erika N. , Lei Xiudong , Melhem-Bertrandt Amal , Giordano Sharon Hermes , Litton Jennifer Keating , Hortobagyi Gabriel N. , Gonzalez-Angulo Ana M. , Chavez-Mac Gregor Mariana
Published: March 2020

537

Background: There is a growing body of evidence to suggest that ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) might have anti-tumor properties. We investigated whether the use of ACEI/ARBs during chemotherapy affects the clinical outcomes of breast cancer patients receiving taxane and anthracycline-based neoadjuvant chemotherapy. Methods: We included in this analysis 1449 patients with diagnosis of invasive primary breast cancer diagnosed at the MD Anderson Cancer Center between 1995 and 2007 who underwent neoadjuvant chemotherapy. Of them, 160 (11%) patients were identified by review of their medical record, as ACEI/ARBs users. We compared pathologic complete response (pCR) rates, relapse-free survival (RFS), disease-specific survival (DSS) and overall survival (OS) between ACEI/ARB users and non-users. pCR was defined as no evidence of invasive carcinoma in the breast and axillary lymph nodes at the time of surgery. Descriptive statistics and Cox proportional hazards model were used in the analyses. Results: There was no difference in the pCR rates between ACEI/ARB users (16%) versus non-users (18.1%) (p=0.50). After adjustment for important demographic and clinical characteristics, no significant differences between ACEI/ARB users and nonusers were observed in RFS (HR=0.81; 95% CI=0.54-1.21; P=0.30), DSS (HR=0.83; 95% CI=0.52-1.31; P=0.42), or OS (HR=0.91; 95% CI =0.61-1.37; P=0.66). In a subgroup analysis among ARB users, the 5-year RFS was 82% vs 71% in ACEI/ARB non-users (P=0.03). In the multivariable analysis, ARB use was also associated with a decreased risk of recurrence (HR=0.35; 95% CI=0.14-0.86; P=0.02). However, no statistically significant differences in DSS or OS were seen. Conclusions: No differences in pCR and survival outcomes were seen between ACEI/ARB users and non-users among breast cancer patients receiving neoadjuvant chemotherapy. ARB use may be associated with improved RFS. Further research is needed to validate this finding.
Impact of the EndoPredict-clin score on risk stratification in ER-positive, HER2-negative breast cancer after considering clinical guidelines.
Authors: Filipits Martin , Dubsky Peter Christian , Rudas Margaretha , Brase Jan C. , Kronenwett Ralf , Weber Karsten E. , Petry Christoph , Schmidt Marcus , Luisser Irmard , Klug Evelyn , Gnant Michael
Published: March 2020

542

Background: Many ER-positive, HER2-negative breast cancer patients are treated by adjuvant chemotherapy according to current clinical guidelines. We retrospectively assessed whether the combined gene expression/ clinicopathological EndoPredict-clin (EPclin) score improved the accuracy of risk classification in addition to considering clinical guidelines. Methods: Three clinical breast cancer guidelines (National Comprehensive Cancer Center Network (NCCN), German S3 and St. Gallen 2011), and the EPclin score - assessed by quantitative RT-PCR in formalin-fixed paraffin-embedded tissue - were used to assign risk groups in 1,702 ER-positive, HER2-negative breast cancer patients from two randomized phase III trials (Austrian Breast and Colorectal Cancer Study Group 6 and 8) treated with endocrine therapy only. Results: Although all analyzed clinical guidelines identified a low-risk group with improved metastasis-free survival, the overwhelming majority of all patients (81-94%) were classified as intermediate / high risk. In contrast to that, the EPclin classified only 37% of all patients as high risk and that stratification resulted in the best separation between low and high risk groups (p < 0.001, HR = 5.11 (3.48-7.51). Consequently, the majority of all patients deemed intermediate / high risk by the clinical guidelines was re-classified as low risk by the EPclin score. Kaplan Meier analyses demonstrated that the re-classified subgroups (47 to 57% of all patients) had an excellent 10-year metastasis-free survival of 95% comparable to the clinical assigned low-risk groups although encompassing a higher proportion of the trial patients. Conclusions: The EPclin score predicted distant recurrence more accurately than all three clinical guidelines and is especially useful to reclassify patients considered as intermediate / high risk by the guidelines. The data suggests that the EPclin score provides clinically useful prognostic information beyond common clinical guidelines and can be used to accurately identify the clinically relevant group of patients who are adequately and sufficiently treated with adjuvant endocrine therapy alone.
Interpathologists discrepancies in Ki67 assessment in the PACS01 trial: An independent prognosis factor.
Authors: Penault-Llorca Frederique Madeleine , Goubar Aicha , Raoelfils Ines , Sagan Christine , Lacroix-Triki Magali , Denoux Yves , Verrielle Veronique , Jacquemier Jocelyne , Martin Anne-Laure , Roche Henri , Andre Fabrice
Published: March 2020

