bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of interval from surgery to chemotherapy and age in advanced-stage ovarian cancer: A GOG ancillary study.
Authors: Menzin Andrew , Java James , Lovecchio John L. , Chi Dennis , Tew William P. , Bookman Michael A. , Lichtman Stuart M.
Published: March 2020

5057

Background: To determine if an age group exists for which the interval from surgery to the initiation of chemotherapy influences progression free survival (PFS) and overall survival (OS) among women with advanced ovarian cancer treated on GOG 182. Methods: GOG 182 was a prospective, randomized trial of first-line chemotherapy in patients with advanced ovarian cancer, including those with optimal and suboptimal residual disease. Patients were randomized to one of five chemotherapy arms, employing combinations of either two or three agents delivered intravenously, with a control arm of paclitaxel and carboplatin. Chemotherapy was to be initiated within 12 weeks of primary surgery. A retrospective analysis was approved by the GOG Ancillary Study Committee to investigate the influence of age on treatment and outcomes. In that analysis, Cox regression was used to identify independent prognostic factors and estimate their covariate effects on the adjusted PFS and OS of the study population. Statistical significance was set at p<0.05. Results: The primary analysis of GOG 182 showed no differences in PFS or OS for any of the experimental arms when compared to the control regimen, and it was felt that the data from all arms could be aggregated for this analysis. Data for all regimens was pooled, and the time interval from surgery to chemotherapy was examined as a prognostic factor of survival. The interval had no statistically significant association with PFS (p=0.105). In the OS model, though, the functional form of the log interval was both significantly linear and nonlinear (p<0.001). After being flat until about 20 days (21.2 days; 95% CI, 15.0–28.2 days), the plot of log interval against log hazard increases, suggesting a changepoint time after which the associated risk of death increases. Conclusions: In this study, time interval from surgery to chemotherapy had no impact on PFS, but there was evidence of a potential time-dependent relationship with OS, which might be elucidated with a meta-analysis incorporating data from other prospective trials. Our observations did not appear to be influenced by patient age. Overall, these findings can reassure patients who are recuperating from extensive cancer surgery.
Phase I safety study of farletuzumab, carboplatin, and pegylated liposomal doxorubicin (PLD) in patients with platinum-sensitive epithelial ovarian cancer (EOC).
Authors: Kim Kenneth H. , Jelovac Danijela , Armstrong Deborah Kay , Weil Susan , Phillips Martin , Schwartz Benjamin M , Estes Jacob Michael , Alvarez Ronald David
Published: March 2020

5062^

Background: Farletuzumab (FAR) is a humanized monoclonal antibody that binds to folate receptor-α, a target which is largely absent in normal epithelium and over-expressed in EOC. A phase I and a phase II study indicate potential utility of FAR in combination with carboplatin/paclitaxel in recurrent platinum sensitive EOC. This study assessed safety and efficacy of FAR in combination with PLD/carboplatin, which has been demonstrated to have greater efficacy than carboplatin/paclitaxel in women with platinum-sensitive EOC. Methods: A multicenter, single-arm study enrolled 15 patients with platinum-sensitive EOC in first or second relapse defined by either CA-125 or RECIST. The primary endpoint is to assess safety of FAR plus PLD/carboplatin in this population. Patients were treated with weekly FAR 2.5 mg/kg plus carboplatin AUC 4-5 and PLD 30 mg/m2 every 4 weeks for 6 cycles, followed by maintenance treatment with single agent FAR until disease progression. Initial dosing of weekly 2.5 mg/kg was later amended to 7.5 mg/kg every 3 weeks. Results: 13 of 15 patients completed 6 cycles of combination therapy; one received a total of 12 cycles of chemotherapy. Two patients progressed during combination therapy: one received 3 cycles, the other 5 cycles. The median number of subsequent single agent maintenance cycles was 8 (range 0-13). No grade 4 toxicities were observed. Of 20 grade 3 toxicities in 14 patients, 3 (1 fatigue; 2 small bowel obstructions in the same patient) were deemed by the investigator to be possibly related to FAR. These events were seen during the combination phase and were deemed by the investigator to be also possibly related to chemotherapy. All patients demonstrated clinical benefit: 1 complete response, 10 partial response and 4 stable disease. 7 patients have come off study, all for disease progression; a median PFS of 11 months was noted. 8 patients remain on study. Conclusions: These preliminary data indicate that the safety profile of FAR in combination with carboplatin and PLD is consistent with that historically recorded for carboplatin and PLD alone. Complete safety profile will be assessed; PK data and final results will be presented.
Management of antiangiogenics’ renovascular safety in ovarian cancer subgroup and intermediate results of the MARS study.
Authors: Launay-Vacher Vincent , Janus Nicolas , Gligorov Joseph , Selle Frédéric , Goldwasser Francois , Mir Olivier , Spano Jean-Philippe , Thery Jean Christophe , Beuzeboc Philippe , Daniel Catherine , Rey Jean-Baptiste , Jouannaud Christelle , Morere Jean F. , Oudard Stephane , Azizi Michel , Dorent Richard , Deray Gilbert , Ray-Coquard Isabelle
Published: March 2020

