Publications by authors named "Jourik A Gietema"

121 Publications

Predicting Outcomes in Men With Metastatic Nonseminomatous Germ Cell Tumors (NSGCT): Results From the IGCCCG Update Consortium.

J Clin Oncol 2021 Apr 6:JCO2003296. Epub 2021 Apr 6.

University Department of Medical Oncology, Inselspital, University Hospital, University of Bern, Bern, Switzerland.

Purpose: The classification of the International Germ Cell Cancer Collaborative Group (IGCCCG) plays a pivotal role in the management of metastatic germ cell tumors but relies on data of patients treated between 1975 and 1990.

Materials And Methods: Data on 9,728 men with metastatic nonseminomatous germ cell tumors treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Europe, North America, and Australia. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS). The survival estimates were updated for the current era. Additionally, a novel prognostic model for PFS was developed in 3,543 patients with complete information on potentially relevant variables. The results were validated in an independent data set.

Results: Compared with the original IGCCCG publication, 5-year PFS remained similar in patients with good prognosis with 89% (87%-91%) versus 90% (95% CI, 89 to 91), but the 5-year OS increased from 92% (90%-94%) to 96% (95%-96%). In patients with intermediate prognosis, PFS remained similar with 75% (71%-79%) versus 78% (76%-80%) and the OS increased from 80% (76%-84%) to 89% (88%-91%). In patients with poor prognosis, the PFS increased from 41% (95% CI, 35 to 47) to 54% (95% CI, 52 to 56) and the OS from 48% (95% CI, 42 to 54) to 67% (95% CI, 65 to 69). A more granular prognostic model was developed and independently validated. This model identified a new cutoff of lactate dehydrogenase at a 2.5 upper limit of normal and increasing age and presence of lung metastases as additional adverse prognostic factors. An online calculator is provided (https://www.eortc.org/IGCCCG-Update).

Conclusion: The IGCCCG Update model improves individual prognostication in metastatic nonseminomatous germ cell tumors. Increasing age and lung metastases add granularity to the original IGCCCG classification as adverse prognostic factors.
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http://dx.doi.org/10.1200/JCO.20.03296DOI Listing
April 2021

Survival and New Prognosticators in Metastatic Seminoma: Results From the IGCCCG-Update Consortium.

J Clin Oncol 2021 Mar 17:JCO2003292. Epub 2021 Mar 17.

Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland.

Purpose: The classification of the International Germ-Cell Cancer Collaborative Group (IGCCCG) has been a major advance in the management of germ-cell tumors, but relies on data of only 660 patients with seminoma treated between 1975 and 1990. We re-evaluated this classification in a database from a large international consortium.

Materials And Methods: Data on 2,451 men with metastatic seminoma treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Australia, Europe, and North America. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS) calculated from day 1 of treatment. Variables at initial presentation were evaluated for their prognostic impact. Results were validated in an independent validation set of 764 additional patients.

Results: Compared with the initial IGCCCG classification, in our modern series, 5-year PFS improved from 82% to 89% (95% CI, 87 to 90) and 5-year OS from 86% to 95% (95% CI, 94 to 96) in good prognosis, and from 67% to 79% (95% CI, 70 to 85) and 72% to 88% (95% CI, 80 to 93) in intermediate prognosis patients. Lactate dehydrogenase (LDH) proved to be an additional adverse prognostic factor. Good prognosis patients with LDH above 2.5× upper limit of normal had a 3-year PFS of 80% (95% CI, 75 to 84) and a 3-year OS of 92% (95% CI, 88 to 95) versus 92% (95% CI, 90 to 94) and 97% (95% CI, 96 to 98) in the group with lower LDH.

Conclusion: PFS and OS in metastatic seminoma significantly improved in our modern series compared with the original data. The original IGCCCG classification retains its relevance, but can be further refined by adding LDH at a cutoff of 2.5× upper limit of normal as an additional adverse prognostic factor.
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http://dx.doi.org/10.1200/JCO.20.03292DOI Listing
March 2021

Establishment and characterisation of testicular cancer patient-derived xenograft models for preclinical evaluation of novel therapeutic strategies.

Sci Rep 2020 11 3;10(1):18938. Epub 2020 Nov 3.

Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.

Testicular cancer (TC) is the most common solid tumour in young men. While cisplatin-based chemotherapy is highly effective in TC patients, chemoresistance still accounts for 10% of disease-related deaths. Pre-clinical models that faithfully reflect patient tumours are needed to assist in target discovery and drug development. Tumour pieces from eight TC patients were subcutaneously implanted in NOD scid gamma (NSG) mice. Three patient-derived xenograft (PDX) models of TC, including one chemoresistant model, were established containing yolk sac tumour and teratoma components. PDX models and corresponding patient tumours were characterised by H&E, Ki-67 and cyclophilin A immunohistochemistry, showing retention of histological subtypes over several passages. Whole-exome sequencing, copy number variation analysis and RNA-sequencing was performed on these TP53 wild type PDX tumours to assess the effects of passaging, showing high concordance of molecular features between passages. Cisplatin sensitivity of PDX models corresponded with patients' response to cisplatin-based chemotherapy. MDM2 and mTORC1/2 targeted drugs showed efficacy in the cisplatin sensitive PDX models. In conclusion, we describe three PDX models faithfully reflecting chemosensitivity of TC patients. These models can be used for mechanistic studies and pre-clinical validation of novel therapeutic strategies in testicular cancer.
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http://dx.doi.org/10.1038/s41598-020-75518-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641131PMC
November 2020

Dose-Dependent Effect of Platinum-Based Chemotherapy on the Risk of Metachronous Contralateral Testicular Cancer.

J Clin Oncol 2021 Feb 29;39(4):319-327. Epub 2020 Oct 29.

Department of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.

Purpose: Patients with testicular germ cell tumor (TGCT) are at increased risk of developing a contralateral TGCT (CTGCT). Although some studies suggest that prior treatment with platinum-based chemotherapy affects CTGCT risk, a relationship between CTGCT risk and platinum dose has not previously been assessed. We analyzed the association between the number of platinum-based chemotherapy cycles and CTGCT risk.

Patients And Methods: The risk of developing a metachronous CTGCT was evaluated in a nationwide cohort of 4,755 patients diagnosed with primary TGCT in the Netherlands between 1989 and 2007. Standardized incidence ratios were computed to compare CTGCT incidence with expected TGCT on the basis of TGCT incidence in the general population. The cumulative incidence of CTGCT was estimated in the presence of death as competing risk. The effect of treatment with platinum-based chemotherapy on CTGCT risk was assessed using multivariable Cox proportional hazards regression models.

Results: CTGCT was diagnosed in 136 patients (standardized incidence ratio, 14.6; 95% CI, 12.2 to 17.2). The cumulative incidence increased up to 20 years after primary diagnosis, reaching 3.4% (95% CI, 2.8% to 4.0%) after 20 years of follow up. The risk of developing a CTGCT decreased with age (hazard ratio [HR], 0.93; 95% CI, 0.90 to 0.96), was lower after nonseminomatous germ cell tumor (HR, 0.58; 95% CI, 0.35 to 0.96) and decreased with every additional cycle of chemotherapy (HR, 0.74; 95% CI, 0.64 to 0.85).

Conclusion: Approximately one in every 30 survivors of TGCT will develop a CTGCT, with CTGCT incidence increasing up to 20 years after a primary TGCT. Treatment with platinum-based chemotherapy shows a dose-dependent inverse association with CTGCT risk.
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http://dx.doi.org/10.1200/JCO.20.02352DOI Listing
February 2021

Genome-wide association study of cardiovascular disease in testicular cancer patients treated with platinum-based chemotherapy.

