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1. Overall survival in patients with endometrial cancer treated with dostarlimab plus carboplatin–paclitaxel in the randomized ENGOT-EN6/GOG-3031/RUBY trial

Author

Powell, M.A., Bjørge, L., Willmott, L., Novák, Z., Black, D., Gilbert, L., Sharma, S., Valabrega, G., Landrum, L.M., Gropp-Meier, M., Stuckey, A., Boere, I., Gold, M.A., Segev, Y., Gill, S.E., Gennigens, C., Sebastianelli, A., Shahin, M.S., Pothuri, B., Monk, B.J., Buscema, J., Coleman, R.L., Slomovitz, B.M., Ring, K.L., Herzog, T.J., Balas, M.M., Grimshaw, M., Stevens, S., Lai, D.W., McCourt, C., and Mirza, M.R.

Published
2024
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2. Maternal death by cancer in pregnancy: A descriptive study of the International Network on Cancer, Infertility and Pregnancy

Author

Heimovaara, J, Huisin'Tveld, E, Lok, C, Garcia, A, Halaska, M, Boere, I, Gziri, M, Fruscio, R, Painter, R, Cardonick, E, van den Heuvel-Eibrink, M, Masturzo, B, Vancalsteren, K, Vanzuylen, L, Amant, F, Heimovaara J. H., Huisin'tVeld E. A., Lok C. A. R., Garcia A. C., Halaska M. J., Boere I., Gziri M. M., Fruscio R., Painter R. C., Cardonick E., van den Heuvel-Eibrink M. M., Masturzo B., VanCalsteren K., vanZuylen L., Amant F., Heimovaara, J, Huisin'Tveld, E, Lok, C, Garcia, A, Halaska, M, Boere, I, Gziri, M, Fruscio, R, Painter, R, Cardonick, E, van den Heuvel-Eibrink, M, Masturzo, B, Vancalsteren, K, Vanzuylen, L, Amant, F, Heimovaara J. H., Huisin'tVeld E. A., Lok C. A. R., Garcia A. C., Halaska M. J., Boere I., Gziri M. M., Fruscio R., Painter R. C., Cardonick E., van den Heuvel-Eibrink M. M., Masturzo B., VanCalsteren K., vanZuylen L., and Amant F.

Abstract

Objective: To characterise pregnant women diagnosed with primary or recurrent cancer who died during pregnancy, during delivery or within 1 year postpartum. Design: A descriptive study. Setting: The registry of the International Network on Cancer, Infertility and Pregnancy (INCIP). Population: Women diagnosed with cancer during pregnancy between 2000 and 2022. Methods: Using the INCIP registry database, we compared the characteristics of all women with cancer who died during pregnancy, delivery or within 1 year postpartum with those of all women with cancer who survived the first year postpartum. Main Outcome Measures: Maternal and tumour characteristics and obstetrical and neonatal outcomes. Results: Of the 2359 women registered in INCIP, there were 131 cases (5.6%) of maternal mortality. Lung cancer (9/14, 64.3% of all registered women with lung cancer), gastro-oesophageal cancer (13/21, 61.9%) and acute leukaemia (17/105, 16.2%) had the highest rates of maternal mortality. Maternal mortality was associated with fewer live births compared with the control group without maternal mortality (99/131, 75.6%, vs 1952/2163, 90.0%; P < 0.001), more elective caesarean sections (64/104, 60.4%, vs 756/1836, 41.2%; P < 0.001) and a lower gestational age at (induced) delivery (34.0 vs 37.1 weeks; P < 0.001), resulting in more preterm births. Conclusions: Maternal mortality occurred in 5.6% of cancer-in-pregnancy cases and is associated with adverse perinatal outcomes.

Published
2024

3. Diagnosis and management of isolated serous tubal intraepithelial carcinoma: A qualitative focus group study

Author

Negri, S, Fisch, C, de Hullu, J, van Bommel, M, Simons, M, Bogaerts, J, Apperloo, M, Baiocchi, G, Bakker, J, Bart, J, van Beekhuizen, H, Bernardini, M, Boere, I, Bulten, J, Chen, L, Chrzan, A, Dorum, A, Ewing-Graham, P, Ferrero, A, Floter Radestad, A, Fruscio, R, Gaarenstroom, K, Garcia, C, Harter, P, Hoogstad-van Evert, J, de Iaco, P, Klooster, A, Kooreman, L, Jacobsen, M, Kruse, A, Kwon, J, Lawson, B, Lax, S, van Lonkhuijzen, L, Lu, K, Manchanda, R, Marchetti, C, Mccluggage, W, Mcnally, O, Mourits, M, Nicum, S, Norquist, B, Perrone, A, Piek, J, Polastro, L, Polee, M, Rabban, J, Reesink, N, de los Reyes Oliver Perez, M, Roes, E, Rychlik, A, Shih, I, Soong, T, Speiser, P, Stone, R, Tamussino, K, Tognon, G, Tuninetti, V, Valabrega, G, Vos, M, Welz, J, Zizioli, V, Hermens, R, Steenbeek, M, Negri S., Fisch C., de Hullu J. A., van Bommel M., Simons M., Bogaerts J., Apperloo M. J. A., Baiocchi G., Bakker J. L., Bart J., van Beekhuizen H. J., Bernardini M. Q., Boere I., Bulten J., Chen L. -M., Chrzan A., Dorum A., Ewing-Graham P. C., Ferrero A., Floter Radestad A., Fruscio R., Gaarenstroom K. N., Garcia C., Harter P., Hoogstad-van Evert J. S., de Iaco P., Klooster A., Kooreman L. F. S., Jacobsen M., Kruse A. -J., Kwon J. S., Lawson B. C., Lax S. F., van Lonkhuijzen L. R. C. W., Lu K. H., Manchanda R., Marchetti C., McCluggage W. G., McNally O. M., Mourits M. J. E., Nicum S., Norquist B. M., Perrone A. M., Piek J. M. J., Polastro L., Polee M. B., Rabban J. T., Reesink N., de los Reyes Oliver Perez M., Roes E. -M., Rychlik A., Shih I. -M., Soong T. R., Speiser P., Stone R. L., Tamussino K., Tognon G., Tuninetti V., Valabrega G., Vos M. C., Welz J., Zizioli V., Hermens R. P. M. G., Steenbeek M. P., Negri, S, Fisch, C, de Hullu, J, van Bommel, M, Simons, M, Bogaerts, J, Apperloo, M, Baiocchi, G, Bakker, J, Bart, J, van Beekhuizen, H, Bernardini, M, Boere, I, Bulten, J, Chen, L, Chrzan, A, Dorum, A, Ewing-Graham, P, Ferrero, A, Floter Radestad, A, Fruscio, R, Gaarenstroom, K, Garcia, C, Harter, P, Hoogstad-van Evert, J, de Iaco, P, Klooster, A, Kooreman, L, Jacobsen, M, Kruse, A, Kwon, J, Lawson, B, Lax, S, van Lonkhuijzen, L, Lu, K, Manchanda, R, Marchetti, C, Mccluggage, W, Mcnally, O, Mourits, M, Nicum, S, Norquist, B, Perrone, A, Piek, J, Polastro, L, Polee, M, Rabban, J, Reesink, N, de los Reyes Oliver Perez, M, Roes, E, Rychlik, A, Shih, I, Soong, T, Speiser, P, Stone, R, Tamussino, K, Tognon, G, Tuninetti, V, Valabrega, G, Vos, M, Welz, J, Zizioli, V, Hermens, R, Steenbeek, M, Negri S., Fisch C., de Hullu J. A., van Bommel M., Simons M., Bogaerts J., Apperloo M. J. A., Baiocchi G., Bakker J. L., Bart J., van Beekhuizen H. J., Bernardini M. Q., Boere I., Bulten J., Chen L. -M., Chrzan A., Dorum A., Ewing-Graham P. C., Ferrero A., Floter Radestad A., Fruscio R., Gaarenstroom K. N., Garcia C., Harter P., Hoogstad-van Evert J. S., de Iaco P., Klooster A., Kooreman L. F. S., Jacobsen M., Kruse A. -J., Kwon J. S., Lawson B. C., Lax S. F., van Lonkhuijzen L. R. C. W., Lu K. H., Manchanda R., Marchetti C., McCluggage W. G., McNally O. M., Mourits M. J. E., Nicum S., Norquist B. M., Perrone A. M., Piek J. M. J., Polastro L., Polee M. B., Rabban J. T., Reesink N., de los Reyes Oliver Perez M., Roes E. -M., Rychlik A., Shih I. -M., Soong T. R., Speiser P., Stone R. L., Tamussino K., Tognon G., Tuninetti V., Valabrega G., Vos M. C., Welz J., Zizioli V., Hermens R. P. M. G., and Steenbeek M. P.

Abstract

Objective: A Serous Tubal Intraepithelial Carcinoma (STIC) without concomitant invasive carcinoma is occasionally identified and associated with a high risk of subsequent peritoneal carcinomatosis. Management needs optimisation. This study explores professionals' opinions and clinical practices regarding the diagnosis, counselling, treatment and follow-up of isolated STIC to facilitate clinical decision making and optimise the direction of future research. A secondary aim is to assess international clinical guidelines. Design: Focus group study. Setting: Four online sessions. Population: International panel (n = 12 countries) of gynaecologists, gynaecologic oncologists, pathologists and medical oncologists (n = 49). Methods: A semi-structured interview guide was used. Two independent researchers analysed transcripts by open and axial coding. Results were organised in domains. Relevant (inter)national guidelines were screened for recommendations regarding isolated STIC. Main Outcome Measures: Professionals' opinions and clinical practices regarding isolated STIC management. Results: Regarding pathology, most professionals identified the SEE-FIM protocol as standard of care for high-risk patients, whereas variation exists in the histopathological examination of fallopian tubes in the general population. Confirmation of STIC diagnosis by a specialised pathologist was recommended. Regarding work-up and follow-up after STIC diagnosis, there was variety and discordance. Data on outcomes is limited. As for treatment, chemotherapy and PARP inhibitors were not recommended by most. Eleven guidelines provided limited recommendations. Conclusions: We identified recommendations and highlighted knowledge gaps in the diagnosis and management of isolated STIC. Moreover, recommendations in clinical guidelines are limited. There is an agreed need for international collaboration for the prospective registration of isolated STIC.

Published
2024

4. Adjuvant Use of PlasmaJet Device During Cytoreductive Surgery for Advanced-Stage Ovarian Cancer: Results of the PlaComOv-study, a Randomized Controlled Trial in The Netherlands

Author

Nieuwenhuyzen-de Boer, G. M., Hofhuis, W., Reesink-Peters, N., Willemsen, S., Boere, I. A., Schoots, I. G., Piek, J. M. J., Hofman, L. N., Beltman, J. J., van Driel, W. J., Werner, H. M. J., Baalbergen, A., van Haaften-de Jong, A. M. L. D., Dorman, M., Haans, L., Nedelcu, I., Ewing-Graham, P. C., and van Beekhuizen, H. J.

Published
2022
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5. Overall survival in patients with endometrial cancer treated with dostarlimab plus carboplatin–paclitaxel in the randomized ENGOT-EN6/GOG-3031/RUBY trial

Author

Powell, M. A., Bjørge, L., Willmott, L., Novák, Z., Black, D., Gilbert, L., Sharma, S., Valabrega, G., Landrum, L. M., Gropp-Meier, M., Stuckey, A., Boere, I., Gold, M. A., Segev, Y., Gill, S. E., Gennigens, C., Sebastianelli, A., Shahin, M. S., Pothuri, B., Monk, B. J., Buscema, J., Coleman, R. L., Slomovitz, B. M., Ring, K. L., Herzog, T. J., Balas, M. M., Grimshaw, M., Stevens, S., Lai, D. W., McCourt, C., Mirza, M. R., Powell, M. A., Bjørge, L., Willmott, L., Novák, Z., Black, D., Gilbert, L., Sharma, S., Valabrega, G., Landrum, L. M., Gropp-Meier, M., Stuckey, A., Boere, I., Gold, M. A., Segev, Y., Gill, S. E., Gennigens, C., Sebastianelli, A., Shahin, M. S., Pothuri, B., Monk, B. J., Buscema, J., Coleman, R. L., Slomovitz, B. M., Ring, K. L., Herzog, T. J., Balas, M. M., Grimshaw, M., Stevens, S., Lai, D. W., McCourt, C., and Mirza, M. R.

