Chemotherapy is considered "state of the art" for the treatment of poorly differentiated neuroendocrine neoplasms. Unfortunately, there is no standard effective post-first-line treatment for ...relapsing high-grade gastroenteropancreatic neuroendocrine neoplasms. We report the case of a patient with a gastric neuroendocrine carcinoma stage IV, with massive gastrointestinal bleeding at diagnosis. After the first line of platin-based chemotherapy a major tumoral response was documented, but the patient relapsed after 4 months. A second line of chemotherapy treatment was given, with the FOLFOX regimen, and the patient has been free of progression for almost 2 years. There is no second-line standard treatment accepted for this type of carcinoma, but 5-fluorouracil combined with oxaliplatin showed interesting antitumor activity.
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Background: FGFR mutations/translocations are druggable targets in metastatic urothelial cancer (mUC). However, the prognostic effect of these genomic alterations (GA) and their ...role in the response to conventional therapy remain poorly characterized. Methods: We undertook an observational retrospective study in four Academic Hospitals in Madrid, Spain. Clinical and molecular information of patients diagnosed of Urothelial Cancer (UC) between January 2010 and December 2020 was systematically reviewed. The objective of this work was to compare the outcome of mUC patients with GA in the FGFR 2-3 genes versus wild type tumors. Analyses for detection of FGFR translocations and mutations using DNA isolated from formalin-fixed and paraffinized tumor tissue samples consisted of either next-generation sequencing (Foundation One test; n = 68) or qualitative real-time polymerase chain reaction–based assays (n = 9) with TFGFR or QIAGEN therascreen® tests that evaluated somatic mutations within the FGFR2-3 gene: R248C, S249C, G370C and Y373C and fusions: FGFR3-TACC3v3, FGFR3-TACC3v1 and FGFR3-BAIAP2L1, FGFR2-BICC1 and FGFR2-CASP7. Overall response rate (ORR), Progression Free Survival (PFS) and Overall Survival (OS) were determined and Cox-regression analysis were performed to assess the prognostic impact of these alterations. Results: We identified 201 patients diagnosed with UC. Genomic profiling was available in 77 mUC with 28 patients harboring any FGFR GA. Regarding ORR to first line a trend towards a better outcome was identified in FGFR GA (mutation/translocation/fusion) vs wild type cases (57,7% vs 45,5%, p=0,46). However, median OS was significantly worse among FGFR GA (mutation/translocation) vs FGFR wt tumours (13.8 vs 26.2 months, p=0,021). Prognostic factors associated with an unfavorable outcome in multivariable analysis were visceral metastases (HR 7,29 95% CI 1.6-32,3), ECOG >1 (HR 7,03 95% CI 2,59-19,1), first line treatment with checkpoint inhibitors (HR 2,67; 95% CI 1,06-6,74) and the presence of FGFR GAs (HR 2,98, 95% CI 1.37-6.5). Conclusions: Despite a better response to first line treatment, overall FGFR GA showed to be an independent risk factor in mUC. Thus, this determination should be included in new prognostic models.Table: see text
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Background: Exosomes have been involved in tumor progression and development of therapeutic resistances in several malignancies. This subtype of extracellular vesicles (EVs) promote ...angiogenesis, premetastatic niches formation and communication between the tumor and its microenvironment. Ovarian cancer (OC) is a highly lethal tumor that typically spreads within the abdominal cavity rather than through blood vessels. Based on this behavior, we aimed to study the presence of EVs in ascitic fluid of OC patients and explore their potential as predictors of tumor volume and chemoresistance. Methods: Observational prospective study in advanced OC patients who underwent a diagnostic laparoscopy or cytoreductive surgery. Abdominal washings of a cohort of non-cancer patients were collected as controls. All cases provided written consent. Clinical data and tumor genomic alterations (NGS, FoundationOne CDx) were recorded. EVs pellets were collected by ultracentrifugation and profiled by NTA and western blot (EVs markers: CD9, TSG101 and ALIX; non EVs related markers: ALB and APOB). EVs proteins were quantified by BCA assay and profiled by mass spectrometry. Results: We obtained 75 peritoneal fluids from 66 OC patients (median age at diagnosis range 62 26-83 years) and 29 peritoneal washings from controls. Our cohort comprises various histological subtypes (high grade serous, n 55; low grade serous, n 2; endometrioid, n 6; clear cell, n 2 and mucinous, n 1) and tumor stages (I-II, n 7; III; n 39; IV, n 20). Samples were collected either from primary (n 36); interval, (n 25); or relapse surgery (n 14). Pathogenic BRCA events: 15 patients. Mean concentration of exosomes (MCE) was 3.0x10
6