5067

Background: Anti-VEGF drugs (AVD) are widely used in cancer patients (pts). Hypertension (HTN) and proteinuria (Pu) are class-side-effects of AVD, related to the inhibition of the VEGF pathway. The MARS study has been conducted to assess the renovascular tolerance of these drugs in the clinical setting. Methods: Hypertension (HTN) and proteinuria (Pu) are class-side-effects of anti-VEGF drugs (AVD), related to the inhibition of the VEGF pathway. The MARS study has been conducted to assess the renovascular tolerance of these drugs in the clinical setting. Results: Among 77 OC pts been included, 38 completed the study to date (1-year follow-up (f/u)). Median age at inclusion (introduction of the AVD) was 62 years. Diabetes and HTN prevalences were 5.2% and 7.9%, respectively. Baseline renal assessment retrieved: Pu 13.2%, Hu 7.9%, mean aMDRD 80.9 ml/min/1.73m2 and 3 pts with aMDRD<60. The incidence of de novo Pu during f/u was 36.4% (Table). All pts with Pu at inclusion improved, except one. Among pts with de novo Pu, 58.3% afterwards improved/normalized. No Grade 3/4 Pu has been reported (at inclusion or during f/u) and no Hu. 17.1% developed HTN. In addition, a mean renal function decrease of -2.7 ml/min/1.73m2/year was observed and 4 pts had aMDRD<60 at the end of f/u. 36.4% had grade 1 SCr increase (median increase of 15.9%) No thrombotic micro-angiopathy (TMA) has been reported. Conclusions: The results of the MARS subgroup of OC pts shows that 1) TMA remains rare, 2) Pu develops in 36.4% of the pts, however with no Grade 3/4, 3) less than 20% developed HTN, and 4) renal function was not especially impaired. Furthermore, in case of a renovascular effect, investigators followed the recommendations from the French Society of Nephrology (Halimi JM et Al. Nephrol Ther 2008) and no treatment withdrawal for unmanageable renovascular toxicity occurred. [Table: see text]
A phase II study of pazopanib in recurrent or persistent ovarian (EOC), peritoneal (PPC), or Fallopian tube cancer (FTC): A Spanish Ovarian Cancer Group (GEICO) study.
Authors: Oaknin Ana , Gonzalez-Martin Antonio , García Yolanda , Catot Silvia , Caballero Cristina , Garcia-Donas Jesus , Bover Isabel , Santaballa Ana , Guerra Eva , Pardo Beatriz , Vidal Laura , Marquez Raul , Rodriguez-Freixinos Victor , Romero Ignacio , Poveda Andres
Published: March 2020

5068

Background: Pazopanib (P) is a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/β, and c-kit that inhibits angiogenesis. Signaling blockade of these pathways is associated with anti-tumor and anti- angiogenesis activity. Methods: Eligible patients (pts) had persistent or recurrent EOC/PPC /FTC up to 2 prior cytotoxic regimens. They had to have received at least a platinum–based line and fulfill platinum resistant criteria. Treatment consisted of P 800 mg orally QD until disease progression or prohibitive toxicity. The primary endpoint was Clinical Benefit Rate (CBR) defined as Complete Response (CR) plus Partial Response (PR) plus Stable Disease (SD) ≥ 8 weeks by RECIST v1.1.An optimal two-stage Simon design was utilized with H1and H0set at 60%and 40% respectively; Power =90% significance level of 5% (Stage 1: = 25pts; total=66). Correlative studies to identify angiogenic biomarkers to predict response to P were performed. Results: From 12/10 to 7/11, 25 pts were enrolled, 21 pts had EOC, 2PPT, and 2FTC. Median age: 64 years (range 43-81), ECOG 0/1/2:12/11/2 pts. Prior chemotherapy regimens 1/2:10/15 pts. Median weeks on treatment: 8 (range 4-25). Most frequent adverse events (AEs) were asthenia (56%), hypertension (36%) and diarrhea, nausea and anorexia (20% each).Grade 3 toxicities: Hypertension (6pts), ALT/AST elevations (3 pts), asthenia (2 pts), DVT (1pt), Fistula (1 pt), Anemia (1 pt). Six pts required dose reduction to 600 mg due to toxicity.Reasons for stopping study treatment: PD (18pts), AEs (3pts) and investigator decision (2pts). First stage analysis showed: PR:1/25, SD: 9/25, CBR:10/25; 40% (95% CI 21.1%-61.3%).No correlation between GCIG CA-125 response and RECIST criteria was established, 8 versus 1 response respectively. Median PFS was 1.83 months (95% CI 1.67-2). Conclusions: The CBR observed at the first stage did not reach the planned statistical hypothesis (CBR:12 pts). Therefore, the lack of activity of P in platinum resistant EOC/PPT/FT led to discontinuation of the study. Translational study results will be presented in an additional abstract.
Inflammatory and nutritional markers as predictors of longer hospital stay and suboptimal residual disease (RD) in ovarian cancer (OVCA).
Authors: Torres Michelle , Hartmann Lynn C. , Cliby William , Kalli Kimberly , Jatoi Aminah , Weaver Amy , Block Matthew Stephen , Mariani Andrea
Published: March 2020

5076

Background: Advanced OVCA should be managed aggressively, and extensive surgery has been the most accepted initial treatment. Medically unfit patients or those with extensive disease, in which complete cytoreduction is unlikely, may not benefit from upfront radical surgery, and neoadjuvant chemotherapy might be an appropriate alternative. Thus, reliable preoperative indicators of surgical outcome are necessary for considering primary surgery vs. neoadjuvant chemotherapy. Our aim is to determine if C-reactive protein (CRP), IL-6, albumin and Glasgow Prognostic Score (GPS – score based on CRP and albumin) correlate with overall survival (OS), length of hospital stay (LOS), surgical morbidity, and suboptimal cytoreduction. Methods: We randomly selected 50 stages III/IV OVCA who underwent surgery as a primary treatment between July 2002 and June 2009 at Mayo Clinic with serum albumin levels and frozen serum available. CRP and IL-6 were measured in stored serum. Univariate and multivariate regression models were fit to evaluate associations with each of the outcomes. Results: Among the 50 patients, the mean age was 67.7 years. 34% had pretreatment albumin <3.5 g/ml, 22.4% had CRP level ≥10 mg/l, 26.5% had IL-6 ≥24 pg/ml and 45% had abnormal GPS score. At 1, 3 and 5 years following surgery, the OS was 75.6%, 49.8% and 36.9%, respectively. RD (0, <1, ≥1cm; p<0.001) was the only independent predictor of OS. Also, IL-6 (p=0.028) and stage (p=0.046) were independently associated with LOS, but no inflammatory or nutritional markers were significant associated with post surgical complications. Stage IV (p=0.019) and elevated CRP (p=0.044) were independent predictors of suboptimal surgery (RD ≥ 1cm). Conclusions: One-third of the patients in our series had low serum albumin at the time of the OVCA diagnosis, and at least one-fourth had elevated inflammatory markers. Advanced stage and elevated inflammatory markers (CRP and IL-6) were independent predictors of longer hospital stay and suboptimal debulking. These pilot data, if confirmed in a larger population, may help in the selection of candidates for neoadjuvant chemotherapy.
Progression-free survival (PFS) as a surrogate end point for overall survival (OS) in first-line treatment of advanced epithelial ovarian cancer (EOC).
Authors: Sjoquist Katrin Marie , Lee Chee , Lord Sally , Chatfield Mark D. , Friedlander Michael , Simes John , Marschner Ian
Published: March 2020