Abstract

Background: Part 1 of the RUBY trial (NCT03981796) evaluated dostarlimab plus carboplatin–paclitaxel compared with placebo plus carboplatin–paclitaxel in patients with primary advanced or recurrent endometrial cancer (EC). At the first interim analysis, the trial met one of its dual primary endpoints with statistically significant progression-free survival benefits in the mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) and overall populations. Overall survival (OS) results are reported from the second interim analysis. Patients and methods: RUBY is a phase III, global, double-blind, randomized, placebo-controlled trial. Part 1 of RUBY enrolled eligible patients with primary advanced stage III or IV or first recurrent EC who were randomly assigned (1: 1) to receive either dostarlimab (500 mg) or placebo, plus carboplatin–paclitaxel every 3 weeks for 6 cycles followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. OS was a dual primary endpoint. Results: A total of 494 patients were randomized (245 in the dostarlimab arm; 249 in the placebo arm). In the overall population, with 51% maturity, RUBY met the dual primary endpoint for OS at this second interim analysis, with a statistically significant reduction in the risk of death [hazard ratio (HR) = 0.69, 95% confidence interval (CI) 0.54-0.89, P = 0.0020] in patients treated with dostarlimab plus carboplatin–paclitaxel versus carboplatin–paclitaxel alone. The risk of death was lower in the dMMR/MSI-H population (HR = 0.32, 95% CI 0.17-0.63, nominal P = 0.0002) and a trend in favor of dostarlimab was seen in the mismatch repair-proficient/microsatellite stable population (HR = 0.79, 95% CI 0.60-1.04, nominal P = 0.0493). The safety profile for dostarlimab plus carboplatin–paclitaxel was consistent with the first interim analysis. Conclusions: Dostarlimab in combination with carboplatin–paclitaxel

Published
2024

6. ASO Visual Abstract: The Role of Adjuvant Use of the PlasmaJet® Device During Cytoreductive Surgery for Advanced-Stage Ovarian Cancer—Results of the PlaComOv-Study, a Randomized, Controlled Trial in the Netherlands

Author

Nieuwenhuyzen-de Boer, G. M., Hofhuis, W., Reesink-Peters, N., Willemsen, S., Boere, I. A., Schoots, I. G., Piek, J. M. J., Hofman, L. N., Beltman, J. J., van Driel, W. J., Werner, H. M. J., Baalbergen, A., van Haaften-de Jong, A. M. L. D., Dorman, M., Haans, L., Nedelcu, I., Ewing-Graham, P. C., and van Beekhuizen, H. J.

Published
2022
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7. CINOVA: a phase II study of CPC634 (nanoparticulate docetaxel) in patients with platinum resistant recurrent ovarian cancer.

Author

Boere, I., Vergote, I., Hanssen, R., Jalving, M., Gennigens, C., Ottevanger, P.B., Wouw, Y.J. van de, Rijcken, C.J.F., Mathijssen, R.H.J., Ledermann, J., Boere, I., Vergote, I., Hanssen, R., Jalving, M., Gennigens, C., Ottevanger, P.B., Wouw, Y.J. van de, Rijcken, C.J.F., Mathijssen, R.H.J., and Ledermann, J.

Abstract

Item does not contain fulltext, OBJECTIVE: Recurrent platinum-resistant ovarian cancer has a poor prognosis with limited therapeutic options. Sub-therapeutic intra-tumoral drug concentrations may add to therapy resistance. CPC634 (docetaxel entrapped in CriPec nanoparticles) was designed to enhance tumor accumulation of drug with localized drug release at the target site to increase therapeutic efficacy. This study investigated the therapeutic effect of CPC634 in patients with platinum-resistant ovarian cancer. METHODS: According to a Simon 2-stage design trial, the first stage included 13 patients, and 12 patients were enrolled in the second stage. Eligible patients had measurable disease and had progressed ≤6 months after the last platinum-based therapy. Platinum-refractory disease was excluded. In stage 1, the number of previous treatment lines was unlimited; in the second stage, a maximum of two prior lines altogether were allowed. The primary endpoint was the objective response rate by Response Evaluation Criteria in Solid Tumor (RECIST) V1.1. Secondary endpoints included safety, progression-free survival at 6 months, cancer antigen 125 (CA125) response, and disease control rate. RESULTS: The patients' median age was 66 years (range 22-77) and most were International Federation of Gynecology and Obstetrics (FIGO) stage III (56%). The median number of previous treatment lines was 3 (range 3-5) in stage I and 2 (range 1-4) in stage II of the study. None of the patients had an objective response, one patient had a CA125 response (5%), and seven patients had stable disease at first evaluation (35%). Median progression-free survival was 1.4 months in stage 1 and 3.0 months in stage 2. Adverse events (all grades) were mainly gastrointestinal in 24 patients (96%), fatigue in 11 (44%), dyspnea in 10 (40%), and infections in 10 (40%) of patients. Grade 3 or higher adverse events occurred in 14 patients (36%), including gastrointestinal in 4 (16%), anemia in 3 (12%), and febrile neutropenia, fatigue, c

Published
2023

8. The potential of RAS/RAF/MEK/ERK (MAPK) signaling pathway inhibitors in ovarian cancer:A systematic review and meta-analysis

Author

Hendrikse, C. S.E., Theelen, P. M.M., van der Ploeg, P., Westgeest, H. M., Boere, I. A., Thijs, A. M.J., Ottevanger, P. B., van de Stolpe, A., Lambrechts, S., Bekkers, R. L.M., Piek, J. M.J., Hendrikse, C. S.E., Theelen, P. M.M., van der Ploeg, P., Westgeest, H. M., Boere, I. A., Thijs, A. M.J., Ottevanger, P. B., van de Stolpe, A., Lambrechts, S., Bekkers, R. L.M., and Piek, J. M.J.

Abstract

Background: The RAS/RAF/MEK/ERK (MAPK) pathway plays a role in ovarian carcinogenesis. Low-grade serous ovarian carcinoma (LGSOC) frequently harbors activating MAPK mutations. MAPK inhibitors have been used in small subsets of ovarian carcinoma (OC) patients to control tumor growth. Therefore, we performed a meta-analysis to evaluate the effectiveness of MAPK inhibitors in OC patients. We aimed to determine the clinical benefit rate (CBR), the subgroup of MAPK inhibitors with the best CBR and overall response rate (ORR), and the most common adverse events. Methods: We conducted a search in PubMed, Embase via Ovid, the Cochrane library and clinicaltrials.gov on studies evaluating the efficacy of single MAPK pathway inhibition with MAPK pathway inhibitors in OC patients. Our primary outcome included the CBR, defined by the proportion of patients with stable disease (SD), complete (CR) and partial response (PR). Secondary outcomes included the ORR (including PR and CR) and grade 3 and 4 adverse events. Meta-analysis was performed using a random-effects model. Results: We included nine studies with a total of 319 OC patients, for which we determined a pooled CBR of 63% (95%-CI 39–84%, I2 = 92%). Combined treatment with Raf- and MEK inhibitors in in BRAFv600 mutated LGSOC (n = 6) had the greatest efficacy with a CBR of 100% and ORR of 83%. MEK inhibitors had the best efficacy as a single agent. Subgroup analysis by tumor histology demonstrated a significantly higher CBR and ORR in patients with LGSOC, with a pooled CBR and ORR of 87% (95%-CI 81–92%, I2 = 0%) and 27% (95%-CI 10–48%, I2 = 77%) respectively. Adverse events of grade 3 or higher were reported frequently: 123 in 167 patients. Conclusions: MEK inhibitors are the most promising single agents in (LGS)OC. However, dual MAPK pathway inhibition should be considered in patients with a BRAFv600 mutation, or non-mutated OC with depleted treatment options due ind

Published
2023

11. Refining adjuvant treatment in endometrial cancer based on molecular features: the RAINBO clinical trial program

Author

Bosse, T., Creutzberg, C.L., Crosbie, E.J., Han, K., Horeweg, N., Leary, A., Kroep, J.R., McAlpine, J.N., Powell, M.E., Blanc-Durand, F., Bruyn, M. de, Church, D.N., Koelzer, V.H., Kommoss, S., Singh, N., Bardet, A., Counsell, N., Putter, H., Tu, D., Edmondson, R., Gordon, C., Ledermann, J., Morice, P., MacKay, H., Nijman, H., Nout, R.A., Smit, V.T.H.B.M., White, H., Alexandre, J., Boer, S.M. de, Boere, I., Cooper, R., Ethier, J.L., Frenel, J.S., McGrane, J., Taylor, A., Welch, S., Westermann, A.M., Linden, H.D. van der, Farrelly, L., Feeney, A., Kaya, M., Liu, W., Melis, A., Ngadjeua-Tchouatieu, F., Parulekar, W., Verhoeven-Adema, K., and RAINBO Res Consortium

Subjects
endometrial neoplasms, Oncology, Obstetrics and Gynecology
Abstract

BackgroundThe endometrial cancer molecular classification has been integrated into the 2020 World Health Organization (WHO) diagnostic classification and European treatment guidelines, and provides direction towards more effective and less toxic adjuvant treatment strategies for women with endometrial cancer.Primary Objective(s)The RAINBO program of clinical trials will investigate four molecular class-directed adjuvant treatment strategies following surgical resection to either increase cure rates through the addition of novel targeted therapies or safely reduce toxicity and improve quality of life through treatment de-escalation.Study HypothesisMolecular-directed adjuvant treatment strategies will improve clinical outcomes and reduce toxicity of unwarranted therapies in women with endometrial cancer. The overarching and translational research RAINBO program will advance knowledge of predictive and prognostic (bio)markers that will improve prognostication and treatment allocation.Trial DesignThe RAINBO program is a platform of four international clinical trials and an overarching research program. The randomized phase III p53abn-RED trial for women with invasive stage I–III p53abn endometrial cancer compares adjuvant chemoradiation followed by olaparib for 2 years with adjuvant chemoradiation alone. The randomized phase III MMRd-GREEN trial for women with stage II (with lymphovascular space invasion (LVSI)) or stage III mismatch repair-deficient (MMRd) endometrial cancer compares adjuvant radiotherapy with concurrent and adjuvant durvalumab for 1 year to radiotherapy alone. The randomized phase III NSMP-ORANGE trial is a treatment de-escalation trial for women with estrogen receptor positive stage II (with LVSI) or stage III no specific molecular profile (NSMP) endometrial cancer comparing radiotherapy followed by progestin for 2 years to adjuvant chemoradiation. ThePOLEmut-BLUE trial is a phase II trial in which the safety of de-escalation of adjuvant therapy is investigated for women with stage I–IIIPOLEmut endometrial cancer: no adjuvant therapy for lower-risk disease and no adjuvant therapy or radiotherapy alone for higher-risk disease. The overarching RAINBO program will combine data and tumor material of all participants to perform translational research and evaluate molecular class-based adjuvant therapy in terms of efficacy, toxicity, quality of life, and cost-utility.Major Inclusion/Exclusion CriteriaInclusion criteria include a histologically confirmed diagnosis of endometrial cancer treated by hysterectomy and bilateral salpingo-oophorectomy with or without lymphadenectomy or sentinel lymph node biopsy, with no macroscopic residual disease after surgery and no distant metastases, and molecular classification according to the WHO 2020 algorithm.Primary Endpoint(s)Recurrence-free survival at 3 years in the p53abn-RED, MMRd-GREEN, and NSMP-ORANGE trials and pelvic recurrence at 3 years in thePOLEmut-BLUE trial.Sample SizeThe p53abn-RED trial will include 554 patients, the MMRd-GREEN trial 316, the NSMP-ORANGE trial 600, and thePOLEmut-BLUE trial 145 (120 for lower-risk disease and approximately 25 for higher-risk disease). The overarching research program will pool the four sub-trials resulting in a total sample size of around 1600.Estimated Dates for Completing Accrual and Presenting ResultsThe four clinical trials will have different completion dates; main results are expected from 2028.Trial Registration NumberThe RAINBO program is registered at clinicaltrials.gov (NCT05255653).

Published
2023

13. Association of Chemotherapy Timing in Pregnancy With Congenital Malformation

Author

van Gerwen, M, Maggen, C, Cardonick, E, Verwaaijen, E, van den Heuvel-Eibrink, M, Shmakov, R, Boere, I, Gziri, M, Ottevanger, P, Lok, C, Halaska, M, Shao, L, Struys, I, van Dijk-Lokkart, E, van Calsteren, K, Fruscio, R, Zola, P, Scarfone, G, Amant, F, van Gerwen M., Maggen C., Cardonick E., Verwaaijen E. J., van den Heuvel-Eibrink M., Shmakov R. G., Boere I., Gziri M. M., Ottevanger P. B., Lok C. A. R., Halaska M., Shao L. T., Struys I., van Dijk-Lokkart E. M., van Calsteren K., Fruscio R., Zola P., Scarfone G., Amant F., van Gerwen, M, Maggen, C, Cardonick, E, Verwaaijen, E, van den Heuvel-Eibrink, M, Shmakov, R, Boere, I, Gziri, M, Ottevanger, P, Lok, C, Halaska, M, Shao, L, Struys, I, van Dijk-Lokkart, E, van Calsteren, K, Fruscio, R, Zola, P, Scarfone, G, Amant, F, van Gerwen M., Maggen C., Cardonick E., Verwaaijen E. J., van den Heuvel-Eibrink M., Shmakov R. G., Boere I., Gziri M. M., Ottevanger P. B., Lok C. A. R., Halaska M., Shao L. T., Struys I., van Dijk-Lokkart E. M., van Calsteren K., Fruscio R., Zola P., Scarfone G., and Amant F.

