bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of gender on efficacy and acute toxicity in standard risk localized (SR) Ewing sarcomas (ES) in the Euro-Ewing99-R1 trial.
Authors: Van Den Berg Hendrik , Paulussen Michael , Gaspar Nathalie , Lewis Ian , Dirksen Uta , Brennan Bernadette , Le Teuff Gwenael , Whelan Jeremy , Ranft Andreas , Michon Jean Marie , Ladenstein Ruth Lydia , Marec-Berard Perrine , Hjort Lars , Wheatley Keith , Judson Ian Robert , Oberlin Odile , Craft A. W , Juergens Herbert , Le Deley Marie-Cécile ,   Euro-E.W.I.N.G. 99
Published: March 2020

10031

Background: The randomized Euro-EWING99-R1 trial assessed noninferiority of cyclophosphamide- vs ifosfamide-based consolidation regimens (VAC vs VAI) in SR localized ES patients. Overall, efficacy of VAC was deemed acceptable compared to VAI, with hazard ratio of event HR = 1.12 [0.89 - 1.41]. Based on its gender-stratified randomization, influence of gender on efficacy and acute toxicity were additionally explored. Methods: Impact of gender on EFS, acute toxicity by course, switches between treatment arms, and cumulative dose of alkylating agents was evaluated in multivariable models, including terms to test for heterogeneity of treatment effect by gender. Analysis was performed on the intention to treat population. Results: 856 patients (509 males, 347 females) were recruited between 2000 and 2010: 425 VAI and 431 VAC. EFS did not significantly differ between genders (p=0.33), but a marginal interaction was seen between treatment and gender (p=0.083): VAC was associated with poorer EFS in males than VAI, HR(VAC/VAI) = 1.34 [0.96 - 1.86], whereas, in females, VAC was slightly better than VAI, HR = 0.83 [0.54 - 1.28]. Similarly, males had a worse EFS than females with VAC, HR(M/F) = 1.42 [0.97 – 2.08], whereas results by gender were very similar with VAI, HR = 0.91 [0.62 – 1.33]. Severe hematological toxicity was more frequent with VAC than VAI whereas tubular renal impairment was more frequent with VAI. Severe toxicity was more frequent in females than in males, whatever the toxicity type, with no significant interaction between treatment and gender effect. 30 patients switched from VAI to VAC (21 F, 9 M) mostly due to renal toxicity, and 3 from VAC to VAI (1 F, 2 M). A reduction of alkylating agent cumulative dose >20% was more frequent in females (15% vs 9%, p=0.01), with no major difference between VAI and VAC (13% vs 10%, p=0.21). Conclusions: The marginal interaction between gender and type of alkylating agent on EFS has to be validated on external data. Differences of acute toxicity rate and compliance are not sufficient explanation. Effects of gender-dependant polymorphism/activity of metabolic enzymes (e.g. known for CYP2B6) of ifosfamide vs cyclophosphamide should be explored. Clinical trial information: NCT00020566.
Barriers to survivorship care in the Consortium for New England Childhood Cancer Survivors (CONNECCS).
Authors: Schwartz Cindy L. , Hirway Priay , Ader Jeremy , Bradeen Heather Appleton , Grewal Satkiran S. , Huang Mary S , Kadan-Lottick Nina , Usmani Naheed , Kenney Lisa Brazzamano
Published: March 2020

10035

Background: Although long-term adverse consequences of childhood cancer treatment may be mitigated by screening, prevention, and interventions, many survivors do not take advantage of survivorship care. We hypothesized that patients who are at risk for poor compliance with long-term follow-up are identifiable at diagnosis. Methods: To identify factors associated with poor follow-up compliance, 7 CONNECCS institutions evaluated a childhood acute lymphoblastic leukemia (ALL) survivor cohort diagnosed 1996-99. Data collected included: diagnosis year, age, race, ethnicity, gender, insurance, distance from center, CNS disease, and risk classification. Primary endpoints were compliance with 5 and 10-year follow-up. Differences in compliance were tested using chi-squared or t-tests. Logistic regression (including institution as a clustering variable) was used to calculate adjusted odds ratios (OR). Results: At diagnosis, the 358 ALL patients were: female (47%), age= 6.5 + 4.6 years, white/non-Hispanic (84%), black non-Hispanic (7%), high-risk (52%), CNS involvement (10%), privately insured (68%). Private insurance (OR 4.0; 95% CI 2.1-7.8) significantly increased the odds of 5-year compliance. Compliance with 10-year follow-up increased with private insurance (OR 3.3; 95% CI 1.4-8.1) but decreased with CNS disease (OR 0.36; 95% CI 0.31- 0.42) and with years of age (OR 0.93; 95% CI 0.88- 0.96). Conclusions: We evaluated predictors of long-term follow-up based on disease/demographic characteristics at diagnosis to identify cohorts in need of early interventions. In this regional cohort, patients from lower socioeconomic background (without private insurance) at diagnosis were less likely to participate in long-term follow-up care at 5 and 10 years from diagnosis. Older survivors and those with CNS disease were less likely to be in follow-up at 10 years. Future studies should investigate reasons why follow-up compliance is affected by 1) private insurance at diagnosis, 2) older age, and 3) CNS disease. Remediable causes might include: understanding of risk, adolescence/young adult transitions, and healthcare access.
Survival, surgical resectability, and late effects in the hepatoblastoma patients treated by cisplatin plus pirarubicin (CITA) chemotherapy.
Authors: Hiyama Eiso , Kamimatsuse Arata , Onitake Yoshiyuku , Ueda Yuka , Watanabe Kenichiro , Hishiki Tomoro , Tajiri Tatsuro , Ida Kohmei , Yano Michihiro , Kondo Satoshi , Oue Takaharu
Published: March 2020