Pharmacogenomics J 2021 Apr 3;21(2):152-164. Epub 2020 Oct 3.

Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.

Genetic variation may mediate the increased risk of cardiovascular disease (CVD) in chemotherapy-treated testicular cancer (TC) patients compared to the general population. Involved single nucleotide polymorphisms (SNPs) might differ from known CVD-associated SNPs in the general population. We performed an explorative genome-wide association study (GWAS) in TC patients. TC patients treated with platinum-based chemotherapy between 1977 and 2011, age ≤55 years at diagnosis, and ≥3 years relapse-free follow-up were genotyped. Association between SNPs and CVD occurrence during treatment or follow-up was analyzed. Data-driven Expression Prioritized Integration for Complex Trait (DEPICT) provided insight into enriched gene sets, i.e., biological themes. During a median follow-up of 11 years (range 3-37), CVD occurred in 53 (14%) of 375 genotyped patients. Based on 179 SNPs associated at p ≤ 0.001, 141 independent genomic loci associated with CVD occurrence. Subsequent, DEPICT found ten biological themes, with the RAC2/RAC3 network (linked to endothelial activation) as the most prominent theme. Biology of this network was illustrated in a TC cohort (n = 60) by increased circulating endothelial cells during chemotherapy. In conclusion, the ten observed biological themes highlight possible pathways involved in CVD in chemotherapy-treated TC patients. Insight in the genetic susceptibility to CVD in TC patients can aid future intervention strategies.
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http://dx.doi.org/10.1038/s41397-020-00191-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997802PMC
April 2021

Vascular aging in long-term survivors of testicular cancer more than 20 years after treatment with cisplatin-based chemotherapy.

Br J Cancer 2020 11 14;123(11):1599-1607. Epub 2020 Sep 14.

Department of Medical Oncology, University Medical Centre Groningen and University of Groningen, Groningen, The Netherlands.

Background: Late effects of cisplatin-based chemotherapy in testicular cancer survivors (TCS) include cardiovascular morbidity, but little data is available beyond 20 years. The objective was to assess vascular damage in very long-term TCS.

Methods: TCS (treated with chemotherapy or orchiectomy only) and age-matched healthy controls were invited. Study assessment included vascular stiffness with ultrasound measurement of carotid-femoral pulse wave velocity (cf-PWV).

Results: We included 127 TCS consisting of a chemotherapy group (70 patients) and an orchiectomy group (57 patients) along with 70 controls. Median follow-up was 28 years (range: 20-42). The cf-PWV (m/s) was higher in TCS than in controls (geometrical mean 8.05 (SD 1.23) vs. 7.60 (SD 1.21), p = 0.04). The cf-PWV was higher in the chemotherapy group than in the orchiectomy group (geometrical mean 8.39 (SD 1.22) vs. 7.61 (SD 1.21), p < 0.01). In the chemotherapy group cf-PWV increased more rapidly as a function of age compared to controls (regression coefficient b 7.59 × 10 vs. 4.04 × 10; p = 0.03).

Conclusion: Very long-term TCS treated with cisplatin-based chemotherapy show increased vascular damage compatible with "accelerated vascular aging" and continue to be at risk for cardiovascular morbidity, thus supporting the need for intensive cardiovascular risk management.

Clinical Trial Registration: The clinical trial registration number is NCT02572934.
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http://dx.doi.org/10.1038/s41416-020-01049-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686327PMC
November 2020

Management of Germ Cell Tumors During the Outbreak of the Novel Coronavirus Disease-19 Pandemic: A Survey of International Expertise Centers.

Oncologist 2020 10 18;25(10):e1509-e1515. Epub 2020 Sep 18.

Department of Clinical Medicine and Surgery, University of Naples "Federico II,", Naples, Italy.

Background: The coronavirus disease 2019 (COVID-19) pandemic has become a public health emergency affecting frail populations, including patients with cancer. This poses the question of whether cancer treatments can be postponed or modified without compromising their efficacy, especially for highly curable cancers such as germ cell tumors (GCTs).

Materials And Methods: To depict the state-of-the-art management of GCTs during the COVID-19 pandemic, a survey including 26 questions was circulated by e-mail among the physicians belonging to three cooperative groups: (a) Italian Germ Cell Cancer Group; (b) European Reference Network-Rare Adult Solid Cancers, Domain G3 (rare male genitourinary cancers); and (c) Genitourinary Medical Oncologists of Canada. Percentages of agreement between Italian respondents (I) versus Canadian respondents (C), I versus European respondents (E), and E versus C were compared by using Fisher's exact tests for dichotomous answers and chi square test for trends for the questions with three or more options.

Results: Fifty-three GCT experts responded to the survey: 20 Italian, 6 in other European countries, and 27 from Canada. Telemedicine was broadly used; there was high consensus to interrupt chemotherapy in COVID-19-positive patients (I = 75%, C = 55%, and E = 83.3%) and for use of granulocyte colony-stimulating factor primary prophylaxis for neutropenia (I = 65%, C = 62.9%, and E = 50%). The main differences emerged regarding the management of stage I and stage IIA disease, likely because of cultural and geographical differences.

Conclusion: Our study highlights the common efforts of GCT experts in Europe and Canada to maintain high standards of treatment for patients with GCT with few changes in their management during the COVID-19 pandemic.

Implications For Practice: Despite the chaos, disruptions, and fears fomented by the COVID-19 illness, oncology care teams in Italy, other European countries, and Canada are delivering the enormous promise of curative management strategies for patients with testicular cancer and other germ cell tumors. At the same time, these teams are applying safe and innovative solutions and sharing best practices to minimize frequency and intensity of patient contacts with thinly stretched health care capacity.
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http://dx.doi.org/10.1634/theoncologist.2020-0420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543332PMC
October 2020

Posterior retroperitoneoscopic resection of recurrent nonseminomatous tumor mass: a case report of the surgical procedure.

J Surg Case Rep 2020 Jul 8;2020(7):rjaa122. Epub 2020 Jul 8.

Department of Surgical Oncology, University of Groningen, University Medical Center Groningen, The Netherlands.

Treatment of stage II-IV nonseminomatous testicular germ cell tumors (NSTGCTs) consists of cisplatin-based combination chemotherapy and, when present, resection of residual retroperitoneal tumor mass (RRTM) by conventional laparotomy or laparoscopy. In case of a retroperitoneal recurrence, a second conventional or laparoscopic procedure may be challenging. A case of late relapse after prior conventional resection of a RRTM and tailor-made surgical management with a posterior retroperitoneoscopic resection (PRR) is reported. A posterior retroperitoneoscopic RRTM resection was performed in a 26-year-old male with a history of stage IIC NSTGCT, presenting with a late left-sided retroperitoneal relapse, 6 years after initial treatment. Postoperative course was uneventful and at 1-year follow-up the patient had no evidence of disease. Reoperative surgery by a minimal invasive retroperitoneoscopic approach should be considered as an alternative for patients with a recurrent retroperitoneal tumor mass of a NSTGCT.
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http://dx.doi.org/10.1093/jscr/rjaa122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7342175PMC
July 2020

Testicular cancer: Determinants of cisplatin sensitivity and novel therapeutic opportunities.

Cancer Treat Rev 2020 Aug 8;88:102054. Epub 2020 Jun 8.