Abstract

Chemotherapy puts a developing fetus at risk of teratogenic effects. The standard recommendation is that chemotherapy be administered after organogenesis is complete, however, the exact gestational age that chemotherapy can be administered safely and avoid causing congenital malformations remains unknown. The goal of this study was to assess the teratogenic role of prenatal chemotherapy by gestational age, to evaluate for the presence of major and minor congenital malformations during pregnancy or at birth.This was a multicenter study that evaluated all pregnant women who received chemotherapy in the International Network on Cancer, Infertility and Pregnancy (INCIP) database between 1977 and 2019.A total of 755 pregnant women treated with chemotherapy between 1977 and 2019 were included in analysis. The median age at cancer diagnosis was 33 (14-48) years. The major congenital malformation rate was 3.6% (95% confidence interval [CI], 2.4%-5.2%), and the minor congenital malformation rate was 1.9% (95% CI, 1.0%-3.1%) among offspring. Chemotherapy exposure before 12 weeks' gestational age was associated with a high rate of major congenital malformations, at 21.7%(95% CI, 7.5%-43.7%; odds ratio, 9.24 [95% CI, 3.13-27.30]). When chemotherapy was initiated after 12 weeks' gestation, the frequency of major congenital malformations decreased to 3.0% (95% CI, 1.9%-4.6%), which was comparable to the anticipated rates in the general population. Minor malformations were similar when exposure occurred before or after 12 weeks' gestation (4.3% [95% CI, 0.1%-21.9%] vs 1.8% [95% CI, 1.0-3.0]; odds ratio, 3.13 [95% CI, 0.39-25.28]). Of 29 women who received chemotherapy before 12 weeks' gestation, 17 (58.6%) were not aware of their pregnancy, and 6 (20.7%) had a miscarriage (3 women [10.3%]) or elected to terminate their pregnancy (3 women [10.3%]).Overall, this study found that chemotherapy was associated with an increased risk of major congenital malformations only when it adminis

Published
2021

14. Olaparib tablets as maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a final analysis of a double-blind, randomised, placebo-controlled, phase 3 trial

Author

Poveda, A, Floquet, A, Ledermann, J, Asher, R, Penson, R, Oza, A, Korach, J, Huzarski, T, Pignata, S, Friedlander, M, Baldoni, A, Park-Simon, T, Tamura, K, Sonke, G, Lisyanskaya, A, Kim, J, Filho, E, Milenkova, T, Lowe, E, Rowe, P, Vergote, I, Pujade-Lauraine, E, Byrski, T, Pautier, P, Harter, P, Colombo, N, Scambia, G, Nicoletto, M, Nussey, F, Clamp, A, Poveda Velasco, A, Rodrigues, M, Lotz, J, Selle, F, Ray-Coquard, I, Provencher, D, Prat Aparicio, A, Vidal Boixader, L, Scott, C, Yunokawa, M, Medioni, J, Pecuchet, N, Dubot, C, De La Motte Rouge, T, Kaminsky, M, Weber, B, Lortholary, A, Parkinson, C, Williams, S, Banerjee, S, Cosin, J, Hoffman, J, Plante, M, Covens, A, Joly, F, Hirte, H, Amit, A, Matsumoto, K, Tjulandin, S, Hoon Kim, J, Gladieff, L, Sabbatini, R, O'Malley, D, Timmins, P, Kredentser, D, Lainez Milagro, N, Barretina Ginesta, M, Tibau Martorell, A, Gomez De Liano Lista, A, Ojeda Gonzalez, B, Mileshkin, L, Mandai, M, Boere, I, Ottevanger, P, Nam, J, Hamizi, S, Cognetti, F, Warshal, D, Dickson-Michelson, E, Kamelle, S, Mckenzie, N, Rodriguez, G, Armstrong, D, Chalas, E, Celano, P, Behbakht, K, Davidson, S, Welch, S, Helpman, L, Fishman, A, Bruchim, I, Sikorska, M, Slowinska, A, Rogowski, W, Bidzinski, M, Spiewankiewicz, B, Casado Herraez, A, Mendiola Fernandez, C, Gropp-Meier, M, Saito, T, Takehara, K, Enomoto, T, Watari, H, Choi, C, Kim, B, Weon Kim, J, Hegg, R, Poveda A., Floquet A., Ledermann J. A., Asher R., Penson R. T., Oza A. M., Korach J., Huzarski T., Pignata S., Friedlander M., Baldoni A., Park-Simon T. -W., Tamura K., Sonke G. S., Lisyanskaya A., Kim J. -H., Filho E. A., Milenkova T., Lowe E. S., Rowe P., Vergote I., Pujade-Lauraine E., Byrski T., Pautier P., Harter P., Colombo N., Scambia G., Nicoletto M., Nussey F., Clamp A., Penson R., Poveda Velasco A., Rodrigues M., Lotz J. -P., Selle F., Ray-Coquard I., Provencher D., Prat Aparicio A., Vidal Boixader L., Scott C., Yunokawa M., Medioni J., Pecuchet N., Dubot C., De La Motte Rouge T., Kaminsky M. -C., Weber B., Lortholary A., Parkinson C., Ledermann J., Williams S., Banerjee S., Cosin J., Hoffman J., Plante M., Covens A., Sonke G., Joly F., Hirte H., Amit A., Matsumoto K., Tjulandin S., Hoon Kim J., Gladieff L., Sabbatini R., O'Malley D., Timmins P., Kredentser D., Lainez Milagro N., Barretina Ginesta M. P., Tibau Martorell A., Gomez De Liano Lista A., Ojeda Gonzalez B., Mileshkin L., Mandai M., Boere I., Ottevanger P., Nam J. -H., Filho E., Hamizi S., Cognetti F., Warshal D., Dickson-Michelson E., Kamelle S., McKenzie N., Rodriguez G., Armstrong D., Chalas E., Celano P., Behbakht K., Davidson S., Welch S., Helpman L., Fishman A., Bruchim I., Sikorska M., Slowinska A., Rogowski W., Bidzinski M., Spiewankiewicz B., Casado Herraez A., Mendiola Fernandez C., Gropp-Meier M., Saito T., Takehara K., Enomoto T., Watari H., Choi C. H., Kim B. -G., Weon Kim J., Hegg R., Poveda, A, Floquet, A, Ledermann, J, Asher, R, Penson, R, Oza, A, Korach, J, Huzarski, T, Pignata, S, Friedlander, M, Baldoni, A, Park-Simon, T, Tamura, K, Sonke, G, Lisyanskaya, A, Kim, J, Filho, E, Milenkova, T, Lowe, E, Rowe, P, Vergote, I, Pujade-Lauraine, E, Byrski, T, Pautier, P, Harter, P, Colombo, N, Scambia, G, Nicoletto, M, Nussey, F, Clamp, A, Poveda Velasco, A, Rodrigues, M, Lotz, J, Selle, F, Ray-Coquard, I, Provencher, D, Prat Aparicio, A, Vidal Boixader, L, Scott, C, Yunokawa, M, Medioni, J, Pecuchet, N, Dubot, C, De La Motte Rouge, T, Kaminsky, M, Weber, B, Lortholary, A, Parkinson, C, Williams, S, Banerjee, S, Cosin, J, Hoffman, J, Plante, M, Covens, A, Joly, F, Hirte, H, Amit, A, Matsumoto, K, Tjulandin, S, Hoon Kim, J, Gladieff, L, Sabbatini, R, O'Malley, D, Timmins, P, Kredentser, D, Lainez Milagro, N, Barretina Ginesta, M, Tibau Martorell, A, Gomez De Liano Lista, A, Ojeda Gonzalez, B, Mileshkin, L, Mandai, M, Boere, I, Ottevanger, P, Nam, J, Hamizi, S, Cognetti, F, Warshal, D, Dickson-Michelson, E, Kamelle, S, Mckenzie, N, Rodriguez, G, Armstrong, D, Chalas, E, Celano, P, Behbakht, K, Davidson, S, Welch, S, Helpman, L, Fishman, A, Bruchim, I, Sikorska, M, Slowinska, A, Rogowski, W, Bidzinski, M, Spiewankiewicz, B, Casado Herraez, A, Mendiola Fernandez, C, Gropp-Meier, M, Saito, T, Takehara, K, Enomoto, T, Watari, H, Choi, C, Kim, B, Weon Kim, J, Hegg, R, Poveda A., Floquet A., Ledermann J. A., Asher R., Penson R. T., Oza A. M., Korach J., Huzarski T., Pignata S., Friedlander M., Baldoni A., Park-Simon T. -W., Tamura K., Sonke G. S., Lisyanskaya A., Kim J. -H., Filho E. A., Milenkova T., Lowe E. S., Rowe P., Vergote I., Pujade-Lauraine E., Byrski T., Pautier P., Harter P., Colombo N., Scambia G., Nicoletto M., Nussey F., Clamp A., Penson R., Poveda Velasco A., Rodrigues M., Lotz J. -P., Selle F., Ray-Coquard I., Provencher D., Prat Aparicio A., Vidal Boixader L., Scott C., Yunokawa M., Medioni J., Pecuchet N., Dubot C., De La Motte Rouge T., Kaminsky M. -C., Weber B., Lortholary A., Parkinson C., Ledermann J., Williams S., Banerjee S., Cosin J., Hoffman J., Plante M., Covens A., Sonke G., Joly F., Hirte H., Amit A., Matsumoto K., Tjulandin S., Hoon Kim J., Gladieff L., Sabbatini R., O'Malley D., Timmins P., Kredentser D., Lainez Milagro N., Barretina Ginesta M. P., Tibau Martorell A., Gomez De Liano Lista A., Ojeda Gonzalez B., Mileshkin L., Mandai M., Boere I., Ottevanger P., Nam J. -H., Filho E., Hamizi S., Cognetti F., Warshal D., Dickson-Michelson E., Kamelle S., McKenzie N., Rodriguez G., Armstrong D., Chalas E., Celano P., Behbakht K., Davidson S., Welch S., Helpman L., Fishman A., Bruchim I., Sikorska M., Slowinska A., Rogowski W., Bidzinski M., Spiewankiewicz B., Casado Herraez A., Mendiola Fernandez C., Gropp-Meier M., Saito T., Takehara K., Enomoto T., Watari H., Choi C. H., Kim B. -G., Weon Kim J., and Hegg R.

Abstract

Background: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has previously been shown to extend progression-free survival versus placebo when given to patients with relapsed high-grade serous or endometrioid ovarian cancer who were platinum sensitive and who had a BRCA1 or BRCA2 (BRCA1/2) mutation, as part of the SOLO2/ENGOT-Ov21 trial. The aim of this final analysis is to investigate the effect of olaparib on overall survival. Methods: This double-blind, randomised, placebo-controlled, phase 3 trial was done across 123 medical centres in 16 countries. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status at baseline of 0–1, had histologically confirmed, relapsed, high-grade serous or high-grade endometrioid ovarian cancer, including primary peritoneal or fallopian tube cancer, and had received two or more previous platinum regimens. Patients were randomly assigned (2:1) to receive olaparib tablets (300 mg in two 150 mg tablets twice daily) or matching placebo tablets using an interactive web or voice-response system. Stratification was by response to previous chemotherapy and length of platinum-free interval. Treatment assignment was masked to patients, treatment providers, and data assessors. The primary endpoint of progression-free survival has been reported previously. Overall survival was a key secondary endpoint and was analysed in all patients as randomly allocated. Safety was assessed in all patients who received at least one treatment dose. This trial is registered with ClinicalTrials.gov, NCT01874353, and is no longer recruiting patients. Findings: Between Sept 3, 2013 and Nov 21, 2014, 295 patients were enrolled. Patients were randomly assigned to receive either olaparib (n=196 [66%]) or placebo (n=99 [34%]). One patient, randomised in error, did not receive olaparib. Median follow-up was 65·7 months (IQR 63·6–69·3) with olaparib and 64·5 months (63·4–68·7) with placebo. Median overall survi

Published
2021

15. Population Pharmacokinetics of Docetaxel, Paclitaxel, Doxorubicin and Epirubicin in Pregnant Women with Cancer: A Study from the International Network of Cancer, Infertility and Pregnancy (INCIP)

Author

Janssen, J, Van Calsteren, K, Dorlo, T, Halaska, M, Fruscio, R, Ottevanger, P, Schroder, C, Boere, I, Witteveen, P, Painter, R, Bekkers, R, Drochytek, V, Beijnen, J, Huitema, A, Amant, F, Janssen J. M., Van Calsteren K., Dorlo T. P. C., Halaska M. J., Fruscio R., Ottevanger P., Schroder C. P., Boere I., Witteveen P. O., Painter R. C., Bekkers R., Drochytek V., Beijnen J. H., Huitema A. D. R., Amant F. C. H., Janssen, J, Van Calsteren, K, Dorlo, T, Halaska, M, Fruscio, R, Ottevanger, P, Schroder, C, Boere, I, Witteveen, P, Painter, R, Bekkers, R, Drochytek, V, Beijnen, J, Huitema, A, Amant, F, Janssen J. M., Van Calsteren K., Dorlo T. P. C., Halaska M. J., Fruscio R., Ottevanger P., Schroder C. P., Boere I., Witteveen P. O., Painter R. C., Bekkers R., Drochytek V., Beijnen J. H., Huitema A. D. R., and Amant F. C. H.

Abstract

Background: Based on reassuring short-term foetal and maternal safety data, there is an increasing trend to administer chemotherapy during the second and third trimesters of pregnancy. The pharmacokinetics (PK) of drugs might change as a result of several physiological changes that occur during pregnancy, potentially affecting the efficacy and safety of chemotherapy. Objective: With this analysis, we aimed to quantitatively describe the changes in the PK of docetaxel, paclitaxel, doxorubicin and epirubicin in pregnant women compared with non-pregnant women. Methods: PK data from 9, 20, 22 and 16 pregnant cancer patients from the International Network of Cancer, Infertility and Pregnancy (INCIP) were available for docetaxel, paclitaxel, doxorubicin and epirubicin, respectively. These samples were combined with available PK data from non-pregnant patients. Empirical non-linear mixed-effects models were developed, evaluating fixed pregnancy effects and gestational age as covariates. Results: Overall, 82, 189, 271, and 227 plasma samples were collected from pregnant patients treated with docetaxel, paclitaxel, doxorubicin and epirubicin, respectively. The plasma PK data were adequately described by the respective models for all cytotoxic drugs. Typical increases in central and peripheral volumes of distribution of pregnant women were identified for docetaxel, paclitaxel, doxorubicin and epirubicin. Additionally, docetaxel, doxorubicin and paclitaxel clearance were increased in pregnant patients, resulting in lower exposure in pregnant women compared with non-pregnant patients. Conclusion: Given the interpatient variability, the identified pregnancy-induced changes in PK do not directly warrant dose adjustments for the studied drugs. Nevertheless, these results underscore the need to investigate the efficacy of chemotherapy, when administered during pregnancy.