10038

Background: The Japanese Study Group for Pediatric Liver Tumor(JPLT) is running cooperative treatment studies on hepatoblastoma (HB) since 1991. The main aim in JPLT-2 study was to evaluate the efficacy of cisplatin/pirarubicin. JPLT-2 protocol was launched in 1999 to evaluate the cure rate of risk-stratified HB: standard risk HB (a tumor involving three or fewer sectors of the liver), intermediate risk HB (a tumor involving all sectors of the liver or invasion into portal or hepatic vein) and high risk HB (a tumor involving all sectors of the liver or with metastasis). Methods: Until 2011, 313 children with hepatic tumors who were younger than 15 years of age were eligible for inclusion in the JPLT2 study. The cisplatin/pirarubicin regimen (CITA) is kept as the first line in 254 cases. In this study, we examined the outcome and late effects of the HB patients by the risk-stratified three groups (standard, intermediate and high risk groups). Results: Until 2011, 254 cases underwent the CITA protocol including 78 cases (18%) with metastatic tumors. The 3-year OS of the cases with standard risk HB were 94%, while that of the cases with Intermediate and high risk HB was 64% and 34%, respectively. Except for23 cases who underwent primary resection, complete resection of primary after CITA was performed 86% of standard risk, 66% of intermediate risk and 56% of high risk patients. And the late phase complications were 4 cases with maldevelopment, 15 with cardiac complications, 24 with ototoxicity and 5 with second malignancies. Conclusions: As compared with other regimens, CITA regimens achieved similar or superior rates of survival and resectability in standard risk patients. More promising strategies including adequate liver transplantation and new targeting drugs should be developed for intermediate and high risk HBs. Clinical trial information: UMIN000001116.
Comparison of standard immunohistochemistry and automated quantitative immunohistochemistry for quantification of signaling proteins in archival Ewing sarcoma samples.
Authors: Applebaum Mark A. , Thomas Dafydd G. , Horvai Andrew , Lawlor Elizabeth R , DuBois Steven G.
Published: March 2020

10045

Background: Targeted therapies are increasingly being evaluated for patients with Ewing sarcoma (EWS). Optimal strategies for quantifying key signaling proteins from paraffin-embedded material remain unclear. We sought to quantify tumor expression of IGF-1R, EGFR, and PTEN in EWS using two different methodologies. Methods: Decalcified paraffin-embedded tissue was obtained from 40 patients with EWS. 28 samples were obtained at time of diagnosis, 6 after initial chemotherapy, and 6 at time of relapse. Tumor was evaluated for the expression of IGF-1R, PTEN, and EGFR using standard immunohistochemistry (IHC) and automated quantitative analysis (AQUA) immunohistochemistry. Standard IHC results were categorized as low, medium and high expression based on a pathologist’s review. Expression by AQUA was measured as a continuous variable in arbitrary units. One sided ANOVA analysis was used to compare the mean AQUA expression for each analyte between categories of expression by IHC. Results: The mean age of patients was 15 years (range 1-49 yrs) at time of diagnosis. 68% were male and 66% had localized disease. Samples displayed a wide range of expression by AQUA: mean IGF-1R = 10702 (range 393 - 14424); EGFR = 2750 (range 672 – 9798); and PTEN = 2250 (range 251 – 6557). Mean IGF-1R expression by AQUA did not differ significantly between standard IHC expression categories (mean IGF-1R expression by AQUA for low IHC = 11255, medium IHC = 11070, high IHC = 11023; p = 0.98). Mean PTEN expression by AQUA was higher in the medium and high IHC categories (mean PTEN expression by AQUA for low IHC = 1229, medium IHC = 2715, high IHC = 2940; p = 0.064). Only two samples expressed EGFR by standard IHC. These samples qualitatively had higher AQUA expression levels, but there were too few samples for a reliable determination of statistical significance. Conclusions: AQUA provides a more dynamic range for each marker, though there was poor correlation with standard IHC results. Larger sample sets are needed to determine the optimal approach for quantifying signaling proteins in Ewing sarcoma.
Targeting apoptosis and autophagy by a novel bcl-2 inhibitor, GX15-070, in neuroblastoma.
Authors: Sartelet Herve , Cournoyer Sonia , Addioui Anissa , Belounis Assila , Beaunoyer Mona , Nyalendo Carine , Teira Pierre , Vassal Gilles , Haddad Elie
Published: March 2020

10048

Background: Neuroblastoma (NB) is a frequent pediatric tumor with poor prognosis. The disregulation of the anti-apoptotic protein Bcl-2 is crucial for the tumoral development and chemoresistance. Autophagy is also implicated in tumor cell survival and chemoresistance. The aim of our study was to demonstrate the in vitro and in vivo therapeutic efficiency of GX 15-070, a Bcl-2 inhibitor, used alone and in combination with conventional drugs used in the treatment of NB and hydroxychloroquine (HCQ), a known autophagy inhibitor. Methods: Using 6 NB cell lines, cell viability (MTT) assays were done at progressively increased concentrations of GX 15-070 alone or in combination with cisplatin or with Z-VAD-FMK, a broad-spectrum caspase inhibitor. Apoptosis was tested by evaluating the cleavage of caspase 3 by western blots (WB) and the Annexin V/7-AAD staining studied by FACS. To assess if autophagy was modified by GX 15-070, the cleavage of LC3 protein was tested by WB and cell survival were tested with combination of GX 15-070 and HCQ. To verify the anti-tumor activity in vivo of GX 15-070, orthotopic injections were made on NSG mice treated with GX 15-070 alone and in combination with HCQ. Results: It was observed a high sensitivity of the NB cells to GX 15-070 with increase of cell death and a potential synergistic of this molecule when it’s combined with cisplatin or HCQ. This cell death was due to apoptosis and may also be inhibited by Z-VAD-FMK. GX 15-070 alone or associated to cisplatin increased the autophagy. The in vivo study showed that GX 15-070 treatment used alone or in combination with HCQ significantly decreased the size of the tumor. Conclusions: Our results support the interest of GX 15-070 in the treatment of NB alone or in combination with classical drugs. Our studies also support that activation of apoptosis associated with inhibition of autophagy have a synergistic potential against tumoral progression and must have to be considered in further mechanistic studies for the optimization of more efficient combined therapies in the treatment of NB.
Differential pathologic complete response rates after neoadjuvant chemotherapy among molecular subtypes of triple-negative breast cancer.
Authors: Masuda Hiroko , Baggerly Keith A. , Wang Ying , Zhang Ya , Gonzalez-Angulo Ana M. , Meric-Bernstam Funda , Valero Vicente , Lehmann Brian D. , Pietenpol Jennifer A. , Hortobagyi Gabriel N. , Symmans William Fraser , Ueno Naoto T.
Published: March 2020