Department of Medical Oncology, Cancer Research Center Groningen, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address:

Testicular cancer (TC) is the most common solid tumor among men aged between 15 and 40 years. TCs are highly aneuploid and the 12p isochromosome is the most frequent chromosomal abnormality. The mutation rate is of TC is low, with recurrent mutations in KIT and KRAS observed only at low frequency in seminomas. Overall cure rates are high, even in a metastatic setting, resulting from excellent cisplatin sensitivity of TCs. Factors contributing to the observed cisplatin sensitivity include defective DNA damage repair and a hypersensitive apoptotic response to DNA damage. Nonetheless, around 10-20% of TC patients with metastatic disease cannot be cured by cisplatin-based chemotherapy. Resistance mechanisms include downregulation of OCT4 and failure to induce PUMA and NOXA, elevated levels of MDM2, and hyperactivity of the PI3K/AKT/mTOR pathway. Several pre-clinical approaches have proven successful in overcoming cisplatin resistance, including specific targeting of PARP, MDM2 or AKT/mTOR combined with cisplatin. Finally, patient-derived xenograft models hold potential for mechanistic studies and pre-clinical validation of novel therapeutic strategies in TC. While clinical trials investigating targeted drugs have been disappointing, pre-clinical successes with chemotherapy and targeted drug combinations fuel the need for further investigation in clinical setting.
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http://dx.doi.org/10.1016/j.ctrv.2020.102054DOI Listing
August 2020

Comparison of Carboplatin With 5-Fluorouracil vs. Cisplatin as Concomitant Chemoradiotherapy for Locally Advanced Head and Neck Squamous Cell Carcinoma.

Front Oncol 2020 5;10:761. Epub 2020 Jun 5.

Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.

Chemoradiotherapy (CRT) including three cycles of cisplatin is considered the standard of care for locally advanced head and neck squamous cell carcinoma (LA-HNSCC). However, around one-third of the patients cannot complete cisplatin because of toxicity. Carboplatin plus 5-fluorouracil (carbo-5FU) is another accepted treatment option with a different toxicity profile. We compared tolerability and efficacy of concomitant carbo-5FU and cisplatin. We conducted a retrospective analysis of LA-HNSCC patients treated with CRT in two Dutch cancer centers between 2007 and 2016. All patients received intensity-modulated radiotherapy. One center routinely administered carboplatin 300-350 mg/m at day 1, 22, and 43 followed by 5FU 600 mg/m/day for 96 h. The other center used cisplatin 100 mg/m at day 1, 22, and 43. The primary endpoint of this study was chemotherapy completion rate. Secondary endpoints included overall survival (OS), disease-free survival (DFS), locoregional control (LRC) and distant metastasis-free interval (DMFS), toxicity, and unplanned admissions. In the carbo-5FU cohort ( = 211), 60.2% of the patients completed chemotherapy vs. 76.7% ( < 0.001) of the patients in the cisplatin cohort ( = 223). Univariate analysis showed a higher risk of death in the carbo-5FU cohort [hazard ratio (HR) 1.53, 95% CI, 1.09-2.14, = 0.01] with a 3-year OS of 65.4 vs. 76.5% for cisplatin. OS was independently associated with T and N stage and p16 status, but not with chemotherapy regimen (HR 1.08, 95% CI, 0.76-1.55, = 0.65). Three-year DFS was 70.0% for carbo-5FU vs. 78.6% for cisplatin (HR 1.37, 95% CI, 0.93-2.01, = 0.05). A similar outcome was observed for both LRC (HR 1.27, 95% CI, 0.74-2.09, = 0.4) and DMFS (HR 1.08, 95% CI 0.62-1.90, = 0.77). The risk of discontinuation for chemotherapy-associated toxicity was higher in the carbo-5FU cohort than in the cisplatin cohort (relative risk = 1.69). LA-HNSCC patients treated with concomitant carbo-5FU completed chemotherapy less frequently than patients treated with cisplatin. Treatment regimen was not an independent prognostic factor for OS.
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http://dx.doi.org/10.3389/fonc.2020.00761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292049PMC
June 2020

Early ageing after cytotoxic treatment for testicular cancer and cellular senescence: Time to act.

Crit Rev Oncol Hematol 2020 Jul 7;151:102963. Epub 2020 May 7.

Department of Medical Oncology, University Medical Center Groningen, University of Groningen, The Netherlands. Electronic address:

Treatment of testicular cancer (TC) has an exceptionally high success rate compared to other cancer types; even in case of metastasized disease, 80-90 % of TC patients can be cured. Consequently, attention has been drawn to a potential downside of this treatment success: late adverse treatment effects such as the accelerated development of otherwise age-associated features like cardiovascular disease and second malignancies. Underlying mechanisms are poorly understood. Emerging data suggest that cytotoxic treatment induces cellular senescence, resulting in secretion of inflammatory factors contributing to this early ageing phenotype. Molecular and cellular characterization of this early ageing will enhance understanding the pathogenesis of TC treatment-induced morbidity and contribute to better recognition and prevention of late effects. In this review, we describe clinical manifestations of the early ageing phenotype among TC survivors, and subsequently focus on potential underlying mechanisms. We discuss the clinical implications and describe perspectives for future research and intervention strategies.
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http://dx.doi.org/10.1016/j.critrevonc.2020.102963DOI Listing
July 2020

Phase I study of metformin in combination with carboplatin/paclitaxel chemotherapy in patients with advanced epithelial ovarian cancer.

Invest New Drugs 2020 10 7;38(5):1454-1462. Epub 2020 Mar 7.

Department of Medical Oncology, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB, Groningen, the Netherlands.

Background Metformin use is associated with reduced cancer risk in epidemiological studies and has preclinical anti-cancer activity in ovarian cancer models. The primary objective of this phase I study was to determine the recommended phase II dose (RP2D) of metformin in combination with carboplatin/paclitaxel in patients with ovarian cancer. Secondary objectives were to describe safety and pharmacokinetics. Methods In this single-center trial the RP2D of metformin in combination with carboplatin area under the concentration-time curve (AUC) 6 and paclitaxel 175 mg/m every 3 weeks (q3w) in patients with advanced epithelial ovarian cancer was determined using a 3 + 3 escalation rule at three fixed dose levels: 500 mg three times daily (tds), 850 mg tds and 1000 mg tds. Metformin was commenced on day 3 of cycle 1 and continued until 3 weeks after the last chemotherapy administration. The RP2D was defined as the dose level at which 0 of 3 or ≤ 1 of 6 evaluable subjects experienced a metformin-related dose-limiting toxicity (DLT). Safety was assessed according to CTCAE v4.0. Plasma and serum samples for pharmacokinetic (PK) analyses were collected during treatment cycles 1 and 2. Results Fifteen patients with epithelial ovarian cancer and an indication for neo-adjuvant (n = 5) or palliative (n = 10) treatment were included. No DLTs were observed. Three patients discontinued study treatment during cycle 1 for other reasons than DLT. Six patients were treated at the RP2D of metformin 1000 mg tds. The most frequent low-grade toxicities were anemia, hypomagnesemia and diarrhea. Grade 3 adverse events (AEs) occurred in ten patients, most common were leucopenia (n = 4), thrombocytopenia (n = 3) and increased GGT (n = 3). There were no grade 4 AEs. Metformin increased the platinum (Pt) AUC (Δ22%, p = 0.013) and decreased the Pt clearance (Δ-28%, p = 0.013). Metformin plasma levels were all within the therapeutic range for diabetic patients (0.1-4 mg/L). Conclusion The RP2D of metformin in combination with carboplatin and paclitaxel in advanced ovarian cancer is 1000 mg tds. This is higher than the RP2D reported for combination with targeted agents. A potential PK interaction of metformin with carboplatin was identified.
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http://dx.doi.org/10.1007/s10637-020-00920-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497683PMC
October 2020

Long-term survivors of early breast cancer treated with chemotherapy are characterized by a pro-inflammatory biomarker profile compared to matched controls.