Published
2021

16. Child development at 6 years after maternal cancer diagnosis and treatment during pregnancy

Author

Vandenbroucke, T, Verheecke, M, van Gerwen, M, Van Calsteren, K, Halaska, M, Fumagalli, M, Fruscio, R, Gandhi, A, Veening, M, Lagae, L, Ottevanger, P, Voigt, J, de Haan, J, Gziri, M, Maggen, C, Mertens, L, Naulaers, G, Claes, L, Amant, F, Blommaert, J, Dekrem, J, Goffin, F, Rigo, V, Fontana, C, Mosca, F, Passera, S, Picciolini, O, Scarfone, G, Peccatori, F, Boffi, M, Delle Marchette, M, Nacinovich, R, Lok, C, Wolters, V, Boere, I, Witteveen, E, Schroder, C, de Groot, C, van Grotel, M, van den Heuvel-Eibrink, M, Babkova, A, Drochytek, V, Vandenbroucke T., Verheecke M., van Gerwen M., Van Calsteren K., Halaska M. J., Fumagalli M., Fruscio R., Gandhi A., Veening M., Lagae L., Ottevanger P. B., Voigt J. -U., de Haan J., Gziri M. M., Maggen C., Mertens L., Naulaers G., Claes L., Amant F., Blommaert J., Dekrem J., Goffin F., Rigo V., Fontana C., Mosca F., Passera S., Picciolini O., Scarfone G., Peccatori F. A., Boffi M. L., Delle Marchette M., Nacinovich R., Lok C., Wolters V., Boere I., Witteveen E., Schroder C., de Groot C., van Grotel M., van den Heuvel-Eibrink M., Babkova A., Drochytek V., Vandenbroucke, T, Verheecke, M, van Gerwen, M, Van Calsteren, K, Halaska, M, Fumagalli, M, Fruscio, R, Gandhi, A, Veening, M, Lagae, L, Ottevanger, P, Voigt, J, de Haan, J, Gziri, M, Maggen, C, Mertens, L, Naulaers, G, Claes, L, Amant, F, Blommaert, J, Dekrem, J, Goffin, F, Rigo, V, Fontana, C, Mosca, F, Passera, S, Picciolini, O, Scarfone, G, Peccatori, F, Boffi, M, Delle Marchette, M, Nacinovich, R, Lok, C, Wolters, V, Boere, I, Witteveen, E, Schroder, C, de Groot, C, van Grotel, M, van den Heuvel-Eibrink, M, Babkova, A, Drochytek, V, Vandenbroucke T., Verheecke M., van Gerwen M., Van Calsteren K., Halaska M. J., Fumagalli M., Fruscio R., Gandhi A., Veening M., Lagae L., Ottevanger P. B., Voigt J. -U., de Haan J., Gziri M. M., Maggen C., Mertens L., Naulaers G., Claes L., Amant F., Blommaert J., Dekrem J., Goffin F., Rigo V., Fontana C., Mosca F., Passera S., Picciolini O., Scarfone G., Peccatori F. A., Boffi M. L., Delle Marchette M., Nacinovich R., Lok C., Wolters V., Boere I., Witteveen E., Schroder C., de Groot C., van Grotel M., van den Heuvel-Eibrink M., Babkova A., and Drochytek V.

Abstract

Background: Data on the long-term effects of prenatal exposure to maternal cancer and its treatment on child development are scarce. Methods: In a multicenter cohort study, the neurologic and cardiac outcomes of 6-year-old children born to women diagnosed with cancer during pregnancy were compared with the outcome of children born after an uncomplicated pregnancy. Assessment included clinical evaluation, comprehensive neuropsychological testing, electrocardiography and echocardiography. Results: In total, 132 study children and 132 controls were included. In the study group, 97 children (73.5%) were prenatally exposed to chemotherapy (alone or in combination with other treatments), 14 (10.6%) to radiotherapy (alone or in combination), 1 (0.8%) to trastuzumab, 12 (9.1%) to surgery alone and 16 (12.1%) to no treatment. Although within normal ranges, statistically significant differences were found in mean verbal IQ and visuospatial long-term memory, with lower scores in the study versus control group (98.1, 95% confidence interval [CI]: 94.5–101.8, versus 104.4, 95% CI: 100.4–108.4, P = 0.001, Q < 0.001 [Q refers to the false discovery rate adjusted P value], and 3.9, 95% CI: 3.6–4.3, versus 4.5, 95% CI: 4.1–4.9, P = 0.005, Q = 0.045, respectively). A significant difference in diastolic blood pressure was found, with higher values in chemotherapy-exposed (61.1, 95% CI: 59.0 to 63.2) versus control children (56.0, 95% CI 54.1 to 57.8) (P < 0.001, Q < 0.001) and in a subgroup of 59 anthracycline-exposed (61.8, 95% CI: 59.3 to 64.4) versus control children (55.9, 95% CI: 53.6 to 58.1) (P < 0.001, Q = 0.02). Conclusions: Children prenatally exposed to maternal cancer and its treatment are at risk for lower verbal IQ and visuospatial long-term memory scores and for higher diastolic blood pressure, but other cognitive functions and cardiac outcomes were normal at the age of 6 years. Clinical trial registration: The study is registered at ClinicalTrials.gov, NCT00330447.

Published
2020

17. Efficacy and safety of durvalumab with olaparib in metastatic or recurrent endometrial cancer (phase II DOMEC trial)

Author

Post, C. C.B., Westermann, A. M., Boere, I. A., Witteveen, P. O., Ottevanger, P. B., Sonke, G. S., Lalisang, R. I., Putter, H., Meershoek-Klein Kranenbarg, E., Braak, J. P.B.M., Creutzberg, C. L., Bosse, T., Kroep, J. R., Post, C. C.B., Westermann, A. M., Boere, I. A., Witteveen, P. O., Ottevanger, P. B., Sonke, G. S., Lalisang, R. I., Putter, H., Meershoek-Klein Kranenbarg, E., Braak, J. P.B.M., Creutzberg, C. L., Bosse, T., and Kroep, J. R.

Abstract

Background: Patients with advanced endometrial cancer have a poor prognosis, and treatment options are limited. The investigator-initiated, multicenter, phase II DOMEC trial (NCT03951415) is the first trial to report data on efficacy and safety of combined treatment with PD-L1 and PARP inhibition for advanced endometrial cancer. Patients and methods: Patients with metastatic or recurrent endometrial cancer were enrolled. Patients received durvalumab 1500 mg intravenously q4w and olaparib 300 mg 2dd until disease progression, unacceptable toxicity, or patient withdrawal. Patients with at least 4 weeks of treatment were evaluable for analysis. The primary endpoint was progression-free survival at 6 months. Evidence for efficacy was defined as progression-free survival at 6 months in ≥50% of patients. Secondary endpoints included safety, objective response and overall survival. Results: From July 2019, through November 2020, 55 patients were enrolled. At data cut-off (September 2021), 4 of the 50 evaluable patients were still on treatment. Seventeen patients (34%) were progression-free at 6 months. Objective response rate was 16% (95% CI, 8.3 to 28.5) with 1 complete and 7 partial responses. With a median follow-up of 17.6 months, median progression-free survival was 3.4 months (95% CI, 2.8 to 6.2) and median overall survival was 8.0 months (95% CI, 7.5 to 14.3). Grade 3 treatment-related adverse events occurred in 8 patients (16%), predominantly anemia. There were no grade 4 or 5 treatment-related adverse events. Conclusion: The combination of durvalumab and olaparib was well tolerated, but did not meet the prespecified 50% 6-month progression-free survival in this heterogeneous patient population with advanced endometrial cancer.

Published
2022

18. Adjuvant Use of PlasmaJet Device During Cytoreductive Surgery for Advanced-Stage Ovarian Cancer:Results of the PlaComOv-study, a Randomized Controlled Trial in The Netherlands

Author

Nieuwenhuyzen-de Boer, G. M., Hofhuis, W., Reesink-Peters, N., Willemsen, S., Boere, I. A., Schoots, I. G., Piek, J. M.J., Hofman, L. N., Beltman, J. J., van Driel, W. J., Werner, H. M.J., Baalbergen, A., van Haaften-de Jong, A. M.L.D., Dorman, M., Haans, L., Nedelcu, I., Ewing-Graham, P. C., van Beekhuizen, H. J., Nieuwenhuyzen-de Boer, G. M., Hofhuis, W., Reesink-Peters, N., Willemsen, S., Boere, I. A., Schoots, I. G., Piek, J. M.J., Hofman, L. N., Beltman, J. J., van Driel, W. J., Werner, H. M.J., Baalbergen, A., van Haaften-de Jong, A. M.L.D., Dorman, M., Haans, L., Nedelcu, I., Ewing-Graham, P. C., and van Beekhuizen, H. J.

Abstract

Objective: Standard surgical treatment of advanced-stage ovarian carcinoma with electrosurgery cannot always result in complete cytoreductive surgery (CRS), especially when many small metastases are found on the mesentery and intestinal surface. We investigated whether adjuvant use of a neutral argon plasma device can help increase the complete cytoreduction rate. Patients and Methods: 327 patients with FIGO stage IIIB–IV epithelial ovarian cancer (EOC) who underwent primary or interval CRS were randomized to either surgery with neutral argon plasma (PlasmaJet) (intervention) or without PlasmaJet (control group). The primary outcome was the percentage of complete CRS. The secondary outcomes were duration of surgery, blood loss, number of bowel resections and colostomies, hospitalization, 30-day morbidity, and quality of life (QoL). Results: Complete CRS was achieved in 119 patients (75.8%) in the intervention group and 115 patients (67.6%) in the control group (risk difference (RD) 8.2%, 95% confidence interval (CI) –0.021 to 0.181; P = 0.131). In a per-protocol analysis excluding patients with unresectable disease, complete CRS was obtained in 85.6% in the intervention group and 71.5% in the control group (RD 14.1%, 95% CI 0.042 to 0.235; P = 0.005). Patient-reported QoL at 6 months after surgery differed between groups in favor of PlasmaJet surgery (95% CI 0.455–8.350; P = 0.029). Other secondary outcomes did not differ significantly. Conclusions: Adjuvant use of PlasmaJet during CRS for advanced-stage ovarian cancer resulted in a significantly higher proportion of complete CRS in patients with resectable disease and higher QoL at 6 months after surgery. (Funded by ZonMw, Trial Register NL62035.078.17.) Trial Registration: Approved by the Medical Ethics Review Board of the Erasmus University Medical Center Rotterdam, the Netherlands, NL62035.078.17 on 20-11-2017. Recruitment started on 30-1-2018.

Published
2022

19. Acute and long-term toxicity in patients undergoing induction chemotherapy followed by thermoradiotherapy for advanced cervical cancer

Author

Gao, X. S., Boere, I. A., van Beekhuizen, H. J., Franckena, M., Nout, R., Kruip, M. J.H.A., Kulawska, M. D., van Doorn, H. C., Gao, X. S., Boere, I. A., van Beekhuizen, H. J., Franckena, M., Nout, R., Kruip, M. J.H.A., Kulawska, M. D., and van Doorn, H. C.