543

Background: Several reports suggest an inter-observer variability in Ki67 assessment. Nevertheless, there is no large study that evaluates the rate of discrepancies, together with their impact. Methods: Ki67 expression was assessed on 663 samples from patients with ER-positive breast cancers included in the PACS01 trial (Roche, J Clin Oncol, 2006). Ki67 staining was done using MiB1 antibody (Dako, Copenhagen, Denmark, Dilution 1:250). Prognostic and predictive values have been reported previously (Penault-Llorca, J Clin Oncol, 2009). A second central review was done by a senior breast pathologist from a French Cancer center. A discrepancy was defined as either a false positive or false negative result. Cut-off for positivity was defined at 15% according to data from Cheang et al (JNCI, 2009). Results: The rate of discrepancy was correlated with the percentage of stained tumor cells. A 10% discrepancy rate between the 2 pathologists was observed when the first pathologist reported <10% tumor cells stained. Same low rate of discrepancy (10%) was observed if more than 30% cancer cells were stained according to the first assessment. At the opposite, discrepancy rates were 47%, 45%, 22%, 34% when the first pathologist reported 10-15%, 15-20%, 20-25% and 25-30% tumor cells stained. Overall, 36% of the patients presented a grade II tumor together with Ki67 <10% or >30%. We then evaluated the impact of discrepancy in terms of prognosis. Patients presenting a concordant result between the two pathologists showed a better outcome as compared to patients presenting a discrepancy, independently to the percentage of tumor stained (p=0.05, patients with concordant Ki67 ranged between 10-30% versus those with one reader <10% and the other one >10%-<30%). Conclusions: Discrepancy rates between pathologists are acceptable when Ki67 is either <10% or >30%. A Ki67 ranged between 10 and 30% could define a grey zone in which Ki67 should be reported with caution or be double checked by another pathologist. Survival analysis suggested that inter-observer discrepancies could act a prognostic factor. Such finding could reflect underlying intra-tumor heterogeneity.
A phase II, randomized trial (CONCERT-1) of chemoradiotherapy (CRT) with or without panitumumab (pmab) in patients (pts) with unresected, locally advanced squamous cell carcinoma of the head and neck (LASCCHN).
Authors: Giralt Jordi , Fortin Andre , Mesia Ricard , Minn Heikki , Henke Michael , Yunes Ancona Alejandro , Cmelak Anthony , Markowitz Avi B. , Hotte Sebastien J. , Singh Simron , Chan Anthony T. C. , Merlano Marco Carlo , Zhang Alicia , Oliner Kelly S. , Vanderwalde Ari M.
Published: March 2020