1005

Background: By gene profiling, Lehmann et al. (J Clin Invest 121:2750-2767, 2011) reported that triple-negative breast cancer (TNBC) can be classified into 6 clusters—basal-like 1 (BL1), basal-like 2 (BL2), immunomodulatory (IM), mesenchymal (M), mesenchymal stem-like (MSL), and luminal androgen receptor (LAR)—plus an unstable (UNS) cluster. While it is clear that patients with TNBC differently respond to chemotherapy, the clinical relevance of these molecular TNBC subtypes is unknown. Methods: We qualitatively reproduced the Lehmann et al. experiments using Affymetrix CEL files from the public datasets. We identified 130 TNBC gene expression microarrays obtained from 03/00 to 03/10. All patients had received neoadjuvant chemotherapy containing sequential taxane and anthracycline-based regimens and had evaluable pathological tumor response data. Median follow-up was 68.1 months. (5.1-147.5). We classified TNBC samples using Lehmann’s gene signatures, then performed Fisher's exact test to correlate TNBC subtype and pCR status. To assess the independent utility of TNBC subtype for predicting pCR status, we fit a logistic regression model to our data and used age, clinical stage, treatment regimens, and nuclear grade as potential explanatory factors. We also performed comparison of the subtypes with the PAM50 intrinsic subtypes and RCB index. Results: The BL1 subtype had the highest pCR rate (52%); BL2 and LAR the lowest (0% and 10%, respectively). TNBC subtype and pCR status were significantly associated (p = 0.044). TNBC subtype was an independent predictor of pCR status (p = 0.022) by a likelihood ratio test.The Lehmann’s subtype classification better predicted pCR status than did the PAM50 intrinsic subtypes (basal-like vs. non basal-like). Conclusions: Dividing TNBC into 7 subtypes predicts high vs. low pCR rate. The 7-subtype classification may lead to innovative personalized medicine strategies for patients with TNBC. There is a need for prospective validation of the hypothesis that pCR rates associated with the seven TNBC subtypes will predict long-term patient outcome.
Results with the intensive chemotherapy Mexican regimen in the treatment of pediatric high-grade osteosarcoma: Experience at the Instituto Nacional de Pediatria.
Authors: Castellanos-Toledo Araceli , Zapata-Tarres Marta , Peña-del-Castillo Humberto , Figueroa Carbajal Jose de Jesus
Published: March 2020

10058

Background: In Mexico, pediatric high-grade osteosarcoma (HGO) occupies the fifth place of all pediatrics cancers, representing the 4.4%. It presents with a high incidence of metastatic pulmonary disease and large primary tumor volume at diagnosis, resulting in poor survival. The results of the named 2005 Chemotherapy Regimen are very promising. Methods: A retrospective, longitudinal, clinical study was performed from January 2005 to January 2012, including 55 patients (<18 years old) with extremity HGO and no prior chemotherapy treatment. All patients received a 10-week neoadjuvant-chemotherapy regimen (6 curses), with cisplatino 120mg/m2 plus doxorrubicina 75mg/m2 and a 15-week adjuvant-treatment (5 curses) with ciclofosfamide 1800 mg/m2 plus etoposide 900 mg/m2. Results: Median age was 12 years, 51% boys and 49% girls. There were 51% distal femur, 11% proximal humerus, 18.2% proximal tibia, 7.3% distal tibia, 5.4% fibula and 5.5% proximal femur. Thirty-two patients (58.2%) had pulmonary metastases at diagnosis. There were 76.4% osteoblastic tumors, 16% chondroblastic and 7.3% telangiectatic. Twenty patients (36.4%) had an amputation procedure and 15 (27%) a limb desarticulation, 18 by a great tumor volume at diagnosis and two by eventual local relapse. Twelve patients (22%) had limb-sparing surgery. There were 10 (18.2%) good-responder patients and 38 (69%) bad-responders to neoadjuvant-chemotherapy. The overall survival (OS) for non-metastatic patients was 70% and 35% for metastatic patients (p 0.016). The event-free survival for non-metastatic patients was 65% and 30% for metastatic patients (p 0.032). OS for good-responders was 80% and 50% for bad-responders (p 0.009). No important toxicity and no second malignancies were reported. Conclusions: In spite of the presence of significant unfavorable prognostic factors in our patients, this intensive chemotherapy regimen showed improved results in overall survival as compared to other standard regimens, being short, inexpensive and with relatively few adverse events. This regimen can be useful in other developing countries.
Comparison of doxorubicin and cyclophosphamide (AC) versus single-agent paclitaxel (T) as adjuvant therapy for breast cancer in women with 0-3 positive axillary nodes: CALGB 40101.
Authors: Shulman Lawrence N. , Berry Donald A. , Cirrincione Constance T. , Becker Heather , Perez Edith A. , O'Regan Ruth , Martino Silvana , Shapiro Charles L. , Atkins James , Schneider Charles , Kimmick Gretchen Genevieve , Burstein Harold J. , Norton Larry , Muss Hyman Bernard , Hudis Clifford , Winer Eric P. ,   Cancer and Leukemia Group B
Published: March 2020