Eur J Heart Fail 2020 07 20;22(7):1239-1246. Epub 2020 Feb 20.

Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Background: Chemo- and radiotherapy for breast cancer (BC) can lead to cardiotoxicity even years after the initial treatment. The pathophysiology behind these late cardiac effects is poorly understood. Therefore, we studied a large panel of biomarkers from different pathophysiological domains in long-term BC survivors, and compared these to matched controls.

Methods And Results: In total 91 biomarkers were measured in 688 subjects: 342 BC survivors stratified either to treatment with chemotherapy ± radiotherapy (n = 170) or radiotherapy alone (n = 172) and matched controls. Mean age was 59 ± 9 years and 65 ± 8 years for women treated with chemotherapy ± radiotherapy and radiotherapy alone, respectively, with a mean time since treatment of 11 ± 5.5 years. No biomarkers were differentially expressed in survivors treated with radiotherapy alone vs. controls (P for all >0.1). In sharp contrast, a total of 19 biomarkers were elevated, relative to controls, in BC survivors treated with chemotherapy ± radiotherapy after correction for multiple comparisons (P <0.05 for all). Network analysis revealed upregulation of pathways relating to collagen degradation and activation of matrix metalloproteinases. Furthermore, several inflammatory biomarkers including growth differentiation factor 15, monocyte chemoattractant protein 1, chemokine (C-X-C motif) ligand 16, tumour necrosis factor super family member 13b and proprotein convertase subtilisin/kexin type 9, elevated in survivors treated with chemotherapy, showed an independent association with lower left ventricular ejection fraction.

Conclusion: Breast cancer survivors treated with chemotherapy ± radiotherapy show a distinct biomarker profile associated with mild cardiac dysfunction even 10 years after treatment. These results suggest that an ongoing pro-inflammatory state and activation of matrix metalloproteinases following initial treatment with chemotherapy might play a role in the observed cardiac dysfunction in late BC survivors.
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http://dx.doi.org/10.1002/ejhf.1758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540448PMC
July 2020

High-Dose Chemotherapy With Hematopoietic Stem Cell Transplant in Patients With High-Risk Breast Cancer and 4 or More Involved Axillary Lymph Nodes: 20-Year Follow-up of a Phase 3 Randomized Clinical Trial.

JAMA Oncol 2020 04;6(4):528-534

Department of Medical Oncology, University Medical Center Groningen, Groningen, the Netherlands.

Importance: Trials of adjuvant high-dose chemotherapy (HDCT) have failed to show a survival benefit in unselected patients with breast cancer, but long-term follow-up is lacking.

Objective: To determine 20-year efficacy and safety outcomes of a large trial of adjuvant HDCT vs conventional-dose chemotherapy (CDCT) for patients with stage III breast cancer.

Design, Setting, And Participants: This secondary analysis used data from a randomized phase 3 multicenter clinical trial of 885 women younger than 56 years with breast cancer and 4 or more involved axillary lymph nodes conducted from August 1, 1993, to July 31, 1999. Additional follow-up data were collected between June 1, 2016, and December 31, 2017, from medical records, general practitioners, the Dutch national statistical office, and nationwide cancer registries. Analysis was performed on an intention-to-treat basis. Statistical analysis was performed from February 1, 2018, to October 14, 2019.

Interventions: Participants were randomized 1:1 to receive 5 cycles of CDCT consisting of fluorouracil, 500 mg/m2, epirubicin, 90 mg/m2, and cyclophosphamide, 500 mg/m2, or HDCT in which the first 4 cycles were identical to CDCT and the fifth cycle was replaced by cyclophosphamide, 6000 mg/m2, thiotepa, 480 mg/m2, and carboplatin, 1600 mg/m2, followed by hematopoietic stem cell transplant.

Main Outcomes And Measures: Main end points were overall survival and safety and cumulative incidence risk of a second malignant neoplasm or cardiovascular events.

Results: Of the 885 women in the study (mean [SD] age, 44.5 [6.6] years), 442 were randomized to receive HDCT, and 443 were randomized to receive CDCT. With 20.4 years median follow-up (interquartile range, 19.2-22.0 years), the 20-year overall survival was 45.3% with HDCT and 41.5% with CDCT (hazard ratio, 0.89; 95% CI, 0.75-1.06). The absolute improvement in 20-year overall survival was 14.6% (hazard ratio, 0.72; 95% CI, 0.54-0.95) for patients with 10 or more invoved axillary lymph nodes and 15.4% (hazard ratio, 0.67; 95% CI, 0.42-1.05) for patients with triple-negative breast cancer. The cumulative incidence risk of a second malignant neoplasm at 20 years or major cardiovascular events was similar in both treatment groups (20-year cumulative incidence risk for second malignant neoplasm was 12.1% in the HDCT group vs 16.2% in the CDCT group, P = .10), although patients in the HDCT group more often had hypertension (21.7% vs 14.3%, P = .02), hypercholesterolemia (15.7% vs 10.6%, P = .04), and dysrhythmias (8.6% vs 4.6%, P = .005).

Conclusions And Relevance: High-dose chemotherapy provided no long-term survival benefit in unselected patients with stage III breast cancer but did provide improved overall survival in very high-risk patients (ie, with ≥10 involved axillary lymph nodes). High-dose chemotherapy did not affect long-term risk of a second malignant neoplasm or major cardiovascular events.

Trial Registration: ClinicalTrials.gov Identifier: NCT03087409.
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http://dx.doi.org/10.1001/jamaoncol.2019.6276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042796PMC
April 2020

Dual mTORC1/2 Inhibition Sensitizes Testicular Cancer Models to Cisplatin Treatment.

Mol Cancer Ther 2020 02 19;19(2):590-601. Epub 2019 Nov 19.

Department of Medical Oncology, Cancer Research Center Groningen, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Testicular cancer is the most common cancer type among young men. Despite highly effective cisplatin-based chemotherapy, around 20% of patients with metastatic disease will still die from the disease. The aim of this study was to explore the use of kinase inhibitors to sensitize testicular cancer cells to cisplatin treatment. Activation of kinases, including receptor tyrosine kinases and downstream substrates, was studied in five cisplatin-sensitive or -resistant testicular cancer cell lines using phospho-kinase arrays and Western blotting. The phospho-kinase array showed AKT and S6 to be among the top phosphorylated proteins in testicular cancer cells, which are part of the PI3K/AKT/mTORC pathway. Inhibitors of most active kinases in the PI3K/AKT/mTORC pathway were tested using apoptosis assays and survival assays. Two mTORC1/2 inhibitors, AZD8055 and MLN0128, strongly enhanced cisplatin-induced apoptosis in all tested testicular cancer cell lines. Inhibition of mTORC1/2 blocked phosphorylation of the mTORC downstream proteins S6 and 4E-BP1. Combined treatment with AZD8055 and cisplatin led to reduced clonogenic survival of testicular cancer cells. Two testicular cancer patient-derived xenografts (PDX), either from a chemosensitive or -resistant patient, were treated with cisplatin in the absence or presence of kinase inhibitor. Combined AZD8055 and cisplatin treatment resulted in effective mTORC1/2 inhibition, increased caspase-3 activity, and enhanced tumor growth inhibition. In conclusion, we identified mTORC1/2 inhibition as an effective strategy to sensitize testicular cancer cell lines and PDX models to cisplatin treatment. Our results warrant further investigation of this combination therapy in the treatment of patients with testicular cancer with high-risk relapsed or refractory disease.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0449DOI Listing
February 2020

Platinum exposure and cause-specific mortality among patients with testicular cancer.