5502

Background: Pmab is a fully human monoclonal antibody against the epidermal growth factor receptor. We evaluated the safety and efficacy in pts receiving CRT alone or CRT plus pmab (PCRT) as 1st‑line treatment of LASCCHN (sponsored and funded by Amgen Inc.). Methods: Pts with stage III, IVA, or IVB previously untreated LASCCHN of all sites excluding the nasopharynx were randomized 2:3 to open-label CRT or PCRT. CRT included cisplatin 100 mg/m2 for 3 cycles during standard fractionation radiotherapy (RT). PCRT included pmab 9.0 mg/kg + cisplatin 75 mg/m2, both administered with RT as in the CRT arm. The primary endpoint was local regional control (LRC) rate at 2 years; key secondary endpoints included PFS, OS, and safety. Preplanned HPV subset analysis, as determined by p16 immunohistochemistry, was performed on available samples. Results: Of 150 treated pts (87 pts PCRT, 63 pts CRT), 87% were men; median (range) age was 57 (39-77) years; ECOG PS 0: 68%. Of 99 pts with tumor evaluable for HPV, 42% were HPV+. Overall, the 2-year LRC rate (95% CI) was 61% (50%-71%) for PCRT and 68% (54%-78%) for CRT. PFS events occurred in 40% of the PCRT and 35% of CRT arm (HR [95% CI] 1.15 [0.68-1.96]; p=0.61). Death occurred in 36% of the PCRT arm vs 24% of the CRT arm (HR [95% Cl] for OS 1.63 [0.88-3.02]; p=0.12). Disease progression was the cause of death in 22% of PCRT pts and 10% of CRT pts. There were no differences in outcome by tumor HPV status. No difference in fatal adverse events (AEs) was seen between arms. Grade 3+ AEs occurred in 85% vs 68% of pts (PCRT vs CRT). Differences in grade 3+ toxicity between treatment arms (PCRT, CRT) were most pronounced for mucosal inflammation (55%, 24%), radiation skin injury (28%, 13%), dysphagia (40%, 27%), and rash (11%, 0%). RT delays of >10 days occurred in 16% of the PCRT arm and 3% of the CRT arm. Median cisplatin cumulative dose received was 223.1 mg/m2 in the PCRT arm and 296.9 mg/m2 in the CRT arm, reflective of differences in planned dose. Conclusions: The addition of pmab to CRT did not show an increase in efficacy and was associated with increased toxicity. Further results of HPV biomarker analysis will be presented.
Cetuximab, docetaxel, and cisplatin (TPEx) as first-line treatment in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): Final results of phase II trial GORTEC 2008-03.
Authors: Guigay Joel , Fayette Jerome , Dillies Anne-Francoise , Sire Christian , Kerger Joseph N. , Tennevet Isabelle , Machiels Jean-Pascal H. , Zanetta Sylvie , Pointreau Yoann , Bozec Le Moal Laurence , Brugel Ribere Lydia , Henry Stefanie , Temam Stéphane ,   GORTEC
Published: March 2020