1007

Background: Determining optimal adjuvant chemotherapy for early stage breast cancer depends on efficacy and toxicity. We sought to determine if T is equivalent to AC but with reduced toxicity. Methods: Pts with operable breast cancer with 0-3 positive nodes were enrolled on a 2x2 factorial design study which addressed (1) superiority of 6 vs. 4 cycles of therapy (previously reported, Shulman, JCO 2012) and (2) equivalence of single-agent T to standard AC, defined as upper bound of 95% confidence interval (CI) of hazard ratio (HR) of T vs. AC < 1.30 for the primary endpoint of relapse-free survival (RFS). A planned target of 567 RFS events required 4,646 pts with 4 yrs FU. At activation in 2002, T (80mg/m2) was q1wk for 12 or 18 wks and AC (60/600 mg/m2) was q3wk for 4 or 6 cycles. In 2003 (570 pts enrolled) schedules were revised to 4 or 6 cycles q2wk for both T (175 mg/m2) and AC. The 6-cycle arms were dropped in 2008 (3,171 pts enrolled) due to slow accrual. Relative effectiveness of T to AC is shown by hazard ratio (HR). Logrank p-values are measures of discordance but are not relevant for the equivalence question and are not adjusted for multiple comparisons. Results: After enrolling 3,871 pts, the study closed in 2010 due to slowing accrual. With a median follow-up of 6.1 yrs there are 437 RFS events. The HR of 1.26 (95% CI: 1.05-1.53; p = 0.02) does not allow a conclusion of equivalence of T with AC. With 266 deaths the HR for overall survival (OS) is 1.27 (95% CI=1.00-1.62; p = 0.05), favoring AC. The estimated absolute advantage of AC at 5 yrs is 3% (91 vs. 88%) for RFS and 1% (95 vs. 94%) for OS. All 9 treatment-related deaths were in pts receiving AC and are included in the survival analysis. The incidence of Grade 3+ toxicity for AC vs T was 33% vs. 4% for hematologic toxicity and 36% vs 22% for non-hematologic toxicity. Conclusions: This trial did not show equivalence of T to AC, a conclusion that is very unlikely to change with additional follow-up. T was less toxic than AC. Clinical trial information: CDR0000069444/NCT00041119.
Screening with whole-body MRI (WB-MRI) in pediatric patients with Li Fraumeni syndrome (LFS).
Authors: O'Neill Allison Frances , Steinberger Allie , Voss Stephan D. , Root Elizabeth J. , Garber Judy Ellen , Diller Lisa
Published: March 2020

10071

Background: LFS is a rare hereditary cancer syndrome characterized by a high risk of developing a wide range of malignancies. Germline mutations in the tp53 gene confer approximately a 12-fold risk of developing cancer by age 20. Given the potential for diverse malignancies, cancer surveillance in LFS patients is challenging. We piloted the use of WB-MRI for pediatric LFS patients as a cancer screening tool. Methods: Eligibility included: documented tp53 mutation, or obligate carrier status based upon family history/genetic testing, and no recent cancer diagnosis. WB-MRI was performed as a research test, in conjunction with recommended clinical screening based upon family history and clinician recommendation. Our primary aim was to determine the feasibility (defined as 87% completion rate) of obtaining two planned annual MRI scans in 15 pediatric LFS patients. Our secondary aim was to calculate the incidence and describe the characteristics of primary cancers detected. Results: Nine pediatric patients from 5 families have been enrolled and all have successfully completed one WB-MRI. Seven patients were known carriers, and 2 underwent genetic testing in order to enroll in the study. Median age was 12 years, range 6 to 15. Scan time was 60-90 minutes and 2 patients required anesthesia with propofol. There were no acute scan complications. Six of the 9 (67%) scans demonstrated incidental findings (T2 cerebral cortex abnormality, L5-S1 synovial cyst, thoracic syrinx, T12 hemangioma, 2 ovarian cysts, and degenerative disc disease). Only one patient underwent a dedicated follow-up imaging study for an abnormality on WB-MRI. None of the patients required biopsy. All patients had normal screening laboratory work. These results are being presented early to foster collaboration. Conclusions: All patients enrolled on our study tolerated WB-MRI; none were diagnosed with a new malignancy. Although preliminary, our results to date are in contrast to previous reports documenting a high incidence of cancers detected during screening of LFS patients. WB-MRI may be a promising approach to screening; a large multi-center trial will be needed to determine its efficacy in detecting incident cancers and true test characteristics.
Proliferation-, estrogen-, and T-cell-related metagenes to predict outcome after adjuvant/neoadjuvant chemotherapy for operable breast cancer in the ECTO trial.
Authors: Bianchini Giampaolo , Cappelletti Vera , Callari Maurizio , Carcangiu Maria Luisa , Eiermann Wolfgang , Semiglazov Vladimir , Guillem Vicente , Lluch Ana , Mansutti Mauro , Zambetti Milvia , Mariani Gabriella , Magazzu Domenico , Valagussa Pinuccia , Paolini Biagio , Musella Valeria , Di Buduo Eleonora , Miodini Patrizia , Scuro Manuela , Daidone Maria Grazia , Gianni Luca
Published: March 2020

1014

Background: Predicting recurrence in operable breast cancer (BC) despite optimal chemotherapy would be relevant to new drug development and tailored treatments. Methods: A large series (n=3,154) of public Affymetrix gene-expression profiles (GEP) was used to define prognostic/predictive metagenes in different BC subtypes. In ER+/HER2- a proliferation and an ER-related metagene were combined to predict low, intermediate and high risk of recurrence. In TN and in HER2+ a T cell metagene was used to predict low, intermediate and high risk (higher expression associated with lower risk). The metagenes were validated in patients enrolled in the phase III ECTO trial (Gianni L. JCO 2009) and treated with the same taxane-anthracycline-CMF regimen as neoadjuvant or adjuvant therapy before endocrine therapy if indicated. The outcome was distant event free survival (DEFS). Results: 283 good quality GEPs were obtained (neoadjuvant n=121; adjuvant n=162) from 464 retrospectively collected samples. Median follow-up was 8.9 years. In ER+/HER2- tumors the 10-yrs DEFS was 92.3, 81.2 and 66.6% in low, intermediate and high risk groups, respectively [high vs low HR 4.38 (1.01-19.1) p=.048] according to proliferation and ER-related metagenes. In HER2+ and TN subgroup the 10-yrs DEFS was 97.2, 75.6 and 78.8% in low, intermediate and high risk groups, respectively [high vs low HR 8.73 (1.09-69.8) p=.041]. In TN tumors, the pCR rate was 20% in the high and 61.5% in the low risk group. By combining the predicted risk group in each molecular subtype the 10-yrs DEFS was 95.3, 79.2 and 71.5% in low (24.2%), intermediate (42.7%) and high (33.1%) risk group, respectively [logrank p=0.003; high vs low HR 6.22 (1.87-20.6) p=.002]. ER, PGR, Ki67 and lymphocyte infiltration (LI) by IHC underperformed compared to genomic predictors. Conclusions: BC patients at higher risk of relapse despite optimal standard treatment can be identified who should be spared ineffective and toxic therapy and considered for investigational new strategies. In TN and HER2+, high T cell metagene and to a lesser extent LI are prognostic/predictive and associated with an extremely low risk of DEFS after chemotherapy.
10-year outcomes of breast cancer patients with histologically confirmed axillary lymph node metastases and pathologic complete response after primary systemic chemotherapy.
Authors: Mougalian Sarah Schellhorn , Lei Xiudong , Hsu Limin , Hortobagyi Gabriel N. , Kuerer Henry Mark , Symmans William Fraser , Valero Vicente
Published: March 2020