Cancer 2020 02 15;126(3):628-639. Epub 2019 Nov 15.

Department of Psychosocial Research and Epidemiology, Netherlands Cancer Institute, Amsterdam, the Netherlands.

Background: Although testicular cancer (TC) treatment has been associated with severe late morbidities, including second malignant neoplasms (SMNs) and ischemic heart disease (IHD), cause-specific excess mortality has been rarely studied among patients treated in the platinum era.

Methods: In a large, multicenter cohort including 6042 patients with TC treated between 1976 and 2006, cause-specific mortality was compared with general population mortality rates. Associations with treatment were assessed with proportional hazards analysis.

Results: With a median follow-up of 17.6 years, 800 patients died; 40.3% of these patients died because of TC. The cumulative mortality was 9.6% (95% confidence interval [CI], 8.5%-10.7%) 25 years after TC treatment. In comparison with general population mortality rates, patients with nonseminoma experienced 2.0 to 11.6 times elevated mortality from lung, stomach, pancreatic, rectal, and kidney cancers, soft-tissue sarcomas, and leukemia; 1.9-fold increased mortality (95% CI, 1.3-2.8) from IHD; and 3.9-fold increased mortality (95% CI, 1.5-8.4) from pneumonia. Seminoma patients experienced 2.5 to 4.6 times increased mortality from stomach, pancreatic, bladder cancer and leukemia. Radiotherapy and chemotherapy were associated with 2.1 (95% CI, 1.8-2.5) and 2.5 times higher SMN mortality (95% CI, 2.0-3.1), respectively, in comparison with the general population. In a multivariable analysis, patients treated with platinum-containing chemotherapy had a 2.5-fold increased hazard ratio (HR; 95% CI, 1.8-3.5) for SMN mortality in comparison with patients without platinum-containing chemotherapy. The HR for SMN mortality increased 0.29 (95% CI, 0.19-0.39) per 100 mg/m platinum dose administered (P  < .001). IHD mortality was increased 2.1-fold (95% CI, 1.5-4.2) after platinum-containing chemotherapy in comparison with patients without platinum exposure.

Conclusions: Platinum-containing chemotherapy is associated with a dose-dependent increase in the risk of SMN mortality.
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http://dx.doi.org/10.1002/cncr.32538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004069PMC
February 2020

The OncoLifeS data-biobank for oncology: a comprehensive repository of clinical data, biological samples, and the patient's perspective.

J Transl Med 2019 11 14;17(1):374. Epub 2019 Nov 14.

Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Background: Understanding cancer heterogeneity, its temporal evolution over time, and the outcomes of guided treatment depend on accurate data collection in a context of routine clinical care. We have developed a hospital-based data-biobank for oncology, entitled OncoLifeS (Oncological Life Study: Living well as a cancer survivor), that links routine clinical data with preserved biological specimens and quality of life assessments. The aim of this study is to describe the organization and development of a data-biobank for cancer research.

Results: We have enrolled 3704 patients aged ≥ 18 years diagnosed with cancer, of which 45 with hereditary breast-ovarian cancer (70% participation rate) as of October 24th, 2019. The average age is 63.6 ± 14.2 years and 1892 (51.1%) are female. The following data are collected: clinical and treatment details, comorbidities, lifestyle, radiological and pathological findings, and long-term outcomes. We also collect and store various biomaterials of patients as well as information from quality of life assessments.

Conclusion: Embedding a data-biobank in clinical care can ensure the collection of high-quality data. Moreover, the inclusion of longitudinal quality of life data allows us to incorporate patients' perspectives and inclusion of imaging data provides an opportunity for analyzing raw imaging data using artificial intelligence (AI) methods, thus adding new dimensions to the collected data.
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http://dx.doi.org/10.1186/s12967-019-2122-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857242PMC
November 2019

Heart failure after treatment for breast cancer.

Eur J Heart Fail 2020 02 12;22(2):366-374. Epub 2019 Nov 12.

Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands.

Background: We aimed to develop dose-response relationships for heart failure (HF) following radiation and anthracyclines in breast cancer treatment, and to assess HF associations with trastuzumab and endocrine therapies.

Methods And Results: A case-control study was performed within a cohort of breast cancer survivors treated during 1980-2009. Cases (n = 102) had HF as first cardiovascular diagnosis and were matched 1:3 on age and date of diagnosis. Individual cardiac radiation doses were estimated, and anthracycline doses and use of trastuzumab and endocrine therapy were abstracted from oncology notes. For HF cases who received radiotherapy, the estimated median mean heart dose (MHD) was 6.8 Gy [interquartile range (IQR) 0.9-13.7]. MHD was not associated with HF risk overall [excess rate ratio (ERR) = 1%/Gy, 95% confidence interval (CI) -2 to 10]. In patients treated with anthracyclines, exposure of ≥20% of the heart to ≥20 Gy was associated with a rate ratio of 5.7 (95% CI 1.7-21.7) compared to <10% exposed to ≥20 Gy. For cases who received radiotherapy, median cumulative anthracycline dose was 247 mg/m (IQR 240-319). A dose-dependent increase was observed after anthracycline without trastuzumab (ERR = 1.5% per mg/m , 95% CI 0.5-4.1). After anthracycline and trastuzumab, the rate ratio was 34.9 (95% CI 11.1-110.1) compared to no chemotherapy.

Conclusions: In absence of anthracyclines, breast cancer radiotherapy was not associated with increased HF risk. Strongly elevated HF risks were observed after treatment with anthracyclines and also after treatment with trastuzumab. The benefits of these systemic treatments usually exceed the risks of HF, but our results emphasize the need to support ongoing efforts to evaluate preventative strategies.
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http://dx.doi.org/10.1002/ejhf.1620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137787PMC
February 2020

Myocardial dysfunction in long-term breast cancer survivors treated at ages 40-50 years.

Eur J Heart Fail 2020 02 6;22(2):338-346. Epub 2019 Nov 6.

Department of Epidemiology & Biostatistics, Netherlands Cancer Institute, Amsterdam, The Netherlands.

Aims: Anthracyclines increase heart failure (HF) risk, but the long-term prevalence of myocardial dysfunction in young breast cancer (BC) survivors is unknown. Early measures of left ventricular myocardial dysfunction are needed to identify BC patients at risk of symptomatic HF.

Methods And Results: Within an established cohort, we studied markers for myocardial dysfunction among 569 women, who were 5-7 years (n = 277) or 10-12 years (n = 292) after BC treatment at ages 40-50 years. Left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) were assessed by echocardiography. N-terminal pro-brain natriuretic peptide (NT-proBNP) was measured in serum. Associations between patient-related and treatment-related risk factors and myocardial dysfunction were evaluated using linear and logistic regression. Median ages at BC diagnosis and cardiac assessment were 46.7 and 55.5 years, respectively. Anthracycline-treated patients (n = 313), compared to the no-anthracycline group (n = 256), more often had decreased LVEF (10% vs. 4%), impaired GLS (34% vs. 27%) and elevated NT-proBNP (23% vs. 8%). GLS and LVEF declined in a linear fashion with increasing cumulative anthracycline dose (GLS: +0.23 and LVEF: -0.40 per cycle of 60 mg/m ; P < 0.001) and GLS was worse for patients with left breast irradiation. The risk of NT-proBNP >125 ng/L was highest for patients who received 241-300 mg/m anthracycline dose compared to the no-anthracycline group (odds ratio: 3.30, 95% confidence interval: 1.83-5.96).