5081

Background: The duration and cost of clinical trials of first-line chemotherapy in advanced EOC could be reduced if a surrogate endpoint were used in place of OS. The consensus of the Gynecological Cancer Intergroup was that PFS is the preferred primary end point for these trials due to potential confounding of post-progression therapy on OS. We performed a systematic review to assess the extent to which treatment effect on PFS is predictive of OS in this patient population. Methods: Randomised trials of first-line chemotherapy comparing platinum containing regimens in advanced EOC were identified; trials with non-platinum backbone, maintenance strategies or biological containing therapies were excluded. Summary data (hazard ratios (HR), median PFS and OS and the ratios of medians between treatment arms) were extracted. Weighted least-square (WLS) R2 by trial sample size derived using linear regression was used to report correlation. Results: 15 eligible trials with 19 treatment comparisons were identified comprising a total of 16,598 patients. There was a good correlation between treatment effect on PFS and OS (correlation of HR: r, 0.88, WLS R2, 0.71; correlation of ratios of medians: r, 0.84, WLS R2, 0.72). Good correlation between treatment effect on PFS and OS was also observed in various prognostic subgroups (Table). Conclusions: In clinical trials of first-line platinum based chemotherapy without biological agents in advanced EOC, treatment effect on PFS and OS is highly correlated. PFS could be considered as a primary end point when evaluating future first line strategies in advanced EOC. [Table: see text]
Prevalence of high-risk human papillomavirus in uterine cervical lesions among older Japanese women.
Authors: Takehara Kazuhiro , Nakamura Hiroko , Samura Osamu , Mizunoe Tomoya , Saito Akihisa , Kuraoka Kazuya , Nishiwaki Morie , Taniyama Kiyomi
Published: March 2020

5084

Background: To estimate the prevalence and genotypes of high-risk human papillomavirus (HPV) among older Japanese women, using liquid-based cytology (LBC). Methods: ThinPrep LBC specimens were collected from 11,039 Japanese women (age range, 14-98 years). After classifying cytodiagnosis, specimens were analyzed for HPV DNA using the multiplex polymerase chain reaction method. Cervical smear specimens from 1,302 women showed positive results. To examine the prevalence of HPV in women defined as negative for intraepithelial lesion or malignancy (NILM), 2,563 samples were randomly selected from the remaining 9,737 women. Comparisons were made between women ≥50 years of age (older age group) and women <50 years of age (younger age group). Written informed consent was obtained from all patients. In this study, the high-risk HPV genotypes encountered were 16, 18, 31, 33, 35, 45, 52, and 58. Results: In the older age group with abnormal smear findings, HPV genotypes were detected in 49.7% (148/298), including high-risk HPV genotypes in 40.9% (122/298). In the younger age group with abnormal smear findings, HPV genotypes were detected in 71.7% (720/1004), including high-risk HPV genotypes in 58.1% (583/1,004). In NILM, HPV-positive rates were 4.5% (39/873) in the older age group and 11.8% (199/1,690) in the younger age group. In high-grade squamous intraepithelial lesion (HSIL) or more severe cytological findings, HPV genotypes of each group (older age group/younger age group) were detected in 61.7%/83.1%, and high-risk HPV genotypes were detected in 56.4%/74.7% of women. In positive cervical smears, HPV 16 was the most frequently detected (28.5%) in the younger age group, while HPV 52 (31.3%) and 58 (27.2%) were detected more frequently than HPV 16 (18.4%) in the older age group. Conclusions: In Japan, although HPV infection as a cause of abnormal cervical cytology is more frequent among younger age groups than in older age groups, high-risk HPV infection was more highly associated with older individuals (older age group/younger age group: abnormal smear findings, 82.4%/81.0%; HSIL or more severe cytological findings, 91.3%/89.9%). In older age groups, HPV 52 and 58 were more frequent than HPV 16.
Nuclear Y-box binding protein-1 expression as a prognostic marker and correlation with epidermal growth factor receptor expression in cervical cancer.
Authors: Nishio Shin , Ushijima Kimio , Takemoto Shuji , Sasajima Yuko , Tsuda Hitoshi , Kasamatsu Takahiro , Kamura Toshiharu
Published: March 2020

5085

Background: Y-box binding protein-1 (YB-1) is a member of the cold shock protein family and functions in transcription and translation. Many reports indicate that YB-1 is highly expressed in tumor cells and is a marker of tumor aggressiveness and clinical prognosis. Overexpression of epidermal growth factor receptor (EGFR) has been associated with poor outcomes in cervical cancer (CC). Clinical trials have shown that EGFR inhibitors are effective against CC (JCO 2011). Nuclear YB-1 expression correlates with EGFR expression in various types of cancer. Methods: Nuclear YB-1 expression was immunohistochemically analyzed in tissue specimens obtained from 204 CC patients who underwent surgery. Associations of nuclear YB-1 expression with clinicopathological factors such as survival and EGFR (HER1 and HER2) expression were investigated. Results: Nuclear YB-1 expression was observed in 41 (20%) of 204 cases and correlated with stage, tumor diameter, stromal invasion, and lymph-node metastasis. Nuclear YB-1 expression also correlated with both HER1 expression (p=0.0114) and HER2 expression (p=0.0053). Kaplan-Meier survival analysis showed that nuclear YB-1 expression was significantly associated with poor outcomes in terms of progression-free survival (p=0.0033) and overall survival (p=0.0003). On multivariate analysis, stromal invasion, parametrial invasion, and nuclear YB-1 expression were independent predictors of survival. Conclusions: Nuclear YB-1 expression is a prognostic marker and correlates with EGFR expression in CC.
External validation of a nomogram predicting overall survival (OS) of women with uterine leiomyosarcoma (ULMS).
Authors: Iasonos Alexia , Keung Emily , Zivanovic Oliver , Mancari Rosanna , Peiretti Michele , Nucci Marisa , George Suzanne , Colombo Nicoletta , Carinelli Silvestro , Hensley Martee Leigh , Raut Chandrajit P.
Published: March 2020