1017

Background: Pathologic complete response (pCR) of tumors in the breast and axillary lymph nodes (ALN) after primary systemic chemotherapy (PST) is associated with an excellent outcome. A previous analysis showed superior 5-year overall survival (OS) and relapse-free survival (RFS) for patients who achieved an ALN pCR after PST compared to those without a pCR in 5 prospective clinical trials. This study is an expanded analysis of all patients treated with PST at our institution examining the impact of ALN pCR on 10-year OS and RFS. Methods: Patients with clinical stage II/III and pathologically confirmed ALN metastases who underwent PST were categorized into 1 of 2 groups: ALN pCR and ALN residual disease. Additional data were collected, including breast cancer subtype, clinical tumor size, and lymph node staging, pathologic tumor (T) stage, and class of PST. RFS and OS were estimated by the Kaplan-Meier product limit method. Subset analyses were performed on patients with HER2-positive cancer. Results: 1,600 women diagnosed between 1989 and 2007 were identified. Median follow-up was 79 months (5-277); 454 (28.4%) achieved an ALN pCR. ALN pCR was associated with triple-negative and higher grade cancers, lower clinical stage, and lower pathologic breast T stage. 5-year OS and RFS estimates were similar to prior analysis. The 10-year OS was 85% and 58% and the 10-year RFS 83% and 55% (p < 0.001), for patients who achieved an ALN pCR and those with residual ALN disease. For HER2-positive breast cancers, 67.3% of patients who received HER2-targeted therapy achieved an ALN pCR vs. 32.3% without HER2-targeted therapy (p < 0.001). For patients receiving HER2-targeted therapy for HER2-positive breast cancer (n = 153), the 10-year OS was 92% and 52% (p = 0.006), and the 10-year RFS was 89% and 59% (p < 0.001) for those with and without an ALN pCR. Conclusions: ALN pCR is an excellent early surrogate marker for long-term outcome, 10-year RFS and OS. In HER2-positive breast cancers, HER2-targeted therapy is associated with high rates of pCR. Despite the aggressive nature of their disease, patients who achieve ALN pCR with PST have an excellent 10-year prognosis.
NCI 8609: Interim fluoro-3’-deoxythymidine (FLT) PET imaging findings from the phase I trial of PARP inhibitor veliparib (V) and carboplatin (C) in advanced breast cancer.
Authors: Ramaswamy Bhuvaneswari , Zhang Jun , Hall Nathan , Schregel Katharina , Lustberg Maryam B. , Wesolowski Robert , Mrozek Ewa , Layman Rachel M. , Olson Erin Macrae , Ottman Susan , Camp Andrea , Chalmers Jeffrey J. , Geyer Susan Michelle , Villalona-Calero Miguel Angel , Shapiro Charles L. , Grever Michael R. , Knopp Michael V.
Published: March 2020

1023

Background: We are currently conducting a phase I trial of PARP inhibitor, V on an intermittent (7 or 14 day) or continuous (21 day) schedule in combination with C in patients (pts) with advanced breast cancer. We are using FLT PET/CT sequentially to assess DNA damage induced by varying dose schedules of PARP inhibitor, where uptake of FLT depends on the proliferation rate of the tumor. Methods: Eligible pts received C-AUC 5 Q 3weeks (except dose level 1-AUC 6) plus escalating doses of V, BID on 7, 14, or 21-day schedules based on a standard 3+3 dose escalation design. We performed FLT PET/CT at baseline, cycle 1 day 7 and 14 and after cycle 3. Lesions were track-matched with the FDG PET/CT and semi-quantitatively assessed using 2D ROI placement in a matched, blinded fashion. Results: 38 pts have been accrued to 7 dose levels and FLT-PET imaging was successfully obtained in all pts with the proliferative whole body mapping revealing expected bone-marrow, liver and RESuptake. FLT-PET uptake showed a significant (p < 0.001) decrease between baseline and day 7 (N = 25) with an overall trend to rebound nearly to baseline at day 14 for pts that did not show a significant decrease in FLT uptake reduction after cycle 3. The 14-day (n = 15) dosing schedule resulted in more pronounced day 14 reduction in FLT uptake when compared to those on the 7-day (n = 7) schedule. A FLT rebound to baseline level appeared to be associated with limited therapy response. There were no reported toxicities from FLT imaging. Conclusions: FLT-PET was consistently obtained with excellent whole body quality. All lesions revealed a FLT (proliferation) uptake that was different from the FDG (metabolism) uptake. FLT uptake indicated an initial reduction of proliferation at day 7, followed by a rebound at day 21 in all patients on the 7 or 14 day schema. The trial protocol was therefore amended to include a 21 day schema which is currently still ongoing. FLT appears to be a promising in-vivo imaging marker that may serve as a guiding tool to optimize dosing schema in addition to assessing/ predicting overall response. Study support- U01 CA076576 /Wright Center of Innovation ODSA TECH09-028. Clinical trial information: NCT01251874.
Effect of metformin versus placebo on weight and metabolic factors in initial patients enrolled onto NCIC CTG MA.32, a multicenter adjuvant randomized controlled trial in early-stage breast cancer (BC).
Authors: Goodwin Pamela Jean , Parulekar Wendy , Gelmon Karen A. , Shepherd Lois E. , Ligibel Jennifer A. , Hershman Dawn L. , Rastogi Priya , Mayer Ingrid A. , Hobday Timothy J. , Lemieux Julie , Thompson Alastair Mark , Pritchard Kathleen I. , Whelan Timothy Joseph , Mukherjee Som Dave , Chalchal Haji I. , Oja Conrad D. , Tonkin Katia Sonia , Bernstein Vanessa , Chen Bingshu E , Stambolic Vuk
Published: March 2020