Abstract

Objectives: To determine rates of vascular toxicity, acute kidney injury (AKI), chronic kidney disease (CKD) and survival in high-risk cervical cancer patients treated with platinum-based induction chemotherapy followed by thermoradiotherapy. Methods: Between January 1999 and April 2017, patients with large primary tumors (>6cm) and/or para-aortic lymph node (LN) metastases >1 cm and/or para-iliac LN >2 cm were included. Patient and tumor characteristics, Common Toxicity Criteria v4.03 scores, laboratory tests and treatment data were retrieved from patient records. CT scans were reviewed for the presence of thrombo-embolic events (TEE). The study protocol was approved by the Medical Ethics Review Committee of Erasmus MC, Rotterdam (MEC2017-133). Results: The 105 included patients had a mean age of 47.9 years (range 22–79) and a median follow-up time of 43 months (IQR 14–72). Median tumor size was 6.0 cm (range 2.6–11.5), 30% had a clinical FIGO stage ≥ IIIB and 42% had enlarged para-aortic LN. Cisplatin-based therapy was started in 86 patients (82%), of whom 30 (35%) switched to carboplatin and 47% of patients completed six cycles of platinum-based chemotherapy. All patients received external beam radiotherapy as planned, 98 patients (93%) underwent brachytherapy as planned or received an external boost, and 95 patients (90%) completed all five planned hyperthermia treatments. During cisplatin chemotherapy, 34 patients experienced AKI (39%). At last follow-up, 35% of patients had chronic renal toxicity (GFR 59 − 15/min/1.73 m2). At presentation, a TEE was present in 10 (10%) and another 23 (22%) patients experienced a TEE (18% venous, 4% arterial) during chemotherapy. Five-year overall survival was 58% (95% CI 47.8–68.6 SE 0.053). Conclusion: Achieving a five-year overall survival of 58%, platinum-based induction chemotherapy followed by thermoradiotherapy is an effective treatment for advanced-stage high-risk cervical cancer. However, treatme

Published
2022

20. Efficacy and safety of durvalumab with olaparib in metastatic or recurrent endometrial cancer (phase II DOMEC trial)

Author

MS Radiotherapie, MS Medische Oncologie, Cancer, Post, C C B, Westermann, A M, Boere, I A, Witteveen, P O, Ottevanger, P B, Sonke, G S, Lalisang, R I, Putter, H, Meershoek-Klein Kranenbarg, E, Braak, J P B M, Creutzberg, C L, Bosse, T, Kroep, J R, MS Radiotherapie, MS Medische Oncologie, Cancer, Post, C C B, Westermann, A M, Boere, I A, Witteveen, P O, Ottevanger, P B, Sonke, G S, Lalisang, R I, Putter, H, Meershoek-Klein Kranenbarg, E, Braak, J P B M, Creutzberg, C L, Bosse, T, and Kroep, J R

Published
2022

24. O013/#573 Tisotumab vedotin (TV) + bevacizumab or pembrolizumab or carboplatin in recurrent/metastatic cervical cancer (R/MCC): phase 1B/2 engot-CX8/GOG-3024/innovaTV 205 study dose-escalation results

Author

Monk, B, primary, Van Gorp, T, additional, Lorusso, D, additional, Eilish O’Cearbhaill, R, additional, Westermann, A, additional, Banerjee, S, additional, Collins, D, additional, Klat, J, additional, Madsen, K, additional, Baurain, J-F, additional, Jackson, A, additional, Boere, I, additional, Pignata, S, additional, Gort, E, additional, Moroney, J, additional, Soumaoro, I, additional, Andreassen, CM, additional, Nicacio, L, additional, Gennigens, C, additional, and Vergote, I, additional

Published
2021
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26. Population Pharmacokinetics of Docetaxel, Paclitaxel, Doxorubicin and Epirubicin in Pregnant Women with Cancer: A Study from the International Network of Cancer, Infertility and Pregnancy (INCIP)

Author

Janssen, J.M., Calsteren, K. van, Dorlo, T.P., Halaska, M.J., Fruscio, R., Ottevanger, P.B., Schröder, C.P., Boere, I., Witteveen, P.O., Painter, R.C., Bekkers, R., Drochytek, V., Beijnen, J.H., Huitema, A.D., Amant, F.C.H., Janssen, J.M., Calsteren, K. van, Dorlo, T.P., Halaska, M.J., Fruscio, R., Ottevanger, P.B., Schröder, C.P., Boere, I., Witteveen, P.O., Painter, R.C., Bekkers, R., Drochytek, V., Beijnen, J.H., Huitema, A.D., and Amant, F.C.H.

Abstract

Contains fulltext : 235476.pdf (Publisher’s version ) (Closed access), BACKGROUND: Based on reassuring short-term foetal and maternal safety data, there is an increasing trend to administer chemotherapy during the second and third trimesters of pregnancy. The pharmacokinetics (PK) of drugs might change as a result of several physiological changes that occur during pregnancy, potentially affecting the efficacy and safety of chemotherapy. OBJECTIVE: With this analysis, we aimed to quantitatively describe the changes in the PK of docetaxel, paclitaxel, doxorubicin and epirubicin in pregnant women compared with non-pregnant women. METHODS: PK data from 9, 20, 22 and 16 pregnant cancer patients from the International Network of Cancer, Infertility and Pregnancy (INCIP) were available for docetaxel, paclitaxel, doxorubicin and epirubicin, respectively. These samples were combined with available PK data from non-pregnant patients. Empirical non-linear mixed-effects models were developed, evaluating fixed pregnancy effects and gestational age as covariates. RESULTS: Overall, 82, 189, 271, and 227 plasma samples were collected from pregnant patients treated with docetaxel, paclitaxel, doxorubicin and epirubicin, respectively. The plasma PK data were adequately described by the respective models for all cytotoxic drugs. Typical increases in central and peripheral volumes of distribution of pregnant women were identified for docetaxel, paclitaxel, doxorubicin and epirubicin. Additionally, docetaxel, doxorubicin and paclitaxel clearance were increased in pregnant patients, resulting in lower exposure in pregnant women compared with non-pregnant patients. CONCLUSION: Given the interpatient variability, the identified pregnancy-induced changes in PK do not directly warrant dose adjustments for the studied drugs. Nevertheless, these results underscore the need to investigate the efficacy of chemotherapy, when administered during pregnancy.