5090

Background: A nomogram for predicting OS of women with ULMS was developed , given the poor prognostic performance of FIGO and AJCC staging systems. We aimed to determine the validity of the ULMS nomogram using independent, external cohorts. Methods: The ULMS nomogram incorporates 7 clinical characteristics: age at diagnosis, tumor size, grade, involvement of cervix, locoregional metastases (direct extrauterine spread, locoregional lymph node), distant metastases, and mitotic index (per 10 HPF) to predict OS following primary surgery. Two independent cohorts from sarcoma centers (1 US, 1 Europe) were included. Eligible women were treated at the institutions (1994-2010) and had undergone hysterectomy. Women with locally advanced or metastatic disease who underwent more extensive surgery were included if the primary tumor (uterus) was resected. Women who previously underwent resection of the primary tumor or recurrences at other institutions were included if they received followup care at 1 of the centers. Women who presented with unresectable disease who never underwent surgery and those with insufficient information on any of the nomogram variables were excluded. Results: 187 women with ULMS were identified who met the above criteria (median age 51 yrs, median tumor size 9 cm, median mitotic index 20). Tumors were generally high grade (88%), FIGO stage I-II (61%) without cervical involvement (93%) and without locoregional (77%) or distant metastases (83%). Median and 5-yr OS rates were 4.5 (95% CI 3.2-5.3) yrs and 46%, respectively; 65 women (35%) were alive at last follow up. The nomogram concordance index was 0.67(SE=0.02) which was as high as the concordance index from the initial cohort used for nomogram development. The concordance between actual OS and nomogram predictions suggests excellent calibration of the nomogram in the validation cohort. Predictions were within 1% of actual 5-yr OS rates, except for the patients with a 5-yr OS rate of greater than 0.68. Conclusions: The ULMS nomogram was externally validated and can be generalized to independent cohorts. The nomogram provides a more individualized and accurate estimation of OS of women diagnosed with ULMS following primary surgery.
Phase II trial on cisplatin-doxorubicin hydrochloride-paclitaxel (TAP) combination as neoadjuvant chemotherapy (NACT) for locally advanced cervical adenocarcinoma (LACA).
Authors: Raspagliesi Francesco , Ramondino Stefano , Zanaboni Flavia , Ditto Antonino , Solima Eugenio , Grijuela Barbara , Spatti Gian Battista , Gabbanini Massimo , Mancini Maria , Martinelli Fabio , Amaya De Carrillo Carla , Fontanelli Rosanna , Lorusso Domenica
Published: March 2020

5096

Background: NACT followed by surgery is a different therapeutic approach to locally advanced cervical cancer that seems to offer specific advantages over chemoradiation such as potential activity against distant micrometastases, a debulking effect improving subsequent surgical outcome, less toxicity, and an easier management of salvage therapy. This phase II trial was designed to evaluate the toxicity and activity of NACT with TAP in patients with LACA. Methods: Patients (pts) with FIGO stage IB2 (9 pts)- II (21 pts) uterine adenocarcinoma were treated with cisplatin 70 mg/mq, doxorubicin hydrochloride 45 mg/mq and paclitaxel 150 mg/mq day 1 every 21 days for 3 cycles. Eight pts (26.6%) presented with positive lymphnodes ( +LY) at diagnosis (5 pelvic and 3 pelvic+paraortic). After the last cycle of chemotherapy patients underwent radical surgery with lymphnode dissection. Clinical responses to chemotherapy was evaluated according to Recist criteria. Pathological response was classified as no residual tumor (pCR), residual disease with <3 mm stromal invasion (pR1) or residual disease with >3 mm stromal invasion (pR2). Due to the slow accrual the trial was closed before the target population of 45 pts was reached. Results: Between 2003 to 2010, 30 women were enrolled. Two complete clinical responses (6.7%), 21 partial responses (70%) and 7 stabilizations of disease (23.3%) were registered. All the patients underwent radical surgery and were assessable for pathologic responses. Five patients (16.6%) achieved a pCR , 8 (26.6 %) a pR1 response; 17 patients (56.7%) a pR2 response. At pathological assessment 10 pts (33.3%) presented with +LY (7 pelvic, 1 paraortic, 2 pelvic+paraortic). At a median follow up of 45 months progression free survival and overall survival were 37 months (95% CI 1-98) and 45 months (95% CI 9-101+) respectively. Hematologic toxicity was the most relevant side effect with 13 pts (43 %) reporting grade 3-4 neutropenia. Conclusions: The TAP combination seems to be feasible with an acceptable toxicity profile and a promising response rate for the treatment of LACA. The effect of NACT on lymphnodes status warrant further investigation.
Analysis of somatic mutation in miRNAs and miRNA regulation-related genes in gynecological cancers: New frameshift mutation of TNRC6A found in endometrial cancer.
Authors: Mei Qi , Yang Yang , Honisch Ellen , Yu Shi Ying , Janni Johann Wolfgang , Niederacher Dieter
Published: March 2020