Conclusion: Impaired GLS and increased NT-proBNP levels are present in a substantial proportion of young BC survivors treated with anthracyclines. Whether this will lead to future cardiac disease needs to be evaluated by longitudinal assessment.
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http://dx.doi.org/10.1002/ejhf.1610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077738PMC
February 2020

Laparoscopic Resection of Residual Retroperitoneal Tumor Mass in Advanced Nonseminomatous Testicular Germ Cell Tumors; a Feasible and Safe Oncological Procedure.

Sci Rep 2019 11 1;9(1):15837. Epub 2019 Nov 1.

Department of Surgical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Ten-year oncological experience of the University Medical Center Groningen with conventional laparotomy (C-RRRTM) and laparoscopy (L-RRRTM) is described concerning resection of residual retroperitoneal tumor masses (RRTM) in a large series of patients with advanced nonseminomatous testicular germ cell tumors (NSTGCT). 150 consecutive patients with disseminated NSTGCT required adjunctive surgery after combination chemotherapy. L-RRRTM was scheduled in 89 and C-RRRTM in 61 patients. Median residual tumor diameter was 20 mm in the L-RRRTM versus 42 mm in the C-RRRTM group (p < 0.001). Conversion rate was 15% in the L-RRRTM group. Perioperative complications occurred in 5 patients (6%) in the L-RRRTM and 7 (12%, NS) in the C-RRRTM group. Median duration of L-RRRTM was 156 minutes vs. 221 minutes for C-RRRTM (p < 0.001). 17/89 patients in the L-RRRTM group had postoperative complications versus 18/61 patients in the C-RRRTM group (NS). Median postoperative stay in the L-RRRTM group was 2 vs. 6 days in the C-RRRTM group (p < 0.001). During a median follow-up of 79 months, 27 patients had recurrences: 8 (9%) in the L-RRRTM group and 19 (31%) in the C-RRRTM group (p < 0.001). Laparoscopic resection of RRTM for advanced NSTGCT is feasible and an oncologically safe option in appropriately selected patients.
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http://dx.doi.org/10.1038/s41598-019-52109-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825184PMC
November 2019

miR-371a-3p, miR-373-3p and miR-367-3p as Serum Biomarkers in Metastatic Testicular Germ Cell Cancers Before, During and After Chemotherapy.

Cells 2019 10 8;8(10). Epub 2019 Oct 8.

Department of Pathology, Erasmus MC Cancer Institute, NL-3015 GD Rotterdam, The Netherlands.

Background: LDH (lactate dehydrogenase), AFP (alpha-fetoprotein) and β-HCG (human chorionic gonadotropin) are used in diagnosis and follow-up of testicular germ cell cancer (TGCC) patients. Our aim was to investigate the association between levels of miR-371a-3p, miR-373-3p and miR-367-3p and clinical features in metastatic TGCC.

Methods: relative levels of miR-371a-3p, miR-373-3p and miR-367-3p were evaluated in serum of metastatic TGCC patients. A prospectively included and a retrospectively selected cohort were studied (total patient number = 109). Blood samples were drawn at start of chemotherapy and during follow-up. Serum microRNA (miR) levels were determined using the ampTSmiR test.

Results: at start of chemotherapy, miR-371a-3p, miR-373-3p and miR-367-3p levels were positively correlated to LDH. The median level of these miRs was higher in patients who developed a relapse after complete biochemical remission ( = 34) than in those who had complete durable remission ( = 60). Higher levels of miR-367-3p were found in patients with refractory disease ( = 15) compared to those who had complete response. miR levels decreased during the first week of chemotherapy in patients with complete response and stayed below threshold after one year of treatment.

Conclusion: high miR levels at start of chemotherapy are associated with worse clinical outcome and can assist in early diagnosing of relapses.
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http://dx.doi.org/10.3390/cells8101221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830325PMC
October 2019

Cardiac Function After Radiation Therapy for Breast Cancer.

Int J Radiat Oncol Biol Phys 2019 06 11;104(2):392-400. Epub 2019 Feb 11.

Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. Electronic address:

Purpose: The main purpose of this study was to test the hypothesis that incidental cardiac irradiation is associated with changes in cardiac function in breast cancer (BC) survivors treated with radiation therapy (RT).

Methods And Materials: We conducted a cross-sectional study consisting of 109 BC survivors treated with RT between 2005 and 2011. The endpoint was cardiac function, assessed by echocardiography. Systolic function was assessed with the left ventricular ejection fraction (LVEF) (n = 107) and the global longitudinal strain (GLS) of the left ventricle (LV) (n = 52). LV diastolic dysfunction (n = 109) was defined by e' at the lateral and septal region, which represents the relaxation velocity of the myocardium. The individual calculated RT dose parameters of the LV and coronary arteries were collected from 3-dimensional computed tomography-based planning data. Univariable and multivariable analysis using forward selection was performed to identify the best predictors of cardiac function. Robustness of selection was assessed using bootstrapping. The resulting multivariable linear regression model was presented for the endpoints of systolic and diastolic function.

Results: The median time between BC diagnosis and echocardiography was 7 years. No relation between RT dose parameters and LVEF was found. In the multivariable analysis for the endpoint GLS of the LV, the maximum dose to the left main coronary artery was most often selected across bootstrap samples. For decreased diastolic function, the most often selected model across bootstrap samples included age at time of BC diagnosis and hypertension at baseline. Cardiac dose-volume histogram parameters were less frequently selected for this endpoint.

Conclusions: This study shows an association between individual cardiac dose distributions and GLS of the LV after RT for BC. No relation between RT dose parameters and LVEF was found. Diastolic function was most associated with age and hypertension at time of BC diagnosis. Further research is needed to make definitive conclusions.
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http://dx.doi.org/10.1016/j.ijrobp.2019.02.003DOI Listing
June 2019

Zr-labeled Bispecific T-cell Engager AMG 211 PET Shows AMG 211 Accumulation in CD3-rich Tissues and Clear, Heterogeneous Tumor Uptake.

Clin Cancer Res 2019 06 11;25(12):3517-3527. Epub 2019 Feb 11.

Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Purpose: Biodistribution of bispecific antibodies in patients is largely unknown. We therefore performed a feasibility study in 9 patients with advanced gastrointestinal adenocarcinomas to explore AMG 211 biodistribution (also known as MEDI-565), an approximately 55 kDa bispecific T-cell engager (BiTE®) directed against carcinoembryonic antigen (CEA) on tumor cells and cluster of differentiation 3 (CD3) on T-cells.

Experimental Design: Zr-labeled AMG 211 as tracer was administered alone or with cold AMG 211, for PET imaging before and/or during AMG 211 treatment.