Published
2021

29. Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes

Author

Fachal, L., Aschard, H., Beesley, J., Barnes, D.R., Allen, J., Kar, S., Pooley, K.A., Dennis, J., Michailidou, K., Turman, C., Soucy, P., Lemaçon, A., Lush, M., Tyrer, J.P., Ghoussaini, M., Marjaneh, M.M., Jiang, X., Agata, S., Aittomäki, K., Alonso, M.R., Andrulis, I.L., Anton-Culver, H., Antonenkova, N.N., Arason, A., Arndt, V., Aronson, K.J., Arun, B.K., Auber, B., Auer, P.L., Azzollini, J., Balmaña, J., Barkardottir, R.B., Barrowdale, D., Beeghly-Fadiel, A., Benitez, J., Bermisheva, M., Białkowska, K., Blanco, A.M., Blomqvist, C., Blot, W., Bogdanova, N.V., Bojesen, S.E., Bolla, M.K., Bonanni, B., Borg, A., Bosse, K., Brauch, H., Brenner, H., Briceno, I., Brock, I.W., Brooks-Wilson, A., Brüning, T., Burwinkel, B., Buys, S.S., Cai, Q., Caldés, T., Caligo, M.A., Camp, N.J., Campbell, I., Canzian, F., Carroll, J.S., Carter, B.D., Castelao, J.E., Chiquette, J., Christiansen, H., Chung, W.K., Claes, K.B.M., Clarke, C.L., Mari, V., Berthet, P., Castera, L., Vaur, D., Lallaoui, H., Bignon, Y.-J., Uhrhammer, N., Bonadona, V., Lasset, C., Révillion, F., Vennin, P., Muller, D., Gomes, D.M., Ingster, O., Coupier, I., Pujol, P., Collonge-Rame, M.-A., Mortemousque, I., Bera, O., Rose, M., Baurand, A., Bertolone, G., Faivre, L., Dreyfus, H., Leroux, D., Venat-Bouvet, L., Bézieau, S., Delnatte, C., Chiesa, J., Gilbert-Dussardier, B., Gesta, P., Prieur, F.P., Bronner, M., Sokolowska, J., Coulet, F., Boutry-Kryza, N., Calender, A., Giraud, S., Leone, M., Fert-Ferrer, S., Stoppa-Lyonnet, D., Jiao, Y., Lesueur, F.L., Mebirouk, N., Barouk-Simonet, E., Bubien, V., Longy, M., Sevenet, N., Gladieff, L., Toulas, C., Reimineras, A., Sobol, H., Paillerets, B.B.-D., Cabaret, O., Caron, O., Guillaud-Bataille, M., Rouleau, E., Belotti, M., Buecher, B., Caputo, S., Colas, C., Pauw, A.D., Fourme, E., Gauthier-Villars, M., Golmard, L., Moncoutier, V., Saule, C., Donaldson, A., Murray, A., Brady, A., Brewer, C., Pottinger, C., Miller, C., Gallagher, D., Gregory, H., Cook, J., Eason, J., Adlard, J., Barwell, J., Ong, K.-R., Snape, K., Walker, L., Izatt, L., Side, L., Tischkowitz, M., Rogers, M.T., Porteous, M.E., Ahmed, M., Morrison, P.J., Brennan, P., Eeles, R., Davidson, R., Collée, M., Cornelissen, S., Couch, F.J., Cox, A., Cross, S.S., Cybulski, C., Czene, K., Daly, M.B., de la Hoya, M., Devilee, P., Diez, O., Ding, Y.C., Dite, G.S., Domchek, S.M., Dörk, T., dos-Santos-Silva, I., Droit, A., Dubois, S., Dumont, M., Duran, M., Durcan, L., Dwek, M., Eccles, D.M., Engel, C., Eriksson, M., Evans, D.G., Fasching, P.A., Fletcher, O., Floris, G., Flyger, H., Foretova, L., Foulkes, W.D., Friedman, E., Fritschi, L., Frost, D., Gabrielson, M., Gago-Dominguez, M., Gambino, G., Ganz, P.A., Gapstur, S.M., Garber, J., García-Sáenz, J.A., Gaudet, M.M., Georgoulias, V., Giles, G., Glendon, G., Godwin, A.K., Goldberg, M.S., Goldgar, D.E., González-Neira, A., Tibiletti, M.G., Greene, M.H., Grip, M., Gronwald, J., Grundy, A., Guénel, P., Hahnen, E., Haiman, C.A., Håkansson, N., Hall, P., Hamann, U., Harrington, P.A., Hartikainen, J.M., Hartman, M., He, W., Healey, C.S., Heemskerk-Gerritsen, B.A.M., Heyworth, J., Hillemanns, P., Hogervorst, F.B.L., Hollestelle, A., Hooning, M., Hopper, J., Howell, A., Huang, G., Hulick, P.J., Imyanitov, E.N., Sexton, A., Christian, A., Trainer, A., Spigelman, A., Fellows, A., Shelling, A., Fazio, A.D., Blackburn, A., Crook, A., Meiser, B., Patterson, B., Clarke, C., Saunders, C., Hunt, C., Scott, C., Amor, D., Marsh, D., Edkins, E., Salisbury, E., Haan, E., Neidermayr, E., Macrea, F., Farshid, G., Lindeman, G., Chenevix-Trench, G., Mann, G., Gill, G., Thorne, H., Hickie, I., Winship, I., Flanagan, J., Kollias, J., Visvader, J., Stone, J., Taylor, J., Burke, J., Saunus, J., Forbes, J., Kirk, J., French, J., Tucker, K., Wu, K., Phillips, K., Lipton, L., Andrews, L., Lobb, L., Kentwell, M., Spurdle, M., Cummings, M., Gleeson, M., Harris, M., Jenkins, M., Young, M.A., Delatycki, M., Wallis, M., Burgess, M., Price, M., Brown, M., Southey, M., Bogwitz, M., Field, M., Friedlander, M., Gattas, M., Saleh, M., Hayward, N., Pachter, N., Cohen, P., Duijf, P., James, P., Simpson, P., Fong, P., Butow, P., Williams, R., Kefford, R., Scott, R., Milne, R.L., Balleine, R., Dawson, S.–J., Lok, S., O’Connell, S., Greening, S., Nightingale, S., Edwards, S., Fox, S., McLachlan, S.-A., Lakhani, S., Antill, Y., Aalfs, C., Meijers-Heijboer, H., van Engelen, K., Gille, H., Boere, I., van Deurzen, C., Obdeijn, I.-M., van den Ouweland, A., Seynaeve, C., Siesling, S., Verloop, J., van Asperen, C.J., van Cronenburg, T., Blok, R., de Boer, M., Garcia, E.G., Adank, M., Hogervorst, F., Jenner, D., van Leeuwen, F., Rookus, M., Russell, N., Schmidt, M., van den Belt-Dusebout, S., Kets, C., Mensenkamp, A., de Bock, T., van der Hout, A., Mourits, M., Oosterwijk, J., Ausems, M., Koudijs, M., Baxter, R., Yip, D., Carpenter, J., Davis, A., Pathmanathan, N., Graham, D., Sachchithananthan, M., Isaacs, C., Iwasaki, M., Jager, A., Jakimovska, M., Jakubowska, A., James, P.A., Janavicius, R., Jankowitz, R.C., John, E.M., Johnson, N., Jones, M.E., Jukkola-Vuorinen, A., Jung, A., Kaaks, R., Kang, D., Kapoor, P.M., Karlan, B.Y., Keeman, R., Kerin, M.J., Khusnutdinova, E., Kiiski, J.I., Kitahara, C.M., Ko, Y.-D., Konstantopoulou, I., Kosma, V.-M., Koutros, S., Kubelka-Sabit, K., Kwong, A., Kyriacou, K., Laitman, Y., Lambrechts, D., Lee, E., Leslie, G., Lester, J., Lesueur, F., Lindblom, A., Lo, W.-Y., Long, J., Lophatananon, A., Loud, J.T., Lubiński, J., MacInnis, R.J., Maishman, T., Makalic, E., Mannermaa, A., Manoochehri, M., Manoukian, S., Margolin, S., Martinez, M.E., Matsuo, K., Maurer, T., Mavroudis, D., Mayes, R., McGuffog, L., McLean, C., Meindl, A., Miller, A., Miller, N., Montagna, M., Moreno, F., Muir, K., Mulligan, A.M., Muñoz-Garzon, V.M., Muranen, T.A., Narod, S.A., Nassir, R., Nathanson, K.L., Neuhausen, S.L., Nevanlinna, H., Neven, P., Nielsen, F.C., Nikitina-Zake, L., Norman, A., Offit, K., Olah, E., Olopade, O.I., Olsson, H., Orr, N., Osorio, A., Pankratz, V.S., Papp, J., Park, S.K., Park-Simon, T.-W., Parsons, M.T., Paul, J., Pedersen, I.S., Peissel, B., Peshkin, B., Peterlongo, P., Peto, J., Plaseska-Karanfilska, D., Prajzendanc, K., Prentice, R., Presneau, N., Prokofyeva, D., Pujana, M.A., Pylkäs, K., Radice, P., Ramus, S.J., Rantala, J., Rau-Murthy, R., Rennert, G., Risch, H.A., Robson, M., Romero, A., Rossing, M., Saloustros, E., Sánchez-Herrero, E., Sandler, D.P., Santamariña, M., Sawyer, E.J., Scheuner, M.T., Schmidt, D.F., Schmutzler, R.K., Schneeweiss, A., Schoemaker, M.J., Schöttker, B., Schürmann, P., Scott, R.J., Senter, L., Seynaeve, C.M., Shah, M., Sharma, P., Shen, C.-Y., Shu, X.-O., Singer, C.F., Slavin, T.P., Smichkoska, S., Southey, M.C., Spinelli, J.J., Spurdle, A.B., Sutter, C., Swerdlow, A.J., Tamimi, R.M., Tan, Y.Y., Tapper, W.J., Taylor, J.A., Teixeira, M.R., Tengström, M., Teo, S.H., Terry, M.B., Teulé, A., Thomassen, M., Thull, D.L., Toland, A.E., Tollenaar, R.A.E.M., Tomlinson, I., Torres, D., Torres-Mejía, G., Troester, M.A., Truong, T., Tung, N., Tzardi, M., Ulmer, H.-U., Vachon, C.M., van der Kolk, L.E., van Rensburg, E.J., Vega, A., Viel, A., Vijai, J., Vogel, M.J., Wang, Q., Wappenschmidt, B., Weinberg, C.R., Weitzel, J.N., Wendt, C., Wildiers, H., Winqvist, R., Wolk, A., Wu, A.H., Yannoukakos, D., Zhang, Y., Zheng, W., Hunter, D., Pharoah, P.D.P., Chang-Claude, J., García-Closas, M., Schmidt, M.K., Kristensen, V.N., French, J.D., Edwards, S.L., Antoniou, A.C., Simard, J., Easton, D.F., Kraft, P., Dunning, A.M., Collaborators, GEMO Study, Collaborators, EMBRACE, Investigators, KConFab, Investigators, HEBON, Investigators, ABCTB, Fachal, Laura, Aschard, Hugues, Beesley, Jonathan, Barnes, Daniel R, Duijf, Pascal, Dunning, Alison M, GEMO Study Collaborators, EMBRACE Collaborators, KConFab Investigators, HEBON Investigators, ABCTB Investigators, MUMC+: MA Medische Oncologie (9), RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Klinische Genetica, MUMC+: DA KG Polikliniek (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), European Commission, Government of Canada, Canadian Institutes of Health Research, National Institutes of Health (US), Cancer Research UK, Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), QIMR Berghofer Medical Research Institute, University of Cambridge [UK] (CAM), NSCAD, University of Cyprus [Nicosia], Harvard T.H. Chan School of Public Health, This work was supported by the European Union’s Horizon 2020 Research and Innovation Programme under Marie Sklodowska-Curie grant agreement number 656144. Genotyping of the OncoArray was principally funded from three sources: the PERSPECTIVE project (funded by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the ‘Ministère de l’Économie de la Science et de l’Innovation du Québec’ (through Genome Québec) and the Quebec Breast Cancer Foundation), the NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative and the Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) project (NIH grants U19 CA148065 and X01HG007492), and Cancer Research UK (C1287/A10118, C8197/A16565 and C1287/A16563). BCAC is funded by Cancer Research UK (C1287/A16563), by the European Community’s Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS) and by the European Union’s Horizon 2020 Research and Innovation Programme under grant agreements 633784 (B-CAST) and 634935 (BRIDGES). Genotyping of the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710), the Canadian Institutes of Health Research for the ‘CIHR Team in Familial Risks of Breast Cancer’ program, and the Ministry of Economic Development, Innovation and Export Trade of Quebec (grant PSR-SIIRI-701). Combining of the GWAS data was supported in part by NIH Cancer Post-Cancer GWAS initiative grant U19 CA 148065 (DRIVE, part of the GAME-ON initiative). For a full description of funding and acknowledgments, see the Supplementary Note., We thank all of the individuals who took part in these studies, as well as all of the researchers, clinicians, technicians and administrative staff who enabled this work to be carried out, European Project: 656144,H2020,H2020-MSCA-IF-2014,RADIOGENFF(2016), European Project: 223175,EC:FP7:HEALTH,FP7-HEALTH-2007-B,COGS(2009), European Project: 633784,H2020,H2020-PHC-2014-two-stage,B-CAST(2015), European Project: 634935,H2020,H2020-PHC-2014-two-stage,BRIDGES(2015), Clinical Genetics, Medical Oncology, Pathology, Radiology & Nuclear Medicine, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of Cyprus [Nicosia] (UCY), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Life Course Epidemiology (LCE), Targeted Gynaecologic Oncology (TARGON), ​Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), Aschard, Hugues [0000-0002-7554-6783], Barnes, Daniel R [0000-0002-3781-7570], Dennis, Joe [0000-0003-4591-1214], Michailidou, Kyriaki [0000-0001-7065-1237], Lemaçon, Audrey [0000-0002-1817-7029], Andrulis, Irene L [0000-0002-4226-6435], Arason, Adalgeir [0000-0003-0480-886X], Arndt, Volker [0000-0001-9320-8684], Auber, Bernd [0000-0003-1880-291X], Azzollini, Jacopo [0000-0002-9364-9778], Bojesen, Stig E [0000-0002-4061-4133], Bonanni, Bernardo [0000-0003-3589-2128], Brauch, Hiltrud [0000-0001-7531-2736], Campbell, Ian [0000-0002-7773-4155], Carroll, Jason S [0000-0003-3643-0080], Claes, Kathleen BM [0000-0003-0841-7372], Collée, J Margriet [0000-0002-9272-9346], Devilee, Peter [0000-0002-8023-2009], Dörk, Thilo [0000-0002-9458-0282], Dwek, Miriam [0000-0001-7184-2932], Fletcher, Olivia [0000-0001-9387-7116], Floris, Giuseppe [0000-0003-2391-5425], Foulkes, William D [0000-0001-7427-4651], García-Sáenz, José A [0000-0001-6880-0301], Greene, Mark H [0000-0003-1852-9239], Guénel, Pascal [0000-0002-8359-518X], Heemskerk-Gerritsen, Bernadette AM [0000-0002-9724-6693], Hollestelle, Antoinette [0000-0003-1166-1966], Hulick, Peter J [0000-0001-8397-4078], Jakimovska, Milena [0000-0002-1506-0669], Jakubowska, Anna [0000-0002-5650-0501], James, Paul A [0000-0002-4361-4657], Jones, Michael E [0000-0001-7479-3451], Kapoor, Pooja Middha [0000-0001-5503-8215], Keeman, Renske [0000-0002-5452-9933], Konstantopoulou, Irene [0000-0002-0470-0309], Leslie, Goska [0000-0001-5756-6222], Lesueur, Fabienne [0000-0001-7404-4549], Matsuo, Keitaro [0000-0003-1761-6314], McLean, Catriona [0000-0002-0302-5727], Miller, Austin [0000-0001-9739-8462], Muir, Kenneth [0000-0001-6429-988X], Muranen, Taru A [0000-0002-5895-1808], Nathanson, Katherine L [0000-0002-6740-0901], Nevanlinna, Heli [0000-0002-0916-2976], Olopade, Olufunmilayo I [0000-0002-9936-1599], Orr, Nick [0000-0003-2866-942X], Pankratz, V Shane [0000-0002-3742-040X], Parsons, Michael T [0000-0003-3242-8477], Paul, James [0000-0001-7367-5816], Peshkin, Beth [0000-0002-2997-4701], Peterlongo, Paolo [0000-0001-6951-6855], Peto, Julian [0000-0002-1685-8912], Plaseska-Karanfilska, Dijana [0000-0001-8877-2416], Pylkäs, Katri [0000-0002-2449-0521], Radice, Paolo [0000-0001-6298-4111], Rennert, Gad [0000-0002-8512-068X], Robson, Mark [0000-0002-3109-1692], Romero, Atocha [0000-0002-1634-7397], Saloustros, Emmanouil [0000-0002-0485-0120], Scott, Christopher [0000-0003-1340-0647], Scott, Rodney J [0000-0001-7724-3404], Spurdle, Amanda B [0000-0003-1337-7897], Stone, Jennifer [0000-0001-5077-0124], Sutter, Christian [0000-0003-4051-5888], Tan, Yen Yen [0000-0003-1063-5352], Teixeira, Manuel R [0000-0002-4896-5982], Toland, Amanda E [0000-0002-0271-1792], Tomlinson, Ian [0000-0003-3037-1470], Viel, Alessandra [0000-0003-2804-0840], Vijai, Joseph [0000-0002-7933-151X], Wolk, Alicja [0000-0001-7387-6845], Yannoukakos, Drakoulis [0000-0001-7509-3510], Pharoah, Paul DP [0000-0001-8494-732X], Schmidt, Marjanka K [0000-0002-2228-429X], Milne, Roger L [0000-0001-5764-7268], Edwards, Stacey L [0000-0001-7428-4139], Simard, Jacques [0000-0001-6906-3390], Easton, Douglas F [0000-0003-2444-3247], Kraft, Peter [0000-0002-4472-8103], Dunning, Alison M [0000-0001-6651-7166], Apollo - University of Cambridge Repository, Academic Medical Center, ARD - Amsterdam Reproduction and Development, Human genetics, CCA - Cancer biology and immunology, Molecular cell biology and Immunology, Medicum, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, University of Helsinki, HUS Comprehensive Cancer Center, Department of Oncology, Clinicum, Doctoral Programme in Clinical Research, Staff Services, INDIVIDRUG - Individualized Drug Therapy, HUS Gynecology and Obstetrics, and Department of Obstetrics and Gynecology

Subjects
CHROMATIN, Linkage disequilibrium, Genome-wide association study, Regulatory Sequences, Nucleic Acid, Genome-wide association studies, Linkage Disequilibrium, Basic medicine, 0302 clinical medicine, Breast cancer, MESH: Risk Factors, Risk Factors, COMPREHENSIVE MOLECULAR PORTRAITS, 11 Medical and Health Sciences, HEBON Investigators, Genetics & Heredity, 0303 health sciences, [STAT.AP]Statistics [stat]/Applications [stat.AP], PROTEIN FUNCTION, Tumor, breast tumor, MESH: Polymorphism, Single Nucleotide, 1184 Genetics, developmental biology, physiology, MESH: Genetic Predisposition to Disease, apoptosis, Chromosome Mapping, Single Nucleotide, 3. Good health, MESH: Linkage Disequilibrium, Female, MESH: Biomarkers, Tumor, Biomarkers, Tumor/genetics, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Life Sciences & Biomedicine, SUSCEPTIBILITY LOCI, MESH: Bayes Theorem, Quantitative Trait Loci, ABCTB Investigators, INTEGRATIVE ANALYSIS, Breast Neoplasms, Computational biology, Biology, Quantitative trait locus, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, Article, ENHANCER, GEMO Study Collaborators, 03 medical and health sciences, breast cancer, SDG 3 - Good Health and Well-being, REVEALS, Genetics, Biomarkers, Tumor, MESH: Regulatory Sequences, Nucleic Acid, Humans, Genetic Predisposition to Disease, Polymorphism, GENOME-WIDE ASSOCIATION, FUNCTIONAL VARIANTS, EMBRACE Collaborators, Gene, 030304 developmental biology, Genetic association, Bayes Theorem, Genome-Wide Association Study, MESH: Humans, Science & Technology, Nucleic Acid, gene mapping, 06 Biological Sciences, MESH: Quantitative Trait Loci, DNA binding site, ESTROGEN-RECEPTOR, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Clinical medicine, Expression quantitative trait loci, MESH: Genome-Wide Association Study, Human genome, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, KConFab Investigators, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], MESH: Chromosome Mapping, Chromosome Mapping/methods, Regulatory Sequences, MESH: Female, Biomarkers, 030217 neurology & neurosurgery, MESH: Breast Neoplasms, Developmental Biology
Abstract

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes., This work was supported by the European Union’s Horizon 2020 Research and Innovation Programme under Marie Sklodowska-Curie grant agreement number 656144. Genotyping of the OncoArray was principally funded from three sources: the PERSPECTIVE project (funded by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the ‘Ministère de l’Économie de la Science et de l’Innovation du Québec’ (through Genome Québec) and the Quebec Breast Cancer Foundation); the NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative and the Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) project (NIH grants U19 CA148065 and X01HG007492); and Cancer Research UK (C1287/A10118, C8197/A16565 and C1287/A16563). BCAC is funded by Cancer Research UK (C1287/A16563), by the European Community’s Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS) and by the European Union’s Horizon 2020 Research and Innovation Programme under grant agreements 633784 (B-CAST) and 634935 (BRIDGES). Genotyping of the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710), the Canadian Institutes of Health Research for the ‘CIHR Team in Familial Risks of Breast Cancer’ program, and the Ministry of Economic Development, Innovation and Export Trade of Quebec (grant PSR-SIIRI-701). Combining of the GWAS data was supported in part by NIH Cancer Post-Cancer GWAS initiative grant U19 CA 148065 (DRIVE; part of the GAME-ON initiative).

Published
2020
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30. Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes.