5097

Background: Micro RNAs (miRNAs) are small non-coding RNAs which plays an important role in tumorigenesis and mutation of a miRNA gene or miRNA regulation-related gene may cause butterfly effect on alteration of global gene expression.In order to investigate this hypothesis,high resolution melting analysis (HRM) and denaturing high-performance liquid chromatography (DHPLC) were used to screen 20 miRNA genes and 6 miRNA regulation-related genes for mutations in gynecologic cancers. Methods: In this study,182 DNA samples from breast cancer tumors,42 from ovrian cancers and 28 from endometrial cancers were obtained.18 human cancer cell lines were also included.We used HRM and/or DHPLC to screen mutations of these genes in human cancer cell lines and tumor tissues. All samples with curves that differed in shape compared to wild-type were directly sequenced for confirmation.Secondary structures for the wild-type and variant primary precursor of miRNA sequences obtained from sequencing were predicted using RNAfold software.Western blot and immunohistochemistry were used to evaluate the related protein change in cancer cell line and tumor tissues. Results: Polymorphisms of these genes were very frequently observed in gynecologic cancers.Two rare variants were found in the primary precursor sequences of mir-200c and mir-142 gene.Moreover,a novel frameshift mutation( c.3547_3548insA) in TNRC6A gene was found in two endometrial cacner cell lines (RL95-2 and Hec-1A) and endometrial cancers (1/28).Western blot and immunohistochemistry showed loss of expression of TNRC6A protein in the endometrial cacner cell lines and endometrial cancers with this mutation. Conclusions: Two rare novel variants in 20 miRNA genes and a novel frameshift mutation in TNRC6A gene were identified in gynecologic cancers.Oue data indicate that mutations in TNRC6A gene may contribute to the cancer development and might be a potential new therapeutic target in endometrial cacner.
Randomized trial of marker-directed versus standard schedule zoledronic acid for bone metastases from breast cancer.
Authors: Coleman Robert Edward , Wright Jonathan , Houston Stephen , Agrawal Rajiv , Purohit Om Pra-Kash , Hayward Larry , Simmonds Peter , Waterhouse Anna , Marshall Helen ,   BISMARK Investigators
Published: March 2020

511

Background: Zoledronic acid (ZOL) reduces skeletal morbidity associated with metastatic bone disease by 30-50%. Current recommendations are for indefinite administration of intravenous 3-4 weekly (w) ZOL 4mg. Over recent years it has become clear that the risk of skeletal morbidity is related to the rate of bone resorption. We have compared a marker directed schedule of ZOL (M-ZOL), using measurements of urinary n-telopeptide of type I collagen (NTX), to a standard treatment schedule (S-ZOL) in patients with bone metastases from breast cancer. Methods: The primary endpoint was skeletal related events (SRE). A non-inferiority study was designed with 80% power and (one-sided) 5% alpha to demonstrate that M-ZOL retained 67% of the efficacy of S-ZOL. This required 1500 patients, assuming a SRE rate of 0.7/year. Following minimisation for known prognostic factors, patients were randomised to receive S-ZOL 3-4 w or M-ZOL (15-16w; 8-9 w or 3-4w if NTX levels were <50, 50-100, >100 nmol/mmol creatinine respectively), with the schedule adjusted according to NTX measured every 16 weeks. The study duration was 24 months. Results: Due to lower than expected recruitment, the study closed in 2009 following recruitment of 289 patients. 90% of patients had received >4 cycles of ZOL or pamidronate prior to randomisation. The median number of ZOL infusions administered to S-ZOL patients was >2x that received on M-ZOL. 46 (32%) S-ZOL and 55 (38%) M-ZOL patients experienced an SRE. The numbers of SRE were 94 and 138 in the S-ZOL and M-ZOL arms, with the excess in SRE being largely due to more patients on M-ZOL experiencing ≥2 SRE. Multivariate analysis adjusting for key minimisation factors and baseline NTX for all SRE showed a hazard ratio for M-ZOL vs. S-ZOL of 1.41 (90%CI 0.98-2.02, p=.12). NTX levels were significantly higher at all time points in the M-ZOL treated patients. Osteonecrosis of the jaw was uncommon with 3 cases with S-ZOL and 1 with M-ZOL. Conclusions: The study is underpowered to demonstrate non-inferiority in SRE outcome between the treatment strategies. However, the results suggest that the adjustment of ZOL schedule based on NTX values alone may represent sub-optimal management.
Genetic variants associated with toxicity-related discontinuation of adjuvant aromatase inhibitor (AI) therapy.
Authors: Henry Norah Lynn , Skaar Todd C. , Dantzer Jessica , Li Lang , Nguyen Anne T , Rae James M. , Desta Zeruesenay , Oesterreich Steffi , Philips Santosh , Carpenter Janet S , Storniolo Anna Maria , Stearns Vered , Hayes Daniel F. , Flockhart David A. ,   Consortium on Breast Cancer Pharmacogenomics
Published: March 2020

525

Background: Discontinuation of adjuvant AI therapy due to intolerable symptoms occurs in up to 30% of patients. Predictors of which patients will be unable to tolerate these medications have not been defined. We hypothesized that inherited variants in candidate genes are associated with treatment discontinuation because of AI-associated toxicity. Methods: We prospectively evaluated reasons for treatment discontinuation in women with hormone receptor positive breast cancer initiating adjuvant AI through a multicenter, prospective, randomized clinical trial of exemestane (exe) versus letrozole (let). Using multiple genetic models, we evaluated potential associations between 136 single nucleotide polymorphisms (SNP) in 24 candidate genes, selected a priori, primarily with roles in estrogen metabolism and signaling, and discontinuation of AI therapy because of toxicity. To account for multiple comparisons, statistical significance was defined as p<0.0003. Results: Of the 467 enrolled patients who had available germ line DNA, 152 (33%) discontinued AI therapy because of toxicity. After adjusting for multiple covariates, multivariable analyses revealed that two inherited genetic variants in ESR1, which encodes estrogen receptor (ER) alpha, and one in CYP19A1 were associated with increased risk of discontinuation of AI therapy because of toxicity (Table). A variant in NCOR1 (ER co-repressor) was associated with decreased risk of discontinuation of letrozole because of toxicity. Conclusions: Variants in genes involved in estrogen metabolism and signaling may be associated with toxicity of AI therapy. [Table: see text]
Impact of adjuvant trastuzumab on outcomes of HER2-positive breast cancer patients treated with HER2-targeted therapy in the metastatic setting.
Authors: Murthy Rashmi Krishna , Varma Ankur , Mishra Priyankana , Hess Kenneth R. , Young Elliana J. , Murray James L. , Koenig Kimberly Higginbotham , Green Marjorie C. , Moulder Stacy L. , Melhem-Bertrandt Amal , Booser Daniel J. , Valero Vicente , Hortobagyi Gabriel N. , Esteva Francisco J.
Published: March 2020