Results: Before AMG 211 treatment, the optimal imaging dose was 200-μg Zr-AMG 211 + 1,800-μg cold AMG 211. At 3 hours, the highest blood pool standardized uptake value (SUV) was 4.0, and tracer serum half-life was 3.3 hours. CD3-mediated uptake was clearly observed in CD3-rich lymphoid tissues including spleen and bone marrow (SUV 3.2 and 1.8, respectively), and the SUV decreased more slowly than in other healthy tissues. Zr-AMG 211 remained intact in plasma and was excreted predominantly via the kidneys in degraded forms. Of 43 visible tumor lesions, 37 were PET quantifiable, with a SUV of 4.0 [interquartile range (IQR) 2.7-4.4] at 3 hours using the optimal imaging dose. The tracer uptake differed between tumor lesions 5-fold within and 9-fold between patients. During AMG 211 treatment, tracer was present in the blood pool, whereas tumor lesions were not visualized, possibly reflecting target saturation.

Conclusions: This first-in-human study shows high, specific Zr-AMG 211 accumulation in CD3-rich lymphoid tissues, as well as a clear, inter- and intraindividual heterogeneous tumor uptake.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2918DOI Listing
June 2019

53BP1 as a potential predictor of response in PARP inhibitor-treated homologous recombination-deficient ovarian cancer.

Gynecol Oncol 2019 04 25;153(1):127-134. Epub 2019 Jan 25.

Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States of America; Department of Oncology, Mayo Clinic, Rochester, MN, United States of America. Electronic address:

Objective: Poly(ADP-ribose) polymerase (PARP) inhibitors have shown substantial activity in homologous recombination- (HR-) deficient ovarian cancer and are undergoing testing in other HR-deficient tumors. For reasons that are incompletely understood, not all patients with HR-deficient cancers respond to these agents. Preclinical studies have demonstrated that changes in alternative DNA repair pathways affect PARP inhibitor (PARPi) sensitivity in ovarian cancer models. This has not previously been assessed in the clinical setting.

Methods: Clonogenic and plasmid-based HR repair assays were performed to compare BRCA1-mutant COV362 ovarian cancer cells with or without 53BP1 gene deletion. Archival biopsies from ovarian cancer patients in the phase I, open-label clinical trial of PARPi ABT-767 were stained for PARP1, RAD51, 53BP1 and multiple components of the nonhomologous end-joining (NHEJ) DNA repair pathway. Modified histochemistry- (H-) scores were determined for each repair protein in each sample. HRD score was determined from tumor DNA.

Results: 53BP1 deletion increased HR in BRCA1-mutant COV362 cells and decreased PARPi sensitivity in vitro. In 36 women with relapsed ovarian cancer, responses to the PARPi ABT-767 were observed exclusively in cancers with HR deficiency. In this subset, 7 of 18 patients (39%) had objective responses. The actual HRD score did not further correlate with change from baseline tumor volume (r = 0.050; p = 0.87). However, in the HR-deficient subset, decreased 53BP1 H-score was associated with decreased antitumor efficacy of ABT-767 (r = -0.69, p = 0.004).

Conclusion: Differences in complementary repair pathways, particularly 53BP1, correlate with PARPi response of HR-deficient ovarian cancers.
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http://dx.doi.org/10.1016/j.ygyno.2019.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430710PMC
April 2019

Diagnosis and Treatment Monitoring of a Patient with Gastrointestinal Stromal Tumor by Next-Generation Sequencing and Droplet Digital Polymerase Chain Reaction Assay of a PDGFRA Mutation in Plasma-Derived Cell-Free Tumor DNA.

Oncologist 2019 06 22;24(6):e387-e390. Epub 2019 Jan 22.

Department of Medical Oncology, Medical Center Groningen, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

In patients with a suspected malignancy, standard-of care management currently includes histopathologic examination and analysis of tumor-specific molecular abnormalities. Herein, we present a 77-year-old patient with an abdominal mass suspected to be a gastrointestinal stromal tumor (GIST) but without the possibility to collect a tumor biopsy. Cell-free DNA extracted from a blood sample was analyzed for the presence of mutations in GIST-specific genes using next generation sequencing. Furthermore, liquid biopsies were used to monitor the levels of mutant DNA copies during treatment with a tumor-specific mutation droplet digital PCR assay that correlated with the clinical and radiological response. Blood-based testing is a good alternative for biopsy-based testing. However, it should only be applied when biopsies are not available or possible to obtain because overall, in only 50%-85% of the cell-free plasma samples is the known tumor mutation detected.
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http://dx.doi.org/10.1634/theoncologist.2018-0460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656511PMC
June 2019

Zr-atezolizumab imaging as a non-invasive approach to assess clinical response to PD-L1 blockade in cancer.

Nat Med 2018 12 26;24(12):1852-1858. Epub 2018 Nov 26.

Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Programmed cell death protein-1/ligand-1 (PD-1/PD-L1) blockade is effective in a subset of patients with several tumor types, but predicting patient benefit using approved diagnostics is inexact, as some patients with PD-L1-negative tumors also show clinical benefit. Moreover, all biopsy-based tests are subject to the errors and limitations of invasive tissue collection. Preclinical studies of positron-emission tomography (PET) imaging with antibodies to PD-L1 suggested that this imaging method might be an approach to selecting patients. Such a technique, however, requires substantial clinical development and validation. Here we present the initial results from a first-in-human study to assess the feasibility of imaging with zirconium-89-labeled atezolizumab (anti-PD-L1), including biodistribution, and secondly test its potential to predict response to PD-L1 blockade (ClinicalTrials.gov identifiers NCT02453984 and NCT02478099). We imaged 22 patients across three tumor types before the start of atezolizumab therapy. The PET signal, a function of tracer exposure and target expression, was high in lymphoid tissues and at sites of inflammation. In tumors, uptake was generally high but heterogeneous, varying within and among lesions, patients, and tumor types. Intriguingly, clinical responses in our patients were better correlated with pretreatment PET signal than with immunohistochemistry- or RNA-sequencing-based predictive biomarkers, encouraging further development of molecular PET imaging for assessment of PD-L1 status and clinical response prediction.
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http://dx.doi.org/10.1038/s41591-018-0255-8DOI Listing
December 2018

Radiation Dose-Response for Risk of Myocardial Infarction in Breast Cancer Survivors.

Int J Radiat Oncol Biol Phys 2019 03 29;103(3):595-604. Epub 2018 Oct 29.

Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.

Purpose: Previous reports suggest that radiation therapy for breast cancer (BC) can cause ischemic heart disease, with the radiation-related risk increasing linearly with mean whole heart dose (MWHD). This study aimed to validate these findings in younger BC patients and to investigate additional risk factors for radiation-related myocardial infarction (MI).

Methods And Materials: A nested case-control study was conducted within a cohort of BC survivors treated during 1970 to 2009. Cases were 183 patients with MI as their first heart disease after BC. One control per case was selected and matched on age and BC diagnosis date. Information on treatment and cardiovascular risk factors was abstracted from medical and radiation charts. Cardiac doses were estimated for each woman by reconstructing her regimen using modern 3-dimensional computed tomography planning on a typical patient computed tomography scan.

Results: Median age at BC of cases and controls was 50.2 years (interquartile range, 45.7-54.7). Median time to MI was 13.6 years (interquartile range, 9.9-18.1). Median MWHD was 8.9 Gy (range, 0.3-35.2 Gy). MI rate increased linearly with increasing MWHD (excess rate ratio [ERR] per Gy, 6.4%; 95% confidence interval, 1.3%-16.0%). Patients receiving ≥20 Gy MWHD had a 3.4-fold (95% confidence interval, 1.5-7.6) higher MI rate than unirradiated patients. ERRs were higher for younger women, with borderline significance (ERR, 24.2%/Gy; ERR, 2.5%/Gy; P = .054). Whole heart dose-volume parameters did not modify the dose-response relationship significantly.