5505

Background: Cetuximab in combination with platinum and 5FU (PFEx) has become a standard in first-line treatment of patients (pts) with R/M SCCHN. Cetuximab and taxane combinations have shown promising activity. This multicenter phase II study evaluates the efficacy and safety of cetuximab, docetaxel and cisplatin combination (TPEx) as first-line treatment in pts with R/M SCCHN. Methods: Pts were required to have WHO PS 0-1, no prior systemic therapy for R/M SCCHN, cumulative dose of cisplatin less than 300 mg/m² and no prior anti-EGFR therapy. Pts received docetaxel 75 mg/m² day 1, cisplatin 75 mg/m² day 1 and cetuximab (400 mg/m² on day 1 of cycle 1 then 250 mg/m² weekly), repeated every 21 days x 4 cycles then followed by cetuximab 500 mg/m² every 2 weeks (wks) as maintenance therapy until disease progression or unacceptable toxicity. G-CSF support with lenograstim 150 µg/m²/day was delivered after each cycle of chemotherapy. Response was assessed every 6 wks, according to RECIST. The primary endpoint was objective response rate (ORR) at 12 wks. Secondary endpoints were safety, best overall response, progression-free survival (PFS), overall survival (OS) and biomarkers. Results: 54 pts have been enrolled: 52 males, median age 57.8years (28-69), 12 (22.2%) oropharynx, 55% metastatic.48 pts could be evaluated for ORR at 12 wks: partial response, stable disease and progression were respectively found in 23 pts (PR 47.9%), 21 pts (SD 43.7%) and 4 pts (PD 8.3%). Best overall ORR was 54% (1 CR, 27 PR). The median PFS and OS were 7.1 and 15.3 months, respectively. The 1-year OS was 58.6%. Median PFS after start of maintenance therapy was 4.2 months. Toxicity was manageable with G-CSF support. Treatment related toxicities included G4 neutropenia (n=3). Grade 3 events were skin rash (n=5), hypersensitivity reaction (n=3), mucositis (n=1), fatigue (n=1) and febrile neutropenia (n=1). Alopecia was common. 1 toxic death was related to sepsis on feeding tube. Conclusions: Efficacy analysis demonstrates that TPEx regimen is effective and might be a relevant substitute for PFEx as first-line treatment in fit pts with R/M SCCHN.
Intra-arterial infusion of recombinant adenoviral human p53 gene combined chemotherapy for advanced oral cancer: A phase II double-blind randomized clinical trial.
Authors: Li Yi , Li Longjiang
Published: March 2020

5507

Background: The p53 tumor suppressor gene has been shown as having multiple anti-tumor functions and being capable of enhancing the efficacy of chemo-therapy. This study is to investigates clinical outcomes of intra-arterial infusion ofrecombinant adenoviral human p53 gene (rAd-p53) combined with chemotherapy in treatment of advanced oral cancer. Methods: Ninety-nine patients with stage III or IV oral carcinoma, satisfying with the inclusion criteria, were randomly allocated to Group I (G1: n=35; rAd-p53 plus chemotherapy), Group II (G2: n=33; rAd-p53), or Group III (G3: n=31; chemotherapy). Intra-artery infusion of rAd-p53 were given through superficial temporal artery reverse intubation at a dose 1-4 ×1012 viral particles (VP) , once every 3 days for 6 times. Chemotherapy regimen consisted of oxaplatin 200 mg/m2 on day1, bleomycin 8 mg/m2 on day 2, 6, 8 and Methotrexate 30 mg/m2 on day1, 8, for squamous cell carcinoma (SCC), and oxaplatin 200 mg/m2 on day1, 5-Fu 200 mg/m2 on day1,3 and cyclophosphamide 400 mg/m2 on day2, 8 for adenoid cystic carcinoma (ACC). Results: The complete response rate (CR) in G1 (48.5%) was significantly higher than in G2 (16.7%) and G3 (17.2%). The overall response rates (RR) were 88.6%, 54.5%, and 51.6% for G1, G2 and G3, respectively. The 3-year overall survival (OS) of G1 (82.9%) was significantly higher than the patients in G2 (60.6%) and G3 (58.1%). All those patients receiving rAd-p53 had a self-limited fever. Positive Bax immunostaining was detected in all the patients receiving rAd-p53. Conclusions: Intra-arterial infusion of combined rAd-p53 and chemotherapy may represent an alternative to the current standard treatment for the late stage oral carcinoma.
An international, double-blind, randomized, placebo-controlled phase III trial (EXAM) of cabozantinib (XL184) in medullary thyroid carcinoma (MTC) patients (pts) with documented RECIST progression at baseline.
Authors: Schoffski Patrick , Elisei Rossella , Müller Stefan , Brose Marcia S. , Shah Manisha H. , Licitra Lisa F. , Jarzab Barbara , Medvedev Viktor , Kreissl Michael , Niederle Bruno , Cohen Ezra E. W. , Wirth Lori J. , Ali Haythem Y. , Hessel Colin , Yaron Yifah , Ball Douglas Wilmot , Nelkin Barry , Sherman Steven I. , Schlumberger Martin ,   EXAM Study Group
Published: March 2020