vs. 1.6x10
6
particles/ml (p/ml) in cases vs. controls (p < 0.0017). No difference in MCE was observed regarding stages I-II vs. III-IV (3.9x10
6
vs. 3.3x10
6
p/ml; p = 0.38). A higher MCE was observed in those samples collected after relapse surgeries compared to those collected from primary (7.2x10
6
vs. 2.8x10
6
p/ml; p < 0.0001) and interval surgeries (7.2x10
6
vs. 3.4x10
6
p/ml; p < 0.0007). Median exosomal protein concentration (MEPC) in EVs of cancer patients vs. controls was 0.99µg/µl and 0.57µg/µl respectively (p = 0.02). Proteomic characterization by mass spectrometry of EVs cargo has identified 1827 proteins, of which 405 proteins were differentially expressed between cases and controls. We also found 38 differentially expressed proteins comparing platinum-sensitive vs. resistant patient samples. Conclusions: Our data show higher concentration of exosomes and exosomal proteins in OC cases vs controls. Differentially expressed proteins have also been found between samples from platinum-sensitive and platinum-resistant patients. These results suggest that exosomes may be involved in the progression and spread of OC and may provide insights into current treatment response.
This report presents the case of a 62-year-old woman who was diagnosed in 1999 with stage I cervical carcinoma treated by surgical resection. In 2021, she presented to the emergency department with a ...complaint of predominantly right-sided lower back pain. A CT scan of the lumbosacral region revealed a bone lesion in the L5 vertebra and retroperitoneal lymphadenopathies suggestive of malignancy. Histology of the L5 vertebra biopsy showed a poorly differentiated carcinoma with an inconclusive immunophenotypic profile. Treatment for carcinoma of unknown primary was started with a combination of carboplatin and paclitaxel every 21 days. A genomic study of the biopsy specimen performed on the FoundationOne CDx platform identified a nonhuman genetic signature compatible with HPV. The presence of HPV 18 DNA in the specimen was confirmed by PCR-reverse dot blot, and the immunophenotypic profile was expanded, revealing strong and diffuse p16 expression, thus corroborating the molecular findings. In view of these findings, the case was reclassified as a recurrence of the cervical adenocarcinoma that had been diagnosed and treated 23 years earlier. Based on the new results, and according to first-line cervical carcinoma protocols, bevacizumab at 15 mg/kg every 21 days was added to her chemotherapy regimen. The identification of HPV DNA sequences by next-generation sequencing facilitated the correct diagnosis and led to a modification of the first-line therapeutic approach.
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Background: FGFR gene alterations are a new target in metastatic urothelial carcinoma (mUC). However, controversial data have been published regarding the outcome of these ...tumors.In order to assess the prognostic value of this gene, we aimed to compare survival and response to treatment of patients harboring FGFR alterations vs wild type (WT) tumors. Methods: Medical records of patients with advanced urothelial cancer screened for FGFR mutations or fusions at our center were reviewed. Results: Between May 2011 and December 2019 up to 149 patients completed any screening test for FGFR alterations. 30 cases (20,1%) were deemed as positive (mutations: 12, amplifications: 9, rearragements /fusions: 4 and not specified in 5). 30% of the cases were Upper Tract Urothelial carcinoma (UTUC) versus 70% bladder UC. 8% patients had liver metastases and 100% PS ≤ 1 at first line.. 73% (22/30) received chemotherapy (1st line:15, 2nd line; 4, 3rd line: 4) with 1CR, 9 PR, 2SD in first line. 50% (15/30) received a checkpoint inhibitor (1st line:5, 2nd line:5, 3rd line:5). Of these, 2 cases responded, 2 remained stable and 8 progressed. Overall, 40% (12/30) received an FGFR inhibitor (1st line: 7, 2nd line: 4, 3rd line: 1). 54% (6/11) experimented tumor response (complete:1, partial:5). Median overall survival for the whole FGFR population was 24,6 month. Median progresion free survival was:1st line: 4,1 mo, 2nd line: 4,1, 3rd line: 7,1 respectively. Among the 119 cases deemed as FGFR WT. 95% of primary tumors were located at the bladder. 64% had liver metastases and PS ≥2: 34% at first line treatment. 43%(52/119) received chemotherapy: 1
st
line:33, 2
nd
line:13, 3
rd
line: with 4CR, 11PR, 4SD, 9PD. And 40% (48/119 ) CPI: 1
st
line: 30, 2
nd
line: 15, 3
rd
line:3 with 1CR, 3 PR, 4SD, 19PD. The median OS was 9,9 months for patients with wild-type patients. Median progresion free survival was: 1st line: 4,5 mo, 2nd line: 2,3, 3rd line: 0.8 month. Conclusions: FGFR is a relatively common molecular alteration in UC. Patients harboring a FGFR alteration present a better prognosis than wild type tumors. Clinical benefit with chemotherapy and CPIs was similar in both populations.