Conclusions: MI rate after radiation for BC increases linearly with MWHD. Reductions in MWHD are expected to contribute to better cardiovascular health of BC survivors.
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http://dx.doi.org/10.1016/j.ijrobp.2018.10.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361769PMC
March 2019

Risk of diabetes after para-aortic radiation for testicular cancer.

Br J Cancer 2018 10 9;119(7):901-907. Epub 2018 Oct 9.

Department of Epidemiology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.

Background: While the risk of diabetes is increased following radiation exposure to the pancreas among childhood cancer survivors, its association among testicular cancer (TC) survivors has not been investigated.

Methods: Diabetes risk was studied in 2998 1-year TC survivors treated before 50 years of age with orchidectomy with/without radiotherapy between 1976 and 2007. Diabetes incidence was compared with general population rates. Treatment-specific risk of diabetes was assessed using a case-cohort design.

Results: With a median follow-up of 13.4 years, 161 TC survivors were diagnosed with diabetes. Diabetes risk was not increased compared to general population rates (standardised incidence ratios (SIR): 0.9; 95% confidence interval (95% CI): 0.7-1.1). Adjusted for age, para-aortic radiotherapy was associated with a 1.66-fold (95% CI: 1.05-2.62) increased diabetes risk compared to no radiotherapy. The excess hazard increased with 0.31 with every 10 Gy increase in the prescribed radiation dose (95% CI: 0.11-0.51, P = 0.003, adjusted for age and BMI); restricted to irradiated patients the excess hazard increased with 0.33 (95% CI: -0.14 to 0.81, P = 0.169) with every 10 Gy increase in radiation dose.

Conclusion: Compared to surgery only, para-aortic irradiation is associated with increased diabetes risk among TC survivors.
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http://dx.doi.org/10.1038/s41416-018-0248-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6189211PMC
October 2018

Cardiovascular disease incidence after internal mammary chain irradiation and anthracycline-based chemotherapy for breast cancer.

Br J Cancer 2018 08 1;119(4):408-418. Epub 2018 Aug 1.

Epidemiology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.

Background: Improved breast cancer (BC) survival and evidence showing beneficial effects of internal mammary chain (IMC) irradiation underscore the importance of studying late cardiovascular effects of BC treatment.

Methods: We assessed cardiovascular disease (CVD) incidence in 14,645 Dutch BC patients aged <62 years, treated during 1970-2009. Analyses included proportional hazards models and general population comparisons.

Results: CVD rate-ratio for left-versus-right breast irradiation without IMC was 1.11 (95% CI 0.93-1.32). Compared to right-sided breast irradiation only, IMC irradiation (interquartile range mean heart doses 9-17 Gy) was associated with increases in CVD rate overall, ischaemic heart disease (IHD), heart failure (HF) and valvular heart disease (hazard ratios (HRs): 1.6-2.4). IHD risk remained increased until at least 20 years after treatment. Anthracycline-based chemotherapy was associated with an increased HF rate (HR = 4.18, 95% CI 3.07-5.69), emerging <5 years and remaining increased at least 10-15 years after treatment. IMC irradiation combined with anthracycline-based chemotherapy was associated with substantially increased HF rate (HR = 9.23 95% CI 6.01-14.18), compared to neither IMC irradiation nor anthracycline-based chemotherapy.

Conclusions: Women treated with anthracycline-based chemotherapy and IMC irradiation (in an older era) with considerable mean heart dose exposure have substantially increased incidence of several CVDs. Screening may be appropriate for some BC patient groups.
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http://dx.doi.org/10.1038/s41416-018-0159-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133926PMC
August 2018

Risk of Solid Cancer After Treatment of Testicular Germ Cell Cancer in the Platinum Era.

J Clin Oncol 2018 08 10;36(24):2504-2513. Epub 2018 Jul 10.

Harmke J. Groot, Jan Martijn Kerst, Katarzyna Jóźwiak, Alexandra W. van den Belt-Dusebout, Simon Horenblas, Flora E. van Leeuwen, and Michael Schaapveld, Netherlands Cancer Institute; Alfons J.M. van den Eertwegh, Vrije Universiteit Medical Center; Heinz-Josef Klümpen, Academic Medical Center, Amsterdam; Sjoukje Lubberts, Igle J. de Jong, Alfons C.M. van den Bergh, and Jourik A. Gietema, University Medical Center Groningen, University of Groningen, Groningen; Ronald de Wit and Luca Incrocci, Erasmus Medical Center Cancer Institute, Rotterdam; Johannes A. Witjes, Radboud University Medical Center, Nijmegen; Gerard Groenewegen, University Medical Center Utrecht Cancer Center, Utrecht; Philip M. Poortmans, Instituut Verbeeten, Tilburg; Hetty A. van den Berg, Catharina Hospital, Eindhoven; Tineke J. Smilde, Jeroen Bosch Hospital, 's-Hertogenbosch; Ben G.L. Vanneste, MAASTRO Clinic; Maureen J. Aarts, Maastricht University Medical Center, Maastricht, the Netherlands; and Philip M. Poortmans, Institut Curie, Paris, France.

Purpose Testicular cancer (TC) treatment increases risk of subsequent malignant neoplasms (SMNs). It is unknown whether changes in TC treatment over time have affected SMN risk. Methods Solid SMN risk was evaluated in a multicenter cohort comprising 5,848 1-year survivors treated for TC before age 50 years between 1976 and 2007. SMN incidence was compared with cancer incidence in the general population. Treatment-specific risks were assessed using multivariable regression in a case-cohort design. Results After a median follow-up of 14.1 years, 350 solid SMNs were observed, translating into a 1.8-fold (95% CI, 1.6-2.0) increased risk compared with general population rates. Solid SMN risk was increased in patients with seminoma and those with nonseminoma (standardized incidence ratio, 1.52 and 2.21, respectively). Patients with nonseminoma experienced increased risk of SMNs of the thyroid, lung, stomach, pancreas, colon, and bladder and of melanoma and soft tissue sarcoma, whereas those with seminoma experienced increased risk of SMNs of the small intestine, pancreas, and urinary bladder. The 25-year cumulative incidence of solid SMNs was 10.3% (95% CI, 9.0% to 11.6%). In multivariable analysis, platinum-based chemotherapy was associated with increased risk of a solid SMN (hazard ratio [HR], 2.40; 95% CI, 1.58 to 3.62), colorectal SMN (HR, 3.85; 95% CI, 1.67 to 8.92), and noncolorectal GI SMN (HR, 5.00; 95% CI, 2.28 to 10.95). Receipt of platinum 400 to 499 and ≥ 500 mg/m increased solid SMN risk compared with surgery only (HR, 2.43; 95% CI, 1.40 to 4.23 and HR, 2.42; 95% CI, 1.50 to 3.90, respectively), whereas risk was not significantly increased with lower doses (HR, 1.75; 95% CI, 0.90 to 3.43). The HR of a GI SMN increased by 53% (95% CI, 26% to 80%) per 100 mg/m of platinum-containing chemotherapy. The HR of an infradiaphragmatic SMN increased by 8% per Gray of radiation dose administered (95% CI, 6% to 9%; P < .001). Conclusion Radiotherapy and platinum-containing chemotherapy are associated with increased solid SMN risk, specifically with GI SMNs.
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http://dx.doi.org/10.1200/JCO.2017.77.4174DOI Listing
August 2018