1033

Background: MA.32 investigates effects of Metformin vs. Placebo, in addition to standard care, on invasive disease free survival and other outcomes. Metformin may improve obesity and metabolic factors [insulin, glucose, leptin, C-reactive protein (CRP)] that have been associated with poor BC outcomes. Maintaining blinding of investigators to outcomes, we conducted a planned, DSMB approved, analysis of the effect of Metformin vs. Placebo on weight and metabolic factors at 6 months, including examination of interactions with baseline body mass index (BMI), in the first 498 subjects with paired fasting plasma samples. Methods: 498 non-diabetic subjects with T1-3, N0-3, M0 BC meeting defined entry criteria who had completed surgery and adjuvant chemo (if given) provided fasting blood samples at randomization and 6 months (while on study drug). Glucose was measured locally; blood was aliquoted, frozen and stored at -80°C then shipped to NCIC CTG (Kingston, Canada). Paired plasma aliquots were shipped to Mount Sinai Hospital (Toronto, Canada) for analysis of Insulin (Dako), hsCRP (Roche Elecsys) and leptin (Luminex). Statistical analysis used the Wilcoxon signed rank test. Results: Mean age was 52.4 ±9.2 years. Arms were balanced for ER/PgR (63% pos), BMI, prior adjuvant chemo (89%), T and N status, grade, mastectomy/lumpectomy and radiation. Conclusions: Metformin significantly improved weight, insulin, glucose, leptin and CRP at 6 months. Effects did not vary by baseline BMI. Funded by: NIH, CCSRI, CBCF, BCRF, Apotex Canada (drug & placebo - in kind). Clinical trial information: NCT01101438. [Table: see text]
Discordant ER, PR, and HER2 status between primary and metastatic breast cancer as prognostic factor.
Authors: Shin Hee-Chul , Han Wonshik , Moon Hyeong-Gon , Im Seock-Ah , Moon Woo Kyung , Park In-Ae , Park Sung Jun , Noh Dong Young
Published: March 2020

1039

Background: The receptor status including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) of metastases may be different from that of the primary breast cancer. This discordance of receptor status may influence patient prognosis. We investigated discordance of receptor status between primary breast cancer and distant metastases in the same patients and its effect on prognosis. Methods: ER, PR, and HER2 status in metastases were available in 173 patients. The receptor status was compared between primary tumors and metastases. Tumors were classified as triple-negative breast cancer (TNBC) or non-triple-negative breast cancer (non-TNBC) according to receptor status and as concordant and discordant depending on the difference of receptor status between primary and metastatic breast cancer. Survival analysis was performed depending on concordant or discordant receptor status. Results: Discordance for ER, PR, and HER2 was 18.5%, 23.7%, and 10.4%, respectively. Concordant non-TNBC and TNBC between primary tumors and metastases was 69.9% and 17.9%, respectively. Discordant TNBC was 12.1%. On multivariate analysis, patients with discordant TNBC had unfavorable survival compared with patients with concordant non-TNBC (relative risk 2.544, 95% confidence interval, 1.220-5.303, p = 0.013). The median survival after recurrence was 41.8 months for patients with concordant non-TNBC, 20.7 months for patients with concordant TNBC, and 19.9 months for patients with discordant TNBC (p < 0.0001). Conclusions: The change of ER, PR, and HER2 status between primary and metastatic tumors occur and discordant TNBC is associated with poor survival.
Molecular biomarkers as predictive factors of pCR for early triple-negative breast cancer.
Authors: Ghanem Ismael , Castañeda Carlos , Perez-Campos Ana , Toldos Oscar , Sancho Perez Blanca , Manso Luis , Rodriguez-Peralto Jose Luis , Calderón Mónica , Cortes-Funes Hernan , Lora David , Garcia-Martin Rosa , Ciruelos Eva
Published: March 2020

1041

Background: Early triple-negative breast cancer (TNBC) patients (p) without pathologic complete response (pCR) after neoadjuvant chemotherapy (NCT) have unsuccessful prognosis. Predictive factors for pCR are necessary in order to improve the treatment choice. The aims of the study are to determine the expression of different biomarkers (BM) in the initial biopsy (IB) of TNBC, to analyze the relationship between the BM expression and pCR, and to determine the expression changes of BM after NCT. Methods: We reviewed retrospectively the medical records of 49 TNBC p treated with NCT between 2001 and 2011 at two institutions. Expression of 14 BM in the IB and after NCT was independently analyzed by inmunohistochemistry by two pathology specialists. Staining intensity 0-1 + was considered as negative expression, and 2-3-4 + as positive. Ki 67>13% was interpreted as positive. Results: Forty-nine p with a median age of 47 years (27-79) were evaluated. Twenty-seven p (55%) had grade 3. Tumor stages were T1(2%), T2(26%), T3(39%), and T4(33%). 38p (77%) were node positive. Five p (10%) received anthracyclines and 42p (86%) anthracyclines plus taxanes. Fourteen p (29%) presented pCR, 27p (55%) partial response, 4p (8%) stable disease, 2p (4%) progressive disease, and 2p (4%) were not evaluable. The BM expression in the IB was: CD44 (88%), CK 5/6 (27%), EGFR ( 0%), Ki 67 (73%), Wt-1 (10%), p-Akt (24%), HER2 (19%), NY-ESO-1 (11%), MAGE A1 (0%), HER3 (14%), BRCA1 (84%), PTEN (12%), IGFR1 (12%) and AR (14%). Diferentially expressed BM in IB for p with and without pCR, respectively, were p-Akt 0/8(0%) vs 5/13(38%) p=0.11, CK 5/6: 4/9 (44%) vs 2/15 (13%) p=0.15 and Ki 67: 7/7(100%) vs 10/17(59%) p=0.06. The Table shows the BM expression before and after NCT for p without pCR. Conclusions: Tumor samples of TNBC show high expression of CD44, ki67, and BRCA1. Most of BM has a decrease in expression after NCT. CK 5/6, Ki 67, and p-Akt could be predictive factor for pCR, although larger prospective studies are needed. [Table: see text]
LMS-02: A phase II single-arm multicenter study of doxorubicin in combination with trabectedin as a first-line treatment of advanced uterine leiomyosarcoma (u-LMS) and soft tissue LMS (ST-LMS): First results in patients with u-LMS.
Authors: Pautier Patricia , Floquet Anne , Cupissol Didier , Lacas Benjamin , Bompas Emmanuelle , Chevreau Christine , Selle Frédéric , Weber Beatrice E. , Guillemet Cecile , Penel Nicolas , Duffaud Florence
Published: March 2020

10505

Background: U-LMS and ST-LMS are rare tumours with poor prognosis when metastatic or locally advanced, presenting moderate chemosensitivity mainly to doxorubicine (doxo), ifosfamide (ifo), cisplatin, gemcitabine (gem) and trabectidine (trab). Response rates (RR) in combination therapies (1stline) does not exceed 50% for U-LMS and 35% for ST-LMS. The most active ones are doxo combinations (most of the time with ifo or dacarbazine) and gem + docetaxel (in particular in U-LMS) with a mean response durations of 3 to 6 months. Trab was demonstrated a definite activity on pre-treated LMS (RR of approximately 20% in LMS overall [U-LMS in particular]). In view of these encouraging results on LMS, a study combining trab with doxo as first line therapy for LMS is of interest. Methods: Patients (pts) received every 3 weeks, 6 cycles of doxo 60 mg/m2 followed by trab 1.1 mg/m23-h at day 1, and pegfilgrastim 6 mg on Day 2. Study primary objective: to determine the disease control rate (DCR) (ORR+SD). Secondary objectives: PFS 12 wks, RR by RECIST and duration, OS and toxicities. Patients were stratified into U-LMS (n=45) and ST-LMS (n=62) group. Herein, we report the first results in pts with U-LMS; mature data will be shown in ASCO Meeting. Results: 45 pts with U-LMS have been enrolled until November 2012. Median age is 58 years, 38 where of with data collected for at least 1 cycle, 85% had metastatic disease (mostly lung 30/33, liver and bone), and 26 pts have received 6 cycles. For 33 pts with at least 1 disease assessment (every 2 cycles), the ORR was 55% (18 PR) and 13 SD (39%) had SD disease for a DCR of 94% at that time. Presently, the median PFS at 12 weeks is 94,3% [95%IC:86-100]. Main grade 3-4 toxicities in 187 cycles were neutropenia (51%), febrile neutropenia (7%), thrombopenia (14%), anemia (7%), fatigue (5%), vomiting (6%) and transiet transaminase increase (22%). Conclusions: The combination of trab plus doxo seems to be an effective first-line treatment for pts with U-LMS, with meaningful clinical benefits and an acceptable and manageable safety profile. Clinical trial information: 2009-012430-70.
Discordance of oncologic surgical classifications in COG studies.
Authors: Morris Carol , Teot Lisa A. , Bernstein Mark L. , Marina Neyssa , Krailo Mark D. , Villaluna Doojduen , Gorlick Richard Greg , Randall R. Lor
Published: March 2020

10528

Background: “Wide resection” (a cuff of normal tissue) versus “radical resection” (the entire compartment) indicate very distinct oncologic surgical procedures and hence potential margin status. Distinguishing between these two oncologic classifications is important for understanding oncologic outcomes. Methods: We examined the available data for COG AOST0331: A Randomized Trial of the European and American Osteosarcoma Study Group to Optimize Treatment Strategies for Resectable Osteosarcoma Based on Histological Response to Pre-Operative Chemotherapy. We reviewed the surgical and pathology reports of patients considered to have received a wide or radical resection according to the investigator at the patient’s institution. Results: In 956 patients, the overall discordance rate was 43%. Of those patients reported to have had a wide excision by the reporting institution, only 5% of patients were reclassified to radical resection. However, of those patients reported to have undergone radical resection, 75% were reclassified to wide. In the absence of this re-review of the data, 56% of the patients would have been reported to have had a radical resection when in fact only 17% met the criteria for true radical resection. The greater number of patient reclassified to wide from radical is likely indicative of the influence and limits of the CPT coding system currently used for billing by surgeons; only CPT codes for radical resection currently exist. Conclusions: These discrepancies complicate subsequent data analysis, particularly assessing predictors of local recurrence. While this reporting problem is not unique to COG studies, we aim to use this example to raise awareness among our colleagues about the importance of accurate data reporting. Providing better training to those individuals responsible for submitting data may decrease the incidence of erroneous data entry and is essential to the successful completion of study objectives.
Claudin-1 as a novel transcriptional target of hedgehog signaling and a predictor for outcome in breast cancer.
Authors: Warrier Sanjay , Sellinger Christina , Beith Jane McNeil , Cazet Aurelie , Swarbrick Alex , Carmalt Hugh , O'Toole Sandra
Published: March 2020

1053

Background: Hedgehog signaling is important in the development of a number of malignancies. We have recently shown that the Hedgehog (Hh) signaling pathway is associated with a poor outcome and is a novel therapeutic target in triple negative breast cancer. Gene expression profiling of M6 murine cell line mammary xenografts overexpressing Hh ligand revealed a series of genes potentially regulated by Hh in breast cancer. We explored the expression patterns of one of the candidates, Claudin-1, an adhesion molecule, and its association with Hh pathway markers and outcome in 292 invasive ductal carcinomas. Methods: Immunohistochemistry for Claudin-1 was performed and scored by two observers for membranous and cytoplasmic localization. Membranous or cytoplasmic expression were scored and its associations with patient outcome were assessed using Kaplan Meier and Cox Proportional hazard model analyses. Correlations with clinicopathological features and Hh pathway protein expression were undertaken using chi squared analysis. Results: Claudin-1 was expressed both in the cytoplasm and at the plasma membrane of breast carcinoma cells. Cytoplasmic predominant expression of Claudin1 was associated with a favorable prognosis (HR 0.59 (95% CI: 0.36, 0.97), p = 0.039. In contrast, membranous predominant expression was associated with larger tumors, histological grade 3, a high Ki67 index and a poor outcome (HR 1.66 (95% CI: 1.064, 2.60), p = 0.026). Importantly, membranous Claudin-1 directly correlated with Hh ligand (p < 0.0001) and paracrine pathway activation as indicated by high epithelial Hh ligand expression (p < 0.0001) and high Gli1in the peritumoral stroma (p=0.027). There is a strong correlation between paracrine hh/gli (p = 0.001) and membrane predominant claudin confirming our in vivo findings. Conclusions: Claudin-1 is an important component of the tight junction in epithelial cells. We have shown for the first time that Claudin-1 is a direct target of Hh pathway activation. Furthermore, we report that the subcellular localization of Claudin-1 shows distinct association with outcome in breast cancer. These findings provide insight into potential mechanisms of metastatic spread of breast cancer.
Demonstration of gender-specific variability in a pharmacokinetic (PK) analysis of the PERSIST-5 trial of adjuvant imatinib (IM) for patients with primary gastrointestinal stromal tumor (GIST) at significant risk of recurrence.
Authors: Espat Joseph , Maki Robert G. , Raut Chandrajit P. , Staveley-O'Carroll Kevin F , Keir Christopher Hunt , Magley Andrea , DeMatteo Ronald P.
Published: March 2020

10538

Background: ThePERSIST-5 phase II trial is evaluating 5 years of adjuvant IM therapy in patients with resected GIST at significant risk of recurrence. This analysis studied the effect of chronic therapy on steady-state trough levels in patients who received IM for up to 24 months to evaluate potential PK variations. Methods: Eligible patients were adults with KIT+ primary GIST who were considered to be at significant risk for recurrence (primary tumor any site ≥2 cm andmitotic rate ≥5/50 high-power fields, or non-gastric primary GIST ≥5 cm) without metastases. R0 resection of primary GIST was performed ≤12 weeks prior to the first IM dose. Patients are to receive oral IM 400 mg/day for up to 5 years or until progression, relapse, or intolerance. Plasma samples for PK analysis were collected at 1, 4, 12, and 24 months. IM plasma concentrations were measured using a validated liquid chromatography-tandem mass spectrometry assay. Results: In-study assay performance (%CV) was ≤9.6% and bias was -1.3% to 5.2%. IM concentrations ranged from below quantifiable limits to 4798 ng/mL. After daily IM doses for up to 12 months (or 24 months in 3 patients), IM trough levels remained constant over time. The range of IM trough levels (mean ± SD) was 957 ± 750 ng/mL to 1219 ± 822 ng/mL at month 1, and 727 ± 430 ng/mL to 996 ± 405 ng/mL at month 12. Inter-patient variability was 40.7-78.4%. There was no significant difference in IM trough levels between months 1 and 4, 1 and 12, or 4 and 12. Trough levels did not significantly differ by location of GIST. Most notably, mean IM trough concentrations were on average ~33% higher in females vs males. Conclusions: In this study,IM trough levels remained relatively unaltered in patients with high-risk GIST who received adjuvant IM for 1 year. The 33% higher mean trough levels in females warrants further study for clinical decision making. Clinical trial information: NCT00867113. [Table: see text]
Frequent mutations in MLH1, MET, KIT, PDGFRA, and PIK3CA genes in human gastrointestinal stromal tumors.
Authors: Xu Zhi , Huo Xinying , Tang Chuanning , Ye Hua , Lou Feng , Chen Si-Yi , Chen Jinfei
Published: March 2020

10544

Background: Identifying mutations in individual tumor is critical to improve the efficacy of cancer therapy by matching targeted drugs to specific mutations. Gastrointestinal stromal tumor (GIST) is a stromal or mesenchymal subepithelial neoplasm affecting the gastrointestinal tract and it frequently contains an activating mutation in either the KIT or platelet-derived growth factor A (PDGFRA) gene. Although GIST is highly responsive to several selective tyrosine kinase inhibitors, combined use of inhibitors targeting other mutations is needed to further prolong survival. Methods: In this study, we aim to screen and identify genetic mutations in GIST for targeted therapy using the new Ion Torrent next-generation sequencing platform. Results: By utilizing the Ion Ampliseq Cancer Panel, we sequenced 737 loci from 45 cancer-related genes from DNA extracted from formalin-fixed and paraffin-embedded (FFPE) samples of 125 human gastrointestinal stromal tumors, set up stringent parameters for reliable variant calling by filtering out potential raw base calling errors, and identified frequent mutations in PDGFRA, KIT, APC, MLH1, MET, RET, and PIK3CA. Moreover, frequent missense mutations were detected in MLH1 (12%), MET (16.8%), KIT (51.2%), and PIK3CA (41.6%) genes. The mutations in MLH1 gene were frequently detected in the exon 14, while MET gene was frequently mutated in the exon 2. In addition, we identified missense mutations in other genes, including FLT3, KRAS, PDGFRA, and STK11, at lower frequencies. Conclusions: This study demonstrates the utility of using Ion Torrent sequencing to efficiently identify human cancer mutations. With the finding of the frequent mutations in MLH1 and MET genes, in addition to KIT, PDGFRA and PIK3CA, in GISTs, this study provides a molecular basis for clinically developing new drugs targeting these gene mutations for GIST therapy.