5508

Background: MTC arises from parafollicular cells of the thyroid gland, accounts for 5-8% of thyroid cancers and represents an unmet medical need. Cabozantinib (cabo) is an oral inhibitor of MET, VEGFR2, and RET. We conducted a phase III study of cabo vs placebo (P) in pts with progressive, unresectable, locally advanced or metastatic MTC. Methods: Eligible pts were required to have documented RECIST progression within 14 months of screening. The primary efficacy measure was progression-free survival (PFS) as assessed by an independent review facility (IRF) using RECIST. Secondary efficacy measures included objective response rate (ORR) and overall survival (OS). The study has 90% power to detect a 75% increase in PFS and 80% power to detect a 50% increase in OS. Tumor assessments occurred every 12 weeks. Crossover between treatment arms was not allowed. Results: Between Sept 2008 and Feb 2011, 330 pts (median age 55 yrs; 67% male; 96% measureable disease; RET mutation status: pos 48%; neg 12%; unknown 39%; prior TKI exposure: yes 21%, no 78%, unknown 2%) were randomized 2:1 to cabo (140 mg free base [175 mg salt form] qd; n=219) or P (n=111). The planned primary PFS analysis included events through the date of the 138th event. As of 15June2011, 44.7% of pts on cabo and 13.5% on P were still receiving study treatment. Statistically significant PFS prolongation of 7.2 mo was observed; median PFS for cabo was 11.2 mo vs 4.0 mo for P (HR 0.28, 95% CI 0.19-0.40, p<0.0001). PFS results favored the cabo group across subset analyses including RET status and prior TKI use. ORR was 28% for cabo vs 0% for P (p<0.0001). An interim analysis of OS (44% of the 217 required events) did not show a difference between cabo and P. The most frequent grade ≥3 adverse events (cabo vs P) were diarrhea (15.9 vs 1.8%), palmar-plantar erythrodysesthesia (12.6 vs 0%), fatigue (9.3 vs 2.8%), hypocalcemia (9.3 vs 0%), and hypertension (7.9 vs 0%). Conclusions: This phase III study met its primary objective of demonstrating substantial PFS prolongation with cabo vs. P in a patient population with MTC and documented progressive disease in need of therapeutic intervention.
A phase II study of temsirolimus/sorafenib in patients with radioactive iodine (RAI)-refractory thyroid carcinoma.
Authors: Sherman Eric Jeffrey , Ho Alan Loh , Fury Matthew G. , Baxi Shrujal S. , Haque Sofia , Korte Susan H. , Smith-Marrone Stephanie , Xiao Han , Ghossein Ronald A. , Fagin James A. , Pfister David G.
Published: March 2020