Author

Ramus S.J., Carroll J.S., Schneeweiss A., Schoemaker M.J., Schottker B., Schurmann P., Scott C., Scott R.J., Senter L., Shah M., Sharma P., Shen C.-Y., Shu X.-O., Singer C.F., Slavin T.P., Smichkoska S., Spinelli J.J., Spurdle A.B., Sutter C., Swerdlow A.J., Tamimi R.M., Tan Y.Y., Tapper W.J., Taylor J., Teixeira M.R., Tengstrom M., Teo S.H., Terry M.B., Teule A., Thomassen M., Thull D.L., Toland A.E., Tollenaar R.A.E.M., Tomlinson I., Torres D., Torres-Mejia G., Troester M.A., Truong T., Tung N., Tzardi M., Ulmer H.-U., Vachon C.M., van der Kolk L.E., van Rensburg E.J., Vega A., Viel A., Vijai J., Vogel M.J., Wang Q., Wappenschmidt B., Weinberg C.R., Weitzel J.N., Wendt C., Wildiers H., Winqvist R., Wolk A., Wu A.H., Yannoukakos D., Zhang Y., Zheng W., Hunter D., Pharoah P.D.P., Chang-Claude J., Garcia-Closas M., Schmidt M.K., Kristensen V.N., French J.D., Antoniou A.C., Chenevix-Trench G., Simard J., Easton D.F., Kraft P., Allen J., Harris M., Fachal L., Aschard H., Beesley J., Barnes D.R., Kar S., Pooley K.A., Dennis J., Michailidou K., Turman C., Soucy P., Lemacon A., Lush M., Tyrer J.P., Ghoussaini M., Marjaneh M.M., Jiang X., Agata S., Aittomaki K., Alonso M.R., Andrulis I.L., Anton-Culver H., Antonenkova N.N., Arason A., Arndt V., Aronson K.J., Arun B.K., Auber B., Auer P.L., Azzollini J., Balmana J., Barkardottir R.B., Barrowdale D., Beeghly-Fadiel A., Benitez J., Bermisheva M., Bialkowska K., Blanco A.M., Blomqvist C., Blot W., Bogdanova N.V., Bojesen S.E., Bolla M.K., Bonanni B., Borg A., Bosse K., Brauch H., Brenner H., Briceno I., Brock I.W., Brooks-Wilson A., Bruning T., Burwinkel B., Buys S.S., Cai Q., Caldes T., Caligo M.A., Camp N.J., Campbell I., Carter B.D., Castelao J.E., Chiquette J., Christiansen H., Chung W.K., Claes K.B.M., Clarke C.L., Mari V., Berthet P., Castera L., Vaur D., Lallaoui H., Bignon Y.-J., Uhrhammer N., Bonadona V., Lasset C., Revillion F., Vennin P., Muller D., Gomes D.M., Ingster O., Coupier I., Pujol P., Collonge-Rame M.-A., Mortemousque I., Bera O., Rose M., Baurand A., Bertolone G., Faivre L., Dreyfus H., Leroux D., Venat-Bouvet L., Bezieau S., Delnatte C., Chiesa J., Gilbert-Dussardier B., Gesta P., Prieur F.P., Bronner M., Sokolowska J., Coulet F., Boutry-Kryza N., Calender A., Giraud S., Leone M., Fert-Ferrer S., Stoppa-Lyonnet D., Jiao Y., Lesueur F.L., Mebirouk N., Barouk-Simonet E., Bubien V., Longy M., Sevenet N., Gladieff L., Toulas C., Reimineras A., Sobol H., Paillerets B.B.-D., Cabaret O., Caron O., Guillaud-Bataille M., Rouleau E., Belotti M., Buecher B., Caputo S., Colas C., Pauw A.D., Fourme E., Gauthier-Villars M., Golmard L., Moncoutier V., Saule C., Donaldson A., Murray A., Brady A., Brewer C., Pottinger C., Miller C., Gallagher D., Gregory H., Cook J., Eason J., Adlard J., Barwell J., Ong K.-R., Snape K., Walker L., Izatt L., Side L., Tischkowitz M., Rogers M.T., Porteous M.E., Ahmed M., Morrison P.J., Brennan P., Eeles R., Davidson R., Collee J.M., Cornelissen S., Couch F.J., Cox A., Cross S.S., Cybulski C., Czene K., Daly M.B., de la Hoya M., Devilee P., Diez O., Ding Y.C., Dite G.S., Domchek S.M., Dork T., dos-Santos-Silva I., Droit A., Dubois S., Dumont M., Duran M., Durcan L., Dwek M., Eccles D.M., Engel C., Eriksson M., Evans D.G., Fasching P.A., Fletcher O., Floris G., Flyger H., Foretova L., Foulkes W.D., Friedman E., Fritschi L., Frost D., Gabrielson M., Gago-Dominguez M., Gambino G., Ganz P.A., Gapstur S.M., Garber J., Garcia-Saenz J.A., Gaudet M.M., Georgoulias V., Giles G., Glendon G., Godwin A.K., Goldberg M.S., Goldgar D.E., Gonzalez-Neira A., Tibiletti M.G., Greene M.H., Grip M., Gronwald J., Grundy A., Guenel P., Hahnen E., Haiman C.A., Hakansson N., Hall P., Hamann U., Harrington P.A., Hartikainen J.M., Hartman M., He W., Healey C.S., Heemskerk-Gerritsen B.A.M., Heyworth J., Hillemanns P., Hogervorst F.B.L., Hollestelle A., Hooning M., Hopper J., Howell A., Huang G., Hulick P.J., Imyanitov E.N., Sexton A., Christian A., Trainer A., Spigelman A., Fellows A., Shelling A., Fazio A.D., Blackburn A., Crook A., Meiser B., Patterson B., Clarke C., Saunders C., Hunt C., Amor D., Marsh D., Edkins E., Salisbury E., Haan E., Neidermayr E., Macrea F., Farshid G., Lindeman G., Trench G., Mann G., Gill G., Thorne H., Hickie I., Winship I., Flanagan J., Kollias J., Visvader J., Stone J., Burke J., Saunus J., Forbes J., French J., Tucker K., Wu K., Phillips K., Lipton L., Andrews L., Lobb L., Kentwell M., Spurdle M., Cummings M., Gleeson M., Jenkins M., Young M.A., Delatycki M., Wallis M., Burgess M., Price M., Brown M., Southey M., Bogwitz M., Field M., Friedlander M., Gattas M., Saleh M., Hayward N., Pachter N., Cohen P., Duijf P., James P., Simpson P., Fong P., Butow P., Williams R., Kefford R., Scott R., Milne R.L., Balleine R., Dawson S.-J., Lok S., O'Connell S., Greening S., Nightingale S., Edwards S., Fox S., McLachlan S.-A., Lakhani S., Antill Y., Aalfs C., Meijers-Heijboer H., van Engelen K., Gille H., Boere I., Collee M., van Deurzen C., Obdeijn I.-M., van den Ouweland A., Seynaeve C., Siesling S., Verloop J., van Asperen C., van Cronenburg T., Blok R., de Boer M., Garcia E.G., Adank M., Hogervorst F., Jenner D., van Leeuwen F., Rookus M., Russell N., Schmidt M., van den Belt-Dusebout S., Kets C., Mensenkamp A., de Bock T., van der Hout A., Mourits M., Oosterwijk J., Ausems M., Koudijs M., Baxter R., Yip D., Carpenter J., Davis A., Pathmanathan N., Graham D., Sachchithananthan M., Isaacs C., Iwasaki M., Jager A., Jakimovska M., Jakubowska A., Janavicius R., Jankowitz R.C., John E.M., Johnson N., Jones M.E., Jukkola-Vuorinen A., Jung A., Kaaks R., Kang D., Kapoor P.M., Karlan B.Y., Keeman R., Kerin M.J., Khusnutdinova E., Kiiski J.I., Kirk J., Kitahara C.M., Ko Y.-D., Konstantopoulou I., Kosma V.-M., Koutros S., Kubelka-Sabit K., Kwong A., Kyriacou K., Laitman Y., Lambrechts D., Lee E., Leslie G., Lester J., Lesueur F., Lindblom A., Lo W.-Y., Long J., Lophatananon A., Loud J.T., Lubinski J., MacInnis R.J., Maishman T., Makalic E., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Martinez M.E., Matsuo K., Maurer T., Mavroudis D., Mayes R., McGuffog L., McLean C., Meindl A., Miller A., Miller N., Montagna M., Moreno F., Muir K., Mulligan A.M., Munoz-Garzon V.M., Muranen T.A., Narod S.A., Nassir R., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Neven P., Nielsen F.C., Nikitina-Zake L., Norman A., Offit K., Olah E., Olopade O.I., Olsson H., Orr N., Osorio A., Pankratz V.S., Papp J., Park S.K., Park-Simon T.-W., Parsons M.T., Paul J., Pedersen I.S., Peissel B., Peshkin B., Peterlongo P., Peto J., Plaseska-Karanfilska D., Prajzendanc K., Prentice R., Presneau N., Prokofyeva D., Pujana M.A., Pylkas K., Radice P., Canzian F., Rantala J., Rau-Murthy R., Rennert G., Risch H.A., Robson M., Romero A., Rossing M., Saloustros E., Sanchez-Herrero E., Sandler D.P., Santamarina M., Sawyer E.J., Scheuner M.T., Schmidt D.F., Schmutzler R.K., Ramus S.J., Carroll J.S., Schneeweiss A., Schoemaker M.J., Schottker B., Schurmann P., Scott C., Scott R.J., Senter L., Shah M., Sharma P., Shen C.-Y., Shu X.-O., Singer C.F., Slavin T.P., Smichkoska S., Spinelli J.J., Spurdle A.B., Sutter C., Swerdlow A.J., Tamimi R.M., Tan Y.Y., Tapper W.J., Taylor J., Teixeira M.R., Tengstrom M., Teo S.H., Terry M.B., Teule A., Thomassen M., Thull D.L., Toland A.E., Tollenaar R.A.E.M., Tomlinson I., Torres D., Torres-Mejia G., Troester M.A., Truong T., Tung N., Tzardi M., Ulmer H.-U., Vachon C.M., van der Kolk L.E., van Rensburg E.J., Vega A., Viel A., Vijai J., Vogel M.J., Wang Q., Wappenschmidt B., Weinberg C.R., Weitzel J.N., Wendt C., Wildiers H., Winqvist R., Wolk A., Wu A.H., Yannoukakos D., Zhang Y., Zheng W., Hunter D., Pharoah P.D.P., Chang-Claude J., Garcia-Closas M., Schmidt M.K., Kristensen V.N., French J.D., Antoniou A.C., Chenevix-Trench G., Simard J., Easton D.F., Kraft P., Allen J., Harris M., Fachal L., Aschard H., Beesley J., Barnes D.R., Kar S., Pooley K.A., Dennis J., Michailidou K., Turman C., Soucy P., Lemacon A., Lush M., Tyrer J.P., Ghoussaini M., Marjaneh M.M., Jiang X., Agata S., Aittomaki K., Alonso M.R., Andrulis I.L., Anton-Culver H., Antonenkova N.N., Arason A., Arndt V., Aronson K.J., Arun B.K., Auber B., Auer P.L., Azzollini J., Balmana J., Barkardottir R.B., Barrowdale D., Beeghly-Fadiel A., Benitez J., Bermisheva M., Bialkowska K., Blanco A.M., Blomqvist C., Blot W., Bogdanova N.V., Bojesen S.E., Bolla M.K., Bonanni B., Borg A., Bosse K., Brauch H., Brenner H., Briceno I., Brock I.W., Brooks-Wilson A., Bruning T., Burwinkel B., Buys S.S., Cai Q., Caldes T., Caligo M.A., Camp N.J., Campbell I., Carter B.D., Castelao J.E., Chiquette J., Christiansen H., Chung W.K., Claes K.B.M., Clarke C.L., Mari V., Berthet P., Castera L., Vaur D., Lallaoui H., Bignon Y.-J., Uhrhammer N., Bonadona V., Lasset C., Revillion F., Vennin P., Muller D., Gomes D.M., Ingster O., Coupier I., Pujol P., Collonge-Rame M.-A., Mortemousque I., Bera O., Rose M., Baurand A., Bertolone G., Faivre L., Dreyfus H., Leroux D., Venat-Bouvet L., Bezieau S., Delnatte C., Chiesa J., Gilbert-Dussardier B., Gesta P., Prieur F.P., Bronner M., Sokolowska J., Coulet F., Boutry-Kryza N., Calender A., Giraud S., Leone M., Fert-Ferrer S., Stoppa-Lyonnet D., Jiao Y., Lesueur F.L., Mebirouk N., Barouk-Simonet E., Bubien V., Longy M., Sevenet N., Gladieff L., Toulas C., Reimineras A., Sobol H., Paillerets B.B.-D., Cabaret O., Caron O., Guillaud-Bataille M., Rouleau E., Belotti M., Buecher B., Caputo S., Colas C., Pauw A.D., Fourme E., Gauthier-Villars M., Golmard L., Moncoutier V., Saule C., Donaldson A., Murray A., Brady A., Brewer C., Pottinger C., Miller C., Gallagher D., Gregory H., Cook J., Eason J., Adlard J., Barwell J., Ong K.-R., Snape K., Walker L., Izatt L., Side L., Tischkowitz M., Rogers M.T., Porteous M.E., Ahmed M., Morrison P.J., Brennan P., Eeles R., Davidson R., Collee J.M., Cornelissen S., Couch F.J., Cox A., Cross S.S., Cybulski C., Czene K., Daly M.B., de la Hoya M., Devilee P., Diez O., Ding Y.C., Dite G.S., Domchek S.M., Dork T., dos-Santos-Silva I., Droit A., Dubois S., Dumont M., Duran M., Durcan L., Dwek M., Eccles D.M., Engel C., Eriksson M., Evans D.G., Fasching P.A., Fletcher O., Floris G., Flyger H., Foretova L., Foulkes W.D., Friedman E., Fritschi L., Frost D., Gabrielson M., Gago-Dominguez M., Gambino G., Ganz P.A., Gapstur S.M., Garber J., Garcia-Saenz J.A., Gaudet M.M., Georgoulias V., Giles G., Glendon G., Godwin A.K., Goldberg M.S., Goldgar D.E., Gonzalez-Neira A., Tibiletti M.G., Greene M.H., Grip M., Gronwald J., Grundy A., Guenel P., Hahnen E., Haiman C.A., Hakansson N., Hall P., Hamann U., Harrington P.A., Hartikainen J.M., Hartman M., He W., Healey C.S., Heemskerk-Gerritsen B.A.M., Heyworth J., Hillemanns P., Hogervorst F.B.L., Hollestelle A., Hooning M., Hopper J., Howell A., Huang G., Hulick P.J., Imyanitov E.N., Sexton A., Christian A., Trainer A., Spigelman A., Fellows A., Shelling A., Fazio A.D., Blackburn A., Crook A., Meiser B., Patterson B., Clarke C., Saunders C., Hunt C., Amor D., Marsh D., Edkins E., Salisbury E., Haan E., Neidermayr E., Macrea F., Farshid G., Lindeman G., Trench G., Mann G., Gill G., Thorne H., Hickie I., Winship I., Flanagan J., Kollias J., Visvader J., Stone J., Burke J., Saunus J., Forbes J., French J., Tucker K., Wu K., Phillips K., Lipton L., Andrews L., Lobb L., Kentwell M., Spurdle M., Cummings M., Gleeson M., Jenkins M., Young M.A., Delatycki M., Wallis M., Burgess M., Price M., Brown M., Southey M., Bogwitz M., Field M., Friedlander M., Gattas M., Saleh M., Hayward N., Pachter N., Cohen P., Duijf P., James P., Simpson P., Fong P., Butow P., Williams R., Kefford R., Scott R., Milne R.L., Balleine R., Dawson S.-J., Lok S., O'Connell S., Greening S., Nightingale S., Edwards S., Fox S., McLachlan S.-A., Lakhani S., Antill Y., Aalfs C., Meijers-Heijboer H., van Engelen K., Gille H., Boere I., Collee M., van Deurzen C., Obdeijn I.-M., van den Ouweland A., Seynaeve C., Siesling S., Verloop J., van Asperen C., van Cronenburg T., Blok R., de Boer M., Garcia E.G., Adank M., Hogervorst F., Jenner D., van Leeuwen F., Rookus M., Russell N., Schmidt M., van den Belt-Dusebout S., Kets C., Mensenkamp A., de Bock T., van der Hout A., Mourits M., Oosterwijk J., Ausems M., Koudijs M., Baxter R., Yip D., Carpenter J., Davis A., Pathmanathan N., Graham D., Sachchithananthan M., Isaacs C., Iwasaki M., Jager A., Jakimovska M., Jakubowska A., Janavicius R., Jankowitz R.C., John E.M., Johnson N., Jones M.E., Jukkola-Vuorinen A., Jung A., Kaaks R., Kang D., Kapoor P.M., Karlan B.Y., Keeman R., Kerin M.J., Khusnutdinova E., Kiiski J.I., Kirk J., Kitahara C.M., Ko Y.-D., Konstantopoulou I., Kosma V.-M., Koutros S., Kubelka-Sabit K., Kwong A., Kyriacou K., Laitman Y., Lambrechts D., Lee E., Leslie G., Lester J., Lesueur F., Lindblom A., Lo W.-Y., Long J., Lophatananon A., Loud J.T., Lubinski J., MacInnis R.J., Maishman T., Makalic E., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Martinez M.E., Matsuo K., Maurer T., Mavroudis D., Mayes R., McGuffog L., McLean C., Meindl A., Miller A., Miller N., Montagna M., Moreno F., Muir K., Mulligan A.M., Munoz-Garzon V.M., Muranen T.A., Narod S.A., Nassir R., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Neven P., Nielsen F.C., Nikitina-Zake L., Norman A., Offit K., Olah E., Olopade O.I., Olsson H., Orr N., Osorio A., Pankratz V.S., Papp J., Park S.K., Park-Simon T.-W., Parsons M.T., Paul J., Pedersen I.S., Peissel B., Peshkin B., Peterlongo P., Peto J., Plaseska-Karanfilska D., Prajzendanc K., Prentice R., Presneau N., Prokofyeva D., Pujana M.A., Pylkas K., Radice P., Canzian F., Rantala J., Rau-Murthy R., Rennert G., Risch H.A., Robson M., Romero A., Rossing M., Saloustros E., Sanchez-Herrero E., Sandler D.P., Santamarina M., Sawyer E.J., Scheuner M.T., Schmidt D.F., and Schmutzler R.K.