To describe patient characteristics, effectiveness and safety in a real-world population treated with niraparib in the Spanish expanded-access programme.
This retrospective observational study ...included women with platinum-sensitive recurrent high-grade serous ovarian cancer who received maintenance niraparib within the Spanish niraparib expanded-access programme. Eligible patients had received ≥2 previous lines of platinum-containing therapy, remained platinum-sensitive after the penultimate line of platinum and had responded to the most recent platinum-containing therapy. Niraparib dosing was at the treating physician's discretion (300 mg/day fixed starting dose or individualised starting dose ISD according to baseline body weight and platelet count). Safety, impact of dose adjustments, patient characteristics and effectiveness were analysed using data extracted from medical records.
Among 316 eligible patients, 80% had BRCA wild-type tumours and 66% received an ISD. Median niraparib duration was 7.8 months. The most common adverse events typically occurred within 3 months of starting niraparib. Median progression-free survival was 8.6 (95% confidence interval CI 7.6–10.0) months. One- and 2-year overall survival rates were 86% (95% CI 81–89%) and 65% (95% CI 59–70%), respectively. Dose interruptions, dose reductions, haematological toxicities and asthenia/fatigue were less common with ISD than fixed starting dose niraparib, but progression-free survival was similar irrespective of dosing strategy. Subsequent therapy included platinum in 71% of patients who received further treatment.
Outcomes in this large real-world dataset of niraparib-treated patients are consistent with phase III trials, providing reassuring evidence of the tolerability and activity of niraparib maintenance therapy for platinum-sensitive recurrent ovarian cancer.
NCT04546373.
•In this real-world study of maintenance niraparib, 80% had BRCAwt ovarian cancer.•Median progression-free survival was 8.6 (95% confidence interval 7.6–10.0) months.•Adverse events typically occurred within 3 months of starting niraparib.•Tolerability was improved with an individualised versus fixed niraparib starting dose.•Real-world data for niraparib are consistent with phase III results.
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Background: Rucaparib is a PARP inhibitor approved for the treatment of high-grade ovarian cancer (HGOC). Clinical trials have demonstrated its benefit both as maintenance therapy (MTN) for ...platinum (Pt)-sensitive recurrent HGOC, and as treatment (Tx) in BRCA-mutated relapsed or recurrent HGOC patients. Here we analyze real-world data from the rucaparib early access program (RAP) in Spain with focus in the long-term responder patients (LTR). Methods: A retrospective observational study was performed by GEICO at 22 hospitals in Spain that had treated patients within the RAP. Adult women with HGOC, fallopian tube, or primary peritoneal cancer were included and received rucaparib (600 mg BID) in the MTN, Tx Pt-sensitive or Tx Pt-resistant setting. Patients’ characteristics, medical history, safety, efficacy, and dosing data were collected. In this analysis, long-term response was defined as progression-free survival (PFS) ≥12 months for the MTN group and ≥6 months for the Tx group. LTR were stratified based on the rucaparib indication (MTN/Tx). Results: Between July 2020 and February 2021, 51 patients were recruited: 18 received rucaparib as MTN and 33 as Tx. In the MTN group, 6 patients (33.3%) were LTR, with a median age of 65 years (54-79). Of them, 2 patients (33.2%) harbored BRCA or RAD51C mutations. The median number of prior lines was 3 (2-6), being ≥5 in 33.2%, and 50.0% received prior bevacizumab. ECOG PS was ≤1 in all these patients, 66.6% had measurable disease and 50.0% achieved a partial response to prior Pt-based chemotherapy. In the Tx group, 10 patients (30.3%) were LTR, with a median age of 71 years (47-86). All of them harbored BRCA and/or RAD51C mutations. The median number of prior lines was 6 (2-9), with 60.0% receiving ≥5 prior lines, and 50.0% received prior bevacizumab. Regarding Pt-status, 40.0% of patients were Pt-sensitive and 60.0% were Pt-resistant. The ECOG PS was ≥1 in 30.0% of patients and 60.0% had measurable disease. The median PFS of LTR was not