5514

Background: Sorafenib is an oral tyrosine kinase inhibitor of multiple targets, including RAF, VEGFR1, and VEGFR2. Published response rates with sorafenib in RAI refractory thyroid cancer have ranged from 11-23%. Temsirolimus is an intravenous inhibitor of mTOR; mutations in the PI3K/mTOR/AKT pathway occur late in thyroid cancer and may be associated with aggressive disease. Methods: The study was a single institution, phase II design. Primary objective was response rate. Eligible patients (pts) had progressive, RAI-refractory/fluorodeoxyglucose (18-F)-avid, recurrent/metastatic, non-medullary, thyroid cancer; RECIST measurable disease; and adequate organ/marrow function. Sorafenib was given at 200 mg orally twice a day and temsirolimus at 25 mg intravenously weekly. 38 patients were enrolled; 37 were eligible and 36 patients started treatment between 12/18/09 – 10/20/11. Data cutoff date is 1/19/12. Fourteen pts are still actively on study. Results: Of the 37 eligible pts, demographics: female-46%; median age-64 years (30-81); histology-papillary (23)/follicular (1)/Hürthle (5)/poorly differentiated (6)/anaplastic (2); prior systemic treatment (21); prior sorafenib (6). Grade 4-5 adverse events at least possibly related to drug: grade 5 – sudden death, NOS (1 pt): grade 4 – colonic perforation (1 pt). Evaluation of best response: partial (PR) (8, including 3 with anaplastic/poorly differentiated); stable disease (SD) (21); progression (1); inevaluable (7). The partial response rate was 38% in the cohort that previously did not receive any systemic treatment. There was no correlation of response to either BRAF (10) or RAS (5) mutational status. Median time on treatment is 203 days (range 14-638 days) at the cutoff date. For the 21 pts with SD, the maximum percentage shrinkage by RECIST criteria ranged from -2% to -35% (one patient with unconfirmed PR) with a median time on treatment of 203 days (range 39-503 days). Conclusions: The combination of sorafenib and temsirolimus shows promising results in a heavily pretreated population. This study was approved and funded by the National Comprehensive Cancer Network (NCCN) from general research support from Pfizer, Inc.
Expression of p16, ERCC1, and EGFR amplification as predictors of responsiveness of locally advanced squamous cell carcinomas of head and neck (SCCHN) to cisplatin, radiotherapy, and erlotinib: A phase II randomized trial.
Authors: Austin Melissa , Schmidt Rodney , Parvathaneni Upendra , Bauman Julie E. , Hayes David N. , Papagikos Michael A. , Eaton Keith D. , Liao Jay Justin , Mendez Eduardo , Kurland Brenda F , Xiaoyu Shawn , Wallace Sarah G. , Martins Renato
Published: March 2020

5515

Background: This study evaluated the expression of p16 and ERCC1 and EGFR amplification as predictive and prognostic factors in a recently completed phase II randomized trial comparing cisplatin (100 mg/m2 on d 1, 22, 43) with radiotherapy (70Gy) +/- erlotinib (150 mg/d during radiotherapy) in locally advanced SCCHN. p16 (HPV surrogate) is a known prognostic factor in oropharyngeal SCCHN, and high ERCC1 expression has been correlated with resistance to cisplatin. EGFR gene copy number may be prognostic in SCCHN and alter response to erlotinib. Methods: Pretreatment formalin-fixed, paraffin-embedded tumor tissue was available for 84/204 patients. EGFR copy number was assessed using Vysis LSI DNA probes, and immunohistochemistry was performed on Leica Bond III machines using Lab Vision ERCC-1 (8F1) and CINtec p16 antibodies. All assays were performed in accordance with manufacturer instructions; all studies were reviewed by a single Pathologist (MA) who was blinded to patient outcome. Logistic regression and Cox regression models fit a treatment arm by marker interaction and tested selected linear contrasts. Results: Efficacy analysis showed no difference in complete response rate (CRR) and progression-free survival (PFS) between treatment arms. However, PFS in both arms was better than historical comparisons, with only 46 events over a median follow-up of 23 months. Positivity in p16 was associated with greater CRR (OR 3.5, p=0.03) and longer PFS (HR=0.38; p= 0.07). The CRR effect was greater for the erlotinib arm (OR 8.1, p=0.01) than for Arm A (OR 1.5, p=0.56). The ERCC1 (+) rate was 46% (39/84).ERCC1 expression above the median was not associated with worse CRR (OR 0.69; p=0.46) or PFS (HR 0.99; p=0.98). Only 4 tumors showed EGFR amplification precluding further analysis. Conclusions: p16(+) tumors had a better outcome, similar to other recent trials, and erlotinib seemed to increase the CRR among p16(+) tumors. ERCC1 expression did not predict chemoradioresistance in this study. EGFR amplification was too rare in the tested population to assess predictive or prognostic value.