Abstract

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.Copyright © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

Published
2020

31. Gastric cancer during pregnancy: A report on 13 cases and review of the literature with focus on chemotherapy during pregnancy

Author

Maggen, C, Lok, C, Cardonick, E, Van Gerwen, M, Ottevanger, N, Boere, I, Koskas, M, Halaska, M, Fruscio, R, Mhallem, M, Witteveen, P, Van Calsteren, K, Amant, F, Maggen, Charlotte, Lok, Christianne, Cardonick, Elyce, Van Gerwen, Mathilde, Ottevanger, Nelleke, Boere, Ingrid, Koskas, Martin, Halaska, Michael J, Fruscio, Robert, Mhallem, Mina, Witteveen, Petronella, Van Calsteren, Kristel, Amant, Frédéric, Maggen, C, Lok, C, Cardonick, E, Van Gerwen, M, Ottevanger, N, Boere, I, Koskas, M, Halaska, M, Fruscio, R, Mhallem, M, Witteveen, P, Van Calsteren, K, Amant, F, Maggen, Charlotte, Lok, Christianne, Cardonick, Elyce, Van Gerwen, Mathilde, Ottevanger, Nelleke, Boere, Ingrid, Koskas, Martin, Halaska, Michael J, Fruscio, Robert, Mhallem, Mina, Witteveen, Petronella, Van Calsteren, Kristel, and Amant, Frédéric

Abstract

Introduction: Gastric cancer during pregnancy is extremely rare and data on optimal treatment and possible chemotherapeutic regimens are scarce. The aim of this study is to describe the obstetric and maternal outcome of women with gastric cancer during pregnancy and review the literature on antenatal chemotherapy for gastric cancer. Material and methods: Treatment and outcome of patients registered in the International Network on Cancer, Infertility and Pregnancy database with gastric cancer diagnosed during pregnancy were analyzed. Results: In total, 13 women with gastric cancer during pregnancy were registered between 2002 and 2018. Median gestational age at diagnosis was 22 weeks (range 6-30 weeks). Twelve women were diagnosed with advanced disease and died within 2 years after pregnancy, most within 6 months. In total, eight out of 10 live births ended in a preterm delivery because of preeclampsia, maternal deterioration, or therapy planning. Two out of six women who initiated chemotherapy during pregnancy delivered at term. Two neonates prenatally exposed to chemotherapy were growth restricted and one of them developed a systemic infection with brain abscess after preterm delivery for preeclampsia 2 weeks after chemotherapy. No malformations were reported. Conclusions: The prognosis of gastric cancer during pregnancy is poor, mainly due to advanced disease at diagnosis, emphasizing the need for early diagnosis. Antenatal chemotherapy can be considered to reach fetal maturity, taking possible complications such as growth restriction, preterm delivery, and hematopoietic suppression at birth into account.

Published
2020

33. Trebananib or placebo plus carboplatin and paclitaxel as first-line treatment for advanced ovarian cancer (TRINOVA-3/ENGOT-ov2/GOG-3001): a randomised, double-blind, phase 3 trial

Author

Vergote, I. Scambia, G. O'Malley, D.M. Van Calster, B. Park, S.-Y. del Campo, J.M. Meier, W. Bamias, A. Colombo, N. Wenham, R.M. Covens, A. Marth, C. Raza Mirza, M. Kroep, J.R. Ma, H. Pickett, C.A. Monk, B.J. Park, S.Y. Song, Y.S. Makarova, Y. Trinidad, J. Ngan, H.Y.S. Aravantinos, G. Nam, J.-H. Gorbunova, V. Krikunova, L. Bae, D.-S. Arija, J.A.A. Mirza, M.R. Zamagni, C. Papandreou, C. Raspagliesi, F. Lisyanskaya, A. Benzaquen, A.O. Tognon, G. Ortega, E. Herraez, A.C. Buscema, J. Green, A. Burger, R. Sakaeva, D. Sanchez, A.R. Ghamande, S. King, L. Petru, E. Peen, U. Takeuchi, S. Ushijima, K. Martin, A.G. Kamelle, S. Carney, M. Forget, F. Bentley, J. Sehouli, J. Zola, P. Kato, H. Fadeeva, N. Gotovkin, E. Vladimirov, V. Marin, M.R. Alia, E.G. Shahin, M. Bhoola, S. Tewari, K. Anderson, D. Honhon, B. Pelgrims, J.G. Oza, A. Jimenez, J.G.-D. Hansen, V. Benjamin, I. Renard, V. Van den Bulck, H. Haenle, C. Koumakis, G. Yokota, H. Popov, V. Bradley, W. Wenham, R. Reid, R. McNamara, D. Friedman, R. Barlin, J. Spirtos, N. Chapman, J. Sevelda, P. Huizing, M. Lamot, C. Goffin, F. Hondt, L.D. Covens, A. Spadafora, S. Rautenberg, B. Reimer, T. Möbus, V. Hilpert, F. Gropp-Meier, M. Savarese, A. Pignata, S. Verderame, F. Mizuno, M. Takano, H. Ottevanger, P. Velasco, A.P. Palacio-Vazquez, I. Law, A. McIntyre, K. Teneriello, M. Fields, A. Lentz, S. Street, D. Schwartz, B. Mannel, R. Lim, P. Pulaski, H. Janni, W. Zorr, A. Karck, U. Cheng, A.C.K. Sorio, R. Gridelli, C. Aoki, D. Oishi, T. Hirashima, Y. Boere, I. Ferrer, E.F. Braly, P. Wilks, S. Lee, C. Schilder, J. Veljovich, D. Secord, A. Davis, K. Rojas-Espaillat, L. Lele, S. DePasquale, S. Squatrito, R. Schauer, C. Dirix, L. Vuylsteke, P. Joosens, E. Provencher, D. Lueck, H.-J. Hein, A. Burges, A. Canzler, U. Park-Simon, T.-W. Griesinger, F. Gadducci, A. Alabiso, O. Okamoto, A. Sawasaki, T. Saito, T. Ibañez, A.H. Calomeni, C. Spillman, M. Choksi, J. Taylor, N. Muller, C. Moore, D. DiSilvestro, P. Cunningham, M. Rose, P. Oppelt, P. Verhoeven, D. Graas, M.-P. Ghatage, P. Tonkin, K. Kurzeder, C. Schnappauf, B. Müller, V. Schmalzrie, H. Kalofonos, H. Bruzzone, M. Kroep, J. Diaz, C.C. Garcia, J.M. Polo, S.H. Garrison, M. Rocconi, R. Andrews, S. Bristow, R. McHale, M. Basil, J. Houck III, W. Bell, M. Cosin, J. Modesitt, S. Kendrick, J. Wade III, J. Wong, C. Evans, A. Buekers, T. Vanderkwaak, T. Ferriss, J. Darus, C. DAndre, S. Higgins, R. Monk, B. Bakkum-Gamez, J. DeMars, L. Van Le, L. Puls, L. Trehan, S. LaPolla, J. Michelson, E.D. Merchant, J. Peterson, C. Reid, G. Seago, D. Zweizig, S. Gajewski, W. Panwalkar, A. Leikermoser, R. Bogner, G. Debruyne, P. D'hondt, R. Berteloot, P. Kerger, J. Biagi, J. Castonguay, V. Welch, S. Muhic, A. Heubner, M. Grischke, E.-M. Rack, B. Fleisch, M. Lordick, F. Pectasides, D. Ho, W.M. Selvaggi, L. Vasquez, F.M. Villanueva, W.O.B. Alavez, A.M. Kessels, L. Bertran, A.S. Fernandez, C.M. Fabregat, M.B. Del Prete, S. Elkas, J. Cecchi, G. Kumar, P. Huh, W. Messing, M. Karimi, M. Kelley, A. Edraki, B. Mutch, D. Leiserowitz, G. Anderson, J. Lentz, S. Chambers, S. Morris, R. Waggoner, S. Gordon, A. Method, M. Johnson, P. Lord, R. Drake, J. Sivarajan, K. Midathada, M. Rice, K. Wadsworth, T. Pavelka, J. Edwards, R. Miller, D.S. Ford, P.L. Hurteau, J. Bender, D. Schimp, V. Creasman, W. Lerner, R. Chamberlain, D. Kueck, A. McDonald, J. Malad, S. Robinson-Bennett, B. Davidson, S. Krivak, T. Lestingi, T. Arango, H. Berard, P. Finkelstein, K. Gaur, R. Krasner, C. Ueland, F. Talmage, L. Yamada, S. Sutton, G. Potkul, R. Prasad-Hayes, M. Osborne, J. Celano, P. Thigpen, J. Sharma, S. Schilder, R. Tammela, J. Kemeny, M. Brown, A. Eisenhauer, E. Williams, J. Rowