Annals of Oncology

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ISSN / EISSN : 09237534 / 15698041
Current Publisher: Oxford University Press (OUP) (10.1093)
Former Publisher: Springer Science and Business Media LLC (10.1023)
Total articles ≅ 32,575
Google Scholar h5-index: 122
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E M O’Reilly, J F Hechtman
Published: 11 October 2019
Annals of Oncology; doi:10.1093/annonc/mdz385

Abstract:Background Although rare, NTRK gene fusions are known to be oncogenic drivers in pancreatic ductal adenocarcinoma (PDAC). We report the response of a metastatic CTRC-NTRK1 gene fusion-positive PDAC to targeted treatment with the oral tropomyosin receptor kinase (TRK) inhibitor larotrectinib and the eventual development of resistance to treatment. Patient, methods and results A 61-year-old woman presented with a 2.5-cm mass in the body of the pancreas and a 1.2-cm liver lesion on routine follow-up for endometrial cancer that was in complete remission. Liver biopsy confirmed a primary PDAC unrelated to the endometrial cancer. The patient was treated with gemcitabine, nab-paclitaxel and ADI-PEG 20 for 12 months until disease progression and toxicity emerged [best overall response (BOR): partial response (PR)]. The patient switched to a modified regimen of folinic acid, fluorouracil, irinotecan and oxaliplatin for 4 months until neuropathy occurred. Oxaliplatin was withheld until disease progression 6 months later (BOR: stable disease). Despite recommencing oxaliplatin, the disease continued to progress. At this time, somatic profiling of the liver lesion revealed a CTRC-NTRK1 gene fusion. Treatment with larotrectinib 100 mg twice daily was commenced with BOR of PR at 2 months. The patient progressed after 6 months and was re-biopsied. Treatment was switched to the investigational next-generation TRK inhibitor LOXO-195 (BAY 2731954) 100 mg twice daily. After 2 months, the disease progressed and dabrafenibtrametinib combination therapy was initiated due to existence of a BRAF-V600E mutation. However, the cancer continued to progress and the patient died 2 months later. Conclusions Targeted TRK inhibition with larotrectinib in PDAC harbouring a CTRC-NTRK1 gene fusion is well tolerated and can improve quality of life for the patient. However, acquired resistance to therapy can emerge in some patients. Next-generation TRK inhibitors such as LOXO-195 are currently in development to overcome this resistance (NCT02576431; NCT03215511).
A R Ferreira, A Di Meglio, B Pistilli, A S Gbenou, M El-Mouhebb, S Dauchy, C Charles, F Joly, S Everhard, M Lambertini, et al.
Annals of Oncology; doi:10.1093/annonc/mdz298

The publisher has not yet granted permission to display this abstract.
S Abdullah, E Oflazoglu, J C Soria, M M Dar
Annals of Oncology; doi:10.1093/annonc/mdz401

J- Y Blay, S Bonvalot, F Gouin, A Le Cesne, N Penel
Annals of Oncology; doi:10.1093/annonc/mdz408

D Moro-Sibilot, N Cozic, M Pérol, J Mazières, J Otto, P J Souquet, R Bahleda, M Wislez, G Zalcman, S De Guibert, et al.
Annals of Oncology; doi:10.1093/annonc/mdz407

The publisher has not yet granted permission to display this abstract.
G V B Gomez, L M O Monteiro, R S Rocha, G J Lourenço, C S P Lima
Annals of Oncology, Volume 30; doi:10.1093/annonc/mdz238.049

Abstract:Background The JAK/STAT signaling pathway supports the development, progression and metastatic potential of cutaneous melanoma (CM). In normal cells the activation of STAT3 is rapid and transient, but in abnormal melanocytes the activation of the protein occurs in a constitutive manner favoring tumor expansion. STAT3 is coded by the polymorphic gene in humans and thus it is possible that normal individuals show inherited differences in pathway functionality. The aim of the study was to evaluate whether STAT3 c.*1671T>C and STAT3 c.-1937C>G variants influence the risk of CM patients and its functional consequences. Methods We evaluated 248 MC patients and 274 controls. DNA was analyzed by real-time polymerase chain reaction (PCR) for genotyping. Luciferase assay and gene expression in a genetically modified SK-MEL-28 melanoma cell line to present the STAT3 c.-1937C>G ancestral and variant genotypes were realized in study. Differences between groups were assessed by the Fisher or chi-square test. Comparisons of luciferase and gene expression were performed using t-tests and ANOVA or Mann-Whitney and Kruskal-Wallis tests. Results Individuals with STAT3 c.*1671TT and T allele, and STAT3 c.-1937CC genotype had 1.76 (95% CI: 1.08-2.85, P = 0.02), 1.42 (95% CI: 1.03-1.96, P = 0.02) and 1.67 (95% CI: 1.06-2.63, P = 0.02)-fold increased risks of CM than individuals with the other genotypes and allele, respectively. Individuals with TC haplotype of the STAT3 variants were at 1.70 (95% CI: 1.22-2.36, P = 0.001)-fold increased risk of CM than those with other haplotypes. In a genetically modified melanoma cell line to present the distinct genotypes of STAT3 c.-1937C> G, we observed a 30% increase in the promoter activity of the gene and increase of mRNA in cells with the CC genotype compared to those with the GG genotype. Conclusions The data present, for the first time, preliminary evidence that inherited abnormalities in the JAK/STAT pathway, related to STAT3 gene, alter the CM risk. These results may contribute to identify individuals at high risk for CM, who deserve special measures for prevention or early diagnosis. Legal entity responsible for the study The authors. Funding FAPESP and CAPES. Disclosure All authors have declared no conflicts of interest.
B Cervantes, B Gayet, F Frosio, N Tabchouri, M Bennamoun, N Alexandra, C Louvet, D Fuks
Annals of Oncology, Volume 30; doi:10.1093/annonc/mdz246.042

Abstract:Background Liver resection is a curative treatment for patients with colorectal liver metastasis (CRLM). However, about 70% patients will experience recurrence after resection. CRLM number and maximum (CRLMmax) size have been associated with recurrence after hepatic resection. Still, association between CRLM minimum (CRLMmin) size and tumor recurrence has never been evaluated. This study aimed to correlate CRLMmin on the liver specimen with recurrence free survival (RFS). Methods We retrospectively included all patients who underwent first laparoscopic liver resection for CRLM from January 2000 to November 2018 in a single institution. Patients with extra hepatic evolutive disease were excluded. A CRLMmin cut off was selected using the time-dependent area under the curve (td-AUC) for 1 and 2-year RFS. Cox uni and multivariate models were constructed. Multivariate analysis was completed for factors with a p value ≤ 0.10 upon univariate analysis, or previously known determinant factors. Primary end point was RFS. Results Overall, 227 patients were included. Median follow- up was 50 months (6-210), 151 (67%) patients presented with recurrence. The optimal CRLMmin cutoff associated with RFS was 9mm (12 and 24-months td-AUC = 0.56 and 0.52, respectively). Median RFS were respectively 11.9 months (CI 95% 7.1-18.7) in patients with CRLMmin size Conclusions The present study suggests that CRLMmin size Legal entity responsible for the study David Fuks. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.
G De La Cruz-Kú, B S Valcarcel, M Luján, A Saavedra, R Luque, E Eyzaguirre, M B Sultanov, Z Morante, S Quintana, S P Neciosup Delgado, et al.
Annals of Oncology, Volume 30; doi:10.1093/annonc/mdz251.028

Abstract:Background Although several studies report the clinical characteristics of bacteremia by Aeromonas species, there is a lack of studies about the bacteremia course in hematologic malignancies. Our aim was to determine the risk factors for bacteremia-associated mortality by Aeromonas sobria in patients with hematological malignancies. Methods We performed a retrospective cohort study, by reviewing 37 medical records of patients treated at the “Instituto Nacional de Enfermedades Neoplasicas-Peru”, in the period of 2000-2017. We considered a bacteremia-related death if it occurred within the first 7 days of A. sobria isolation, or during the acute course of sepsis. Risk factors were assessed by the Multivariate Cox regression analysis at 30 days after the patient’s admission. Results The median age was 24y (2-74y), six patients (16.2%) had ≥65y, and 54.1% were male. The most common diagnosis was lymphoid leukemia (51.4%), followed by myeloid leukemia (27%), high-grade lymphoma (18.9%), and multiple myeloma (2.7%); and 37.8% had community-acquired bacteremia. The gastrointestinal system was the most common primary source of infection (62.2%), followed by the osteoarticular system (18.9%). The mortality rate was 27%, and 11 cases (29.7%) presented septic shock. Furthermore, antibiotic use was as follow, meropenem (64.9%), ceftazidime (37.8%), and amikacin (29.7%). Multivariate Cox regression identified age ≥65, shock, and no disease remission as independent risk factors for mortality (Table). Risk factors for Bacteremia-Associated Mortality of Aeromona sobria. Table: 1093PUnivariate analysisMultivariate analysisHR95% CIP-valueHR95% CIP-valueAge ≥655.481.5-19.70.018.131.7-39.40.009Community-acquire bacteremia9.732.1– 46.10.004---Shock13.212.8–63.00.0017.061.5-34.40.016Non-disease remission14.311.8–113.30.01210.461.2-89.80.024 Conclusions Patients with hematological malignancy infected by A. sobria that either is ≥ 65-years-old does not have a disease remission or develop shock, the risk of dying increases. The physicians can use our results to guide the prognosis of patients infected by this bacteria. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.
M P Lux, K Lewis, A Rider, A Niyazov
Annals of Oncology, Volume 30; doi:10.1093/annonc/mdz241

Abstract:Background Mutations in breast cancer susceptibility gene 1 or 2 (BRCA1/2) are risk factors for developing cancer, especially for breast cancer (BC) and ovarian cancer (OC). Recently, European BC guidelines have expanded the eligibility criteria for BRCA1/2 testing. This study assessed BRCA1/2 testing rates in HER2- adult women with ABC in Germany, France, Italy, Spain and UK (EU5). Methods Patient (pt) demographics/clinical characteristics were collected from oncologists in EU5 via Adelphi Advanced Breast Cancer Disease Specific Program. Data collected from 2 years (2015 and 2017) were merged across common variables. Differences in pt demographics/characteristics among BRCA1/2 tested/untested pts were analyzed via t-tests and z-tests. BRCA1/2 testing was analyzed via z-tests. Analyses of BRCA1/2 testing rates were stratified by hormone receptor status [hormone receptor positive (HR+)/HER2- or triple negative breast cancer (TNBC)] and HR status by family history (FHx) of BC or OC. Results 4,876 records were provided by 742 oncologists. The mean age was 63.6 yrs; 75% HR+/HER2-, 23% TNBC, 2% unknown HR status. Compared to BRCA1/2 untested pts, BRCA1/2 tested pts were younger [57.7 vs 65.2 yrs (p<.001)]and had TNBC [35% vs 20% (p<.001)]. Across all EU5 countries, the mean BRCA1/2 testing rate was 21%; France 20%, Germany 30%, Italy 24%, Spain 20%, UK 14%. Lower BRCA1/2 testing was seen among HR+/HER2- vs TNBC pts [18% vs 33% (p<.001)]. Among HR+/HER2- and TNBC pts, higher BRCA1/2 testing rates were observed among women with a known FHx of BC or OC. (Table). Table. BRCA1/2 Testing by HR Status and known FHx of BC or OC. Conclusions In this analysis of adult women with ABC, both HR+/HER2- and TNBC pts with a known FHx of BC or OC (vs no known FHx) were more likely to receive BRCA1/2 testing but testing rates are still low especially among HR+/HER2- pts. With the broadening of BRCA1/2 testing eligibility criteria in BC guidelines, opportunities exist to increase BRCA1/2 testing in EU5. Legal entity responsible for the study Pfizer Inc. Funding Pfizer Inc. Disclosure M.P. Lux: Honoraria (self), Advisory / Consultancy: Pfizer Inc.; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Genomic Health; Honoraria (self), Advisory / Consultancy: medac; Honoraria (self), Advisory / Consultancy: Grünethal; Honoraria (self), Advisory / Consultancy: Tesaro; Honoraria (self), Advisory / Consultancy: Eisai. A. Niyazov: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer Inc. All other authors have declared no conflicts of interest. Table: 292PHR+/HER2- with FHx (n = 321)HR+/HER2- without FHx (n = 2,953)TNBC with FHx (n = 178)TNBC without FHx (n = 789)Pts tested, N (%)116 (36)476 (16)99 (56)234 (30)P value<.001<.001
M Voskoboynik, L Mileshkin, H Gan, M Millward, G Au-Yeung, T M Meniawy, G Kichenadasse, K Zhang, M Zhang, S Mu, et al.
Annals of Oncology, Volume 30; doi:10.1093/annonc/mdz244.014

Abstract:Background Pamiparib is an investigational PARP1/2 inhibitor that has demonstrated brain penetration and PARP–DNA complex trapping in preclinical studies. In the phase 1 dose-escalation/expansion study of pts with advanced solid tumors, pamiparib was generally well tolerated and showed preliminary antitumor activity. Here we report updated antitumor activity focused on the ovarian cancer cohort and safety data. Methods This is a two-stage dose-escalation/expansion study (NCT02361723). The dose-escalation study component established the pamiparib PK profile, and the recommended phase 2 dose (RP2D) of pamiparib administered orally 60 mg BID in pts with solid tumors. The dose-expansion component was conducted in pts with ovarian, breast, prostate, gastric, and small cell lung cancer. Results As of 1 January 2019, 97 pts (median age, 60 years; Eastern Cooperative Oncology Group performance status of 0, 1, or 2 [37%, 62%, and 1%, respectively]) were enrolled in the dose-escalation (n = 60) and dose-expansion (n = 37) components. Among the 97 enrolled pts, 48 pts (n = 30, ovarian pts) received 60 mg BID, the RP2D. Of 57 ovarian pts in the efficacy evaluable population (≥1 postbaseline tumor assessment), 22 (39%) achieved a confirmed objective response (complete response, n = 4; partial response, n = 18) per RECIST v1.1 criteria. Median duration of response was 12.3 months (range, 1.3–40.8). Biomarker data will be included in future analyses. In the safety population (n = 97), drug-related adverse events (AEs) in ≥ 10% of pts were nausea, fatigue, anemia, diarrhea, vomiting, and decreased appetite. The most common drug-related G3 (no G4 or G5) AEs were anemia (18.6%) and neutropenia (6.2%). AEs led to treatment discontinuation in 6.2% of pts. Four pts died due to disease progression with non-drug–related AEs. Pamiparib plasma exposure generally increased with increased dose, with a median t1/2 of ∼13 hours. Conclusions Pamiparib continues to be generally well tolerated and demonstrates antitumor activity in this update of an ongoing, phase 1 dose-escalation/expansion study in pts with advanced solid tumors. Clinical trial identification NCT02361723. Editorial acknowledgement Editorial/writing support was provided by Ira Mills, PhD, and Shannon Davis at Ashfield Healthcare Communications, Middletown, CT. Legal entity responsible for the study BeiGene. Funding BeiGene. Disclosure M. Voskoboynik: Honoraria (self): AstraZeneca; Honoraria (self): MSD Oncology; Travel / Accommodation / Expenses: Bristol-Myers Squibb. L. Mileshkin: Travel / Accommodation / Expenses, Beigene paid for flights and accommodation for me to attend and present at the ASCO STIC meeting Jan 2018: Beigene. M. Millward: Research grant / Funding (self), Per patient payments for clinical trials: Beigene; Advisory / Consultancy, Advisory Board for Immuno-Oncology: Bristol-Myers Squibb; Advisory / Consultancy, Advisory Board for Immuno-Oncology: Merck Sharp & Dohme; Advisory...