527

Background: Trastuzumab (T) was approved for the adjuvant treatment of women with early-stage, HER-2 overexpressing (HER2+) breast cancer in 2006. There are limited data outlining the outcomes of patients with HER2+ breast cancer who receive adjuvant T-based therapy and then receive T and/or lapatinib in the metastatic setting. Methods: We identified 540 patients with HER2+ breast cancer treated with T or lapatinib as part of their first-line treatment for metastatic disease from 01/1997 to 11/2011. HER-2 positivity was assessed by immunohistochemistry (score, 3+) or fluorescence in situ hybridization (HER2/CEP17 ratio ≥ 2). We excluded 17 patients from this analysis because they were either lost to follow-up or received less than 2 cycles of therapy at the institution. Statistical analyses were performed using the chi-square test to compare proportions between groups and the Cox proportional hazards regression analysis to compare survival times and estimate the corresponding hazard ratio with 95% confidence interval. Results: Of the 523 patients eligible for analysis, 76 patients had received T in the adjuvant setting and 447 had not. In the group who did not receive adjuvant T, 48% (213/447) of patients achieved a complete or partial response (CR/PR), whereas only 13% (14/76) achieved a CR/PR in the adjuvant T group (P<.0001). After adjustment for age, disease-free interval, post-menopausal status, stage at presentation, ER/PR status, and nuclear grade, the odds ratio was 0.27 (CI 0.13 - 0.56, p = 0.0004). Overall survival from first evidence of metastasis was significantly longer in the group who did not receive adjuvant T (39 months vs. 24 months, HR = 1.8, 95% CI 1.3-2.4). For OS, the adjusted hazard ratio was 1.5 (CI 1.04 - 2.1, p = 0.029). Age, DFI and stage were also significant predictors of OS. Conclusions: Patients with HER2+ metastatic breast cancer who were T naive, had a higher response rate (CR/PR) to front line HER2 targeted therapy and a longer OS compared to patients with metastatic HER2+ breast cancer who received T in the adjuvant setting. These findings highlight the importance of recognizing a pre-treated population and calls for further research in this area.
Phase Ib study of open-label AMG 386 plus paclitaxel (P) and trastuzumab (T) or capecitabine (C) and lapatinib (L) in patients (pts) with HER2+ locally recurrent or metastatic breast cancer (MBC).
Authors: Wildiers Hans , Goncalves Anthony , Kemeny Margaret , Swart Rachel Elizabeth , Freyer Gilles , Nanayakkara Nuwan , Wu Benjamin , Pickett-Gies Cheryl Ann , Kaufman Peter Andrew
Published: March 2020

529

Background: AMG 386, an investigational peptibody, reduces tumor angiogenesis by blocking interaction of angiopoietins 1 and 2 with the Tie2 receptor. This interim analysis evaluates the tolerability and efficacy of AMG 386 + P/T or C/L in HER2+ MBC. Methods: In part 1, pts in cohorts A1 and A3 (no prior 1st-line MBC T or L ) received AMG 386 IV QW plus P 80 mg/m2 IV QW and T 8 mg/kg loading dose, then 6 mg/kg Q3W; pts in cohorts B1 and B3 (history of failed 1st-line MBC T treatment; no prior L or C) received AMG 386 IV QW plus C 1000 mg/m2 PO Q12 hrs, days 1-14 Q21D and L 1250 mg PO QD. A1 and B1 received AMG 386 at 10 mg/kg; A3 and B3 received AMG 386 at 30 mg/kg. In part 2, cohorts were expanded to n = 20 if ≤ 1 of 6 or ≤ 2 of 9 pts had dose-limiting toxicities (DLTs). Primary endpoints were adverse events (AEs) and DLTs; secondary endpoints included efficacy and pharmacokinetics (PK). Interim results from A1, A3, and B1 will be presented. Results: 46 pts were enrolled at interim analysis; all received ≥ 1 dose of study treatment (A1, A3, B1; n = 20, 6, 20). The median follow-up for A1, A3, and B1 was 39.6, 22.7, and 31.3 wks. Across cohorts, there was 1 DLT in A1. AEs > 50% were peripheral edema, diarrhea, fatigue and alopecia in A1 and A3 combined, and diarrhea, nausea, palmar-plantar erythrodysaesthesia syndrome (PPES), and peripheral edema in B1. AEs grade ≥3 occurring in > 2 pts were peripheral neuropathy, peripheral sensory neuropathy, dyspnea (n = 5, 4, 3, respectively, in A1 and A3 combined); PPES, diarrhea, and neutropenia (n = 6, 5, 3, respectively, in B1). Objective response rates were 80% in A1, 50% in A3, and 50% in B1. Median (95% CI) progression-free survival was 14.5 mo (6.8-20.5) in A1 and 10.1 mo (3.7-14.7) in B1. Median duration of response (DOR) was 12.6 mo (4.3-20.2) in A1 and 8.5 mo (4.1-not evaluable) in B1. PFS and DOR were not yet evaluable in A3. No changes were apparent in any PK parameters in these combinations relative to within study or historical monotherapy PK data. Conclusions: In this ongoing phase 1b study of pts with HER2+ MBC, interim results suggest that adding AMG 386 to P/T or C/L is tolerable and has antitumor activity. Updated data will be presented.
Phase IB/II study of the HSP90 inhibitor AUY922, in combination with trastuzumab, in patients with HER2+ advanced breast cancer.
Authors: Kong Anthony , Rea Daniel , Ahmed Samreen , Beck J. Thaddeus , López López Rafael , Biganzoli Laura , Armstrong Anne , Aglietta Massimo , Alba Emilio , Campone Mario , Akimov Mikhail , Matano Alessandro , Lefebvre Caroline , Lee Soo-Chin
Published: March 2020

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Background: AUY922 is a novel HSP90 inhibitor that causes degradation of oncogenic proteins. A Phase I study in advanced solid tumors gave a recommended Phase II dose (RP2D) of 70 mg/m2. In the Phase II part of the study, single-agent AUY922 showed preliminary activity in HER2+ metastatic breast cancer (mBC) (Schröder et al ASCO 2011). This Phase Ib/II study assessed safety and efficacy of AUY922 + trastuzumab (T) in pts with T-refractory HER2+ advanced/mBC. Methods: Pts with HER2+ BC (ECOG PS ≤1) who progressed on 1–2 prior anti-HER2 regimens with at least 1 T-containing regimen, received weekly AUY922 (55 or 70 mg/m2, IV) + T (2 mg/kg) in a 28-day cycle. The Phase Ib primary objective was to define a MTD/RP2D of AUY922 combined with T using an adaptive Bayesian logistic regression model. The Phase II primary objective is to evaluate preliminary antitumor activity at this dose (ORR). Secondary objectives included evaluation of PK, safety and preliminary efficacy (PFS, OS). Results: In the Phase Ib part (11 pts) there was 1 DLT (Grade [Gr] 3 diarrhea), and the full standard single dose of AUY922 was recommended for use in combination with T. As of 11th January 2012, 31 HER2+ BC pts (median age 51 years [range 29–71]; 84% invasive ductal carcinoma; 52% estrogen receptor-positive; 81% had received ≥2 prior antineoplastic regimens) received AUY922 at 55 mg/m2 (n=5) or 70 mg/m2 (n=26) + T. The most common study drug-related AEs (all Gr) were diarrhea (25 [81%] pts), visual AEs (e.g. vision blurred, visual impairment, photopsia) (25 [81%] pts), and nausea (11 [35%] pts). Gr 3/4 AEs were rare; most frequently diarrhea and visual impairment (both 6%). Treatment was ongoing for 13 (37%) pts at the cutoff date. Preliminary Phase II best overall response data (RECIST, investigator assessed) was available for 22 pts at AUY922 70 mg/m2. Any partial responses were reported in 5/22 (23%) pts. Conclusions: The data suggests AUY922 + T is well tolerated. Common AEs were considered manageable, and eye disorders were reversible with treatment interruption, dose reduction or discontinuation. The combination of AUY922 + T is active in pts with HER2+ mBC who progressed on T-based therapy, and the regimen warrants further investigation.
A randomized phase II study (VEG108838) of lapatanib plus pazopanib (L+P) versus lapatanib (L) in patients with ErbB2+ inflammatory breast cancer (IBC).
Authors: Cristofanilli Massimo , Johnston Stephen R. D. , Manikhas Alexey , Gomez Henry Leonidas , Gladkov Oleg , Shao Zhimin , Safina Sufia , Rubin Stephen D. , Ranganathan Sulabha , Lata Suman , Trudeau Maureen E.
Published: March 2020

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Background: ErbB2 amplification is frequently reported in IBC and there is evidence of positive association between ErbB2 and VEGF expression. We evaluated the combination of anti ErbB2 and VEGF therapy in ErbB2+ IBC. Methods: We conducted a multicenter, randomized clinical trial for patients (pts) with relapsed ErbB2+ IBC. Cohort 1: Pts stratified (prior trastuzumab; cutaneous disease only vs systemic) and randomized 1:1 to receive L 1500 mg + placebo or L 1500 mg + P 800 mg, QD. Due to high incidence of Grade 3/4 diarrhea in pts treated with L 1500 mg+ P 800 mg in another study, Cohort 1 was closed after 76 pts randomized. Cohort 2 (87 pts ): Pts were stratified (prior trastuzumab) and randomized 5:5:2 to receive L 1500 mg + placebo or L 1000 mg + P 400 mg (double-blind) or P 800 mg (open-label), respectively, QD. Treatment continued until PD, unacceptable toxicity or death. Primary endpoint was ORR. Secondary endpoints included PFS, OS, and safety. Results: Cohort 1: 76 pts were randomized and treated: L, n=38; L+P, n=38. ORR was 29% for the L arm, and 45% for the L+P arm. Median PFS was 16.1 and 14.3 wks, respectively, for the L and L+P arms. The most frequent Grade ≥3 AEs were diarrhea (0% vs 18%) vomiting (0% vs 8%), ALT increased (0% vs 8%), neutropenia (3% vs 13%), and bilirubin increased (0% vs 5%). Dose reductions due to AE were 3% and 21% and dose interruptions due to AE were 11% and 55% in the L and L+P arms, respectively. Cohort 2: 88 pts were randomized (87 treated): L, n=36; P, n=14; L+P, n=38. The ORR was 47%, 31%, and 58% for the L, P, and L+P arms, respectively. Median PFS was 16.0, 11.4, and 16.0 wks for the L, P, and L+P arms, respectively. The most frequent Grade ≥3 AEs were ALT increased (0%, 0%, 21%), AST increased (0%, 0%, 18%), diarrhea (3%, 8%, 8%), and fatigue (3%, 8%, 8%). Dose reductions due to AE occurred in 0%, 0%, and 13% of pts and dose interruptions due to AE occurred in 22%, 23%, and 39% of pts in the L, P, and L+P arms, respectively. Conclusions: This prospective, randomized study confirmed the clinical activity of lapatinib single agent in metastatic ErbB2+ IBC. Furthermore, we demonstrated increased toxicity associated with the combination without a clinically meaningful improvement in efficacy.
Cardiac safety in a phase II study of trastuzumab emtansine (T-DM1) following anthracycline-based chemotherapy as adjuvant or neoadjuvant therapy for early-stage HER2-positive breast cancer.
Authors: Dang Chau T. , Gianni Luca , Romieu Gilles , Dirix Luc , Campone Mario , Citron Marc L. , Zamagni Claudio , Krop Ian E. , Xu Na , Smitt Melanie , Suter Thomas
Published: March 2020