achieved in the MTN group and was 10.9 months (95% CI: 7.0-16.7) in the Tx group. Adverse events (AE) of any grade were reported in 66.6% of LTR within the MTN group and in 100.0% within the Tx group, while AE of grade ≥3 occurred in 16.6% and 50.0%, respectively. Rucaparib dose was reduced in 50.0% of LTR in the MTN group and 80.0% in the Tx group. Discontinuation rate due to rucaparib toxicity was 20.0% in the Tx group and there were no discontinuations due to toxicity in the MTN group. No new safety signals were detected. At present, 3 and 1 patients are still receiving rucaparib as MTN and Tx, respectively. Conclusions: A durable response was achieved in a notable proportion of patients, even despite their unfavorable conditions at treatment initiation (heavily pre-treated patients, partial response or resistance to Pt, or high volume of disease). The safety profile of rucaparib in this real-world setting is consistent with that reported in clinical trials.
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Background: Rucaparib is a PARP inhibitor (PARPi) approved as maintenance therapy for platinum (Pt)-sensitive recurrent high-grade ovarian cancer (HGOC), and as treatment for BRCA-mutant HGOC ...patients. To date, there is little evidence about the efficacy and safety of rucaparib after prior exposure to PARPi. This subanalysis aims to describe the patients’ characteristics and treatment outcomes with rucaparib in women who were included in the rucaparib early access program (RAP) in Spain and had received a prior PARPi. Methods: A retrospective study was conducted by GEICO at 22 hospitals in Spain to analyze data of 51 women treated within the RAP (600 mg BID). Adult women with HGOC, fallopian tube, or primary peritoneal cancer, who had received at least one prior PARPi before rucaparib were analyzed. Patients’ characteristics, medical history, safety, efficacy, and dosing data were collected. Results: A total of 14 women, with a median age of 63 years old (42-78) were included in this subanalysis. Of them, 92.9% were diagnosed of epithelial ovarian cancer and 78.6% had mutations in BRCA1/ 2 genes. The median number of lines before rucaparib was 5 (3-8), while the number of lines before the first PARPi was 3 (2-5). Except for one woman who had received 2 prior PARPis before rucaparib, the others had received just 1. Most patients were given olaparib as the first PARPi (n = 12, 85.8%), while niraparib was the initial PARPi in the remaining cases (n = 2, 14.3%). The outcomes of the treatment with rucaparib in these patients are outlined in table 1. Rucaparib was given as maintenance therapy in 1 patient and as treatment in 13 patients, 12 of them being Pt-resistant. The progression-free survival (PFS) ranged from 0.23 to 9.12 months. Adverse events (AE) of any grade were detected in 78.6% of patients, whereas AE of grade ≥3 affected 28.6% of women. Rucaparib dose was interrupted in 57.1% and reduced in 42.9% of patients. Only 1 patient discontinued rucaparib due to toxicity. No new safety signals were detected. Conclusions: This is one of the first real-word studies reporting the use of rucaparib after treatment with another PARPi. Even in these heavily pre-treated patients who had received prior PARPi, rucaparib efficacy has been notable in some cases, and its safety profile is consistent with that reported in previous clinical trials. Future studies should focus on the selection of patients who could benefit from rucaparib after prior PARPi exposure. Table: see text
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546
Background: Immune checkpoint inhibitors have been incorporated to early-stage bladder carcinoma treatment recently. Durvalumab is a PD-L1 blocking antibody active in advance ...urothelial tumors and under evaluation in other settings of the disease. PARP inhibitors have shown activity in a variety of tumors with Homologous Recombination Deficiencies (HRD). The combination of Durvalumab plus Olaparib could present a synergistic effect, but its efficacy and potential biomarkers are under exploration. NEODURVARIB is a phase II clinical trial assessing the combination of Durvalumab plus Olaparib in MIBC (NCT03534492; SOGUG-2017-AIEC(VEJ)-2). Clinical activity and safety have been previously communicated by our group. Here we present the basal molecular profiles and their evolution under treatment with this combination. Methods: cT2-T4a MIBC aimed for cystectomy were treated during 6-8 weeks precystectomy. Pre- and post-treatment tumor and blood samples from 26 patients were collected. Pattern of immune infiltration was determined by IHQ. Genomics (mutational pattern, HRD and Tumor Mutation Burden TMB) and transcriptomics (differentially expressed loci, functional enrichment, molecular clustering and MIBC molecular subtyping) analysis were performed. Circulating immune populations were assessed using flow cytometry. Results: In basal (TURBT) samples, the frequency of mutations in genes commonly altered in MIBC ( TP53, MLL2, ARID1A, FGFR3, among others), HRD and TMB were similar to previous reports in MIBC and did not differ between responders and non-responders. Additionally, mutational patterns remained stable between baseline (TURBT) and post-treatment (cystectomy) samples. Regarding transcriptomics, GSEA showed enrichment of Epithelial Mesenchymal Transition (EMT), TGFβ and inflammatory/infection related classes in resistant tumors. Interestingly, differentially expressed genes in responders vs. non-responders were significantly regulated by epigenetic factors (EZH2/Suz12/PRC2 network). Transcriptomic-based estimations of the stromal/immune infiltration and MIBC molecular subtyping also showed a switch of the tumor microenvironment due to the treatment (luminal to basal/squamous transitions), reinforced by significant changes in the expression of immune markers (higher PDL1 and FAP scores in cystectomies). Lastly, circulating senescent T-cells were correlated with pathological complete response. Conclusions: Genetic alterations remained unchanged in bladder cancers treated with Durvalumab plus Olaparib. However, an enrichment of EMT signatures and a switch towards basal/squamous phenotypes were observed in resistant tumors. These findings underscore the relevance of modifications in gene expression as potential mechanisms of resistance to this combination. Clinical trial information: NCT03534492.
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Background: ALK rearrangements are key targets in non-small-cell lung cancer (NSCLC). Unfortunately, the optimal sequential strategy of ALK-tyrosine kinase inhibitors (TKI) ...remains to be defined. Testing drug sensitivity in patient derived organoids (PDOs) could support a rational drug selection in this setting. Methods: We designed an observational study assessing the correlation between drug sensitivity of PDOs established in Invitrocue and the clinical outcome in our institution. To date, forty cases have been included, of which nine were lung cancers. Results: PDO was sucessfully established in 7/9 cases (77%). Three patients did not receive any of the drugs tested in vitro due to clinical deterioration. One patient was deemed as sensitive to carboplatin but tumor showed to be resistant. A meaningful correlation was observed in an oncogenic addicted tumor. A 54-year-old never-smoker man who had been diagnosed with lung adenocarcinoma stage IVa (T3N1M1a). He received standard first-line therapy with platinum-based chemotherapy, immunotherapy and antiangiogenics achieving tumor progression. A next-generation sequencing (NGS) panel revealed the presence of the EML4-ALK fusion variant 3a/b. The patient started alectinib but showed progression after 12 months. A second NGS panel did not identify any new ALK resistance mutation but acquiring TP53. Treatment was switched to brigatinib with no response. Finally, fresh tumor tissue was obtained from a liver biopsy to establish PDOs and drug sensitivity to 8 compounds was tested. The In vitro results demonstrated no activity of lorlatinib but a strong response to crizotinib. The patient started Crizotinib 250mg BID achieving partial response after 8 weeks and treatment duration of 6 months. A third liver biopsy for PDOs and NGS revealed acquired ALK C1156Y and I1171T mutations that confer resistance to crizotinib but sensitive to ceritinib, respectively. Conclusions: We present clinical evidence that PDOs are an alternative tool in oncogenic addicted tumors helping to guide treatment decisions and increasing a more personalized sequential treatment approach.
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