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Background: T-DM1 has demonstrated clinical activity as a single agent in patients (pts) with previously untreated MBC. In a previous phase II randomized trial of T-DM1 vs trastuzumab + docetaxel, T-DM1 had no clinically significant cardiac events, no cases of post-baseline left ventricular ejection fraction (LVEF) ≤40%, and fewer grade ≥3 adverse events (AEs; Hurvitz, ESMO 2011). This phase II study assessed the clinical safety and feasibility of T-DM1 following anthracycline-based chemotherapy in the adjuvant or neoadjuvant setting for early-stage HER2-positive breast cancer. Methods: TDM4874g (NCT01196052) is a phase II single-arm, open-label study of T-DM1 (3.6 mg/kg q3w IV; up to 17 cycles) following completion of doxorubicin/cyclophosphamide (AC; q2w or q3w for 4 cycles), or 5-fluorouracil/epirubicin (100 mg/m2)/cyclophosphamide (FEC; q3w for 3-4 cycles) chemotherapy in pts with early-stage HER2-positive breast cancer. Pre-chemotherapy LVEF by MUGA/ECHO ≥55% was required for enrollment. Co-primary endpoints are safety and rate of pre-specified cardiac events following initiation of T-DM1 treatment. An interim analysis was planned for the first 60 pts evaluable for cardiac safety (received ≥1 T-DM1 dose). Results: For pts in the interim analysis (20 received AC, 40 FEC), the most common all-grade T-DM1-related AEs were nausea (n=20), asthenia (n=17), and headache (n=17); 8 pts had grade 3/4 T-DM1-related AEs (including 3 with grade 3 increased aspartate aminotransferase [AST] and/or alanine aminotransferase [ALT]). No deaths occurred. Two pts had AEs leading to T-DM1 discontinuation (grade 3 AST and grade 2 ALT increase; grade 3 thrombocytopenia). No pre-specified cardiac events occurred; no pts delayed or discontinued T-DM1 due to cardiac AEs; there were no reports of grade ≥2 left ventricular systolic dysfunction, heart failure, or LVEF <50%. Results will be updated with data from all 153 enrolled pts. Conclusions: T-DM1 following anthracycline-based chemotherapy was not associated with cardiac toxicity in pts with early-stage HER2-positive breast cancer; this study continues without modification.
Adjuvant capecitabine for invasive lobular/mixed early breast cancer (EBC): USON 01062 exploratory analyses.
Authors: O'Shaughnessy Joyce , Pippen John E. , Paul Devchand , Stokoe Christopher T. , Blum Joanne Lorraine , Krekow Lea , Holmes Frankie Ann , Lopez-Diaz Christine , Vukelja Svetislava J. , Lindquist Deborah , Sedlacek Scot M. , Rivera Ragene Ruth , Brooks Robert J. , McIntyre Kristi , Wang Yunfei
Published: March 2020

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Background: Randomized phase III USON 01062 trial determining if patients with EBC would benefit from addition of capecitabine to docetaxel after AC (AC-T vs AC-XT). AC-T: docetaxel 100mg/M2 IV; AC-XT: docetaxel 75mg/M2 IV with capecitabine 825mg/M2 PO BID 14/7 days every 21days for 4 cycles. The primary endpoint, improvement in disease-free survival (DFS) at 5 years, was not met (HR=0.84, p=0.12) likely due to lower-than-expected event rate. The secondary endpoint, overall survival (OS), was improved with capecitabine (HR 0.68, p=0.01) (O’Shaughnessy, J. ASCO, 2011). Methods: Molecular analyses demonstrate that pleomorphic lobular (mixed lobular/ductal) carcinomas evolve from the same precursor and/or through the same genetic pathway as classical lobular cancers (Reis-Filho, J., J Path, 2005). We conducted exploratory analyses to evaluate the addition of adjuvant capecitabine in ductal vs lobular or lobular/ductal (mixed) EBC within USON 01062. Histology was classified according to local pathology assessment on patients’ primary cancers. Results: In ductal patients (n=2195), there was no difference in DFS (HR=0.92, p=0.48) and OS (HR=0.75, p=0.07) with AC-T vs AC-XT. In lobular/mixed patients (n=355), adding capecitabine improved DFS (HR=0.55, p=0.055) and OS (HR=0.38, p=0.04). There was no difference in DFS (HR=1.004, p=0.98) in the ER+ ductal patients (n=1258) with the addition of capecitabine. Conclusions: Ductal and lobular cancers have distinct histologic and molecular characteristics; lobular cancers are generally less sensitive to chemotherapy (Cristofanilli, M. JCO, 2005). This exploratory analysis suggests that patients with lobular/mixed EBC may benefit from adjuvant capecitabine. This hypothesis requires evaluation in other adjuvant capecitabine trials. [Table: see text]
Safety and efficacy of panitumumab (pmab) in HPV-positive (+) and HPV-negative (-) recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN): Analysis of the global phase III SPECTRUM trial.
Authors: Stoehlmacher-Williams Jan , Villanueva Cristian , Foa Paolo , Rottey Sylvie , Winquist Eric , Licitra Lisa F. , Davidenko Irina , Skladowski Krzysztof A. , Tahara Makoto , Faivre Sandrine J. , Oliner Kelly S. , Pan Zhiying , Bach Bruce A. , Vermorken Jan Baptist
Published: March 2020

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Background: SPECTRUM evaluated the safety and efficacy of pmab, a fully human monoclonal antibody against the epidermal growth factor receptor, with platinum‑based chemotherapy (CT) vs CT alone in patients (pts) with R/M SCCHN. This predefined analysis presents outcomes by tumor HPV status. Methods: All tumor samples were centrally reviewed. HPV status was determined using a validated immunohistochemistry assay to p16INK4A by an independent lab blinded to treatment assignments. Tumor samples were scored positive or negative according to prespecified criteria. Results: Of 657 enrolled pts (ITT), 443 (67%) had samples evaluable for HPV testing. Ninety‑nine (22%) tumors were HPV+ and 344 (78%) were HPV-. HPV+ rates varied by site (37% oropharynx, 19% larynx, 15% oral cavity, and 13% hypopharynx) and geographic region (44% N America, 22% W Europe, 21% Asia Pacific, 19% S America, and 18% E Europe). Demographics were generally balanced except pts with HPV+ vs HPV- tumors were more often non‑smokers (31% vs 14%), had oropharyngeal tumors (47% vs 23%), and had poorly differentiated tumors (30% vs 13%). Efficacy results are shown (Table). Adverse events were generally balanced between HPV+ and HPV- pts. Conclusions: Pts with HPV- R/M SCCHN administered pmab + CT had improved overall survival (OS) and progression‑free survival (PFS), whereas no improvement in OS or PFS was observed in pts with HPV+ tumors. [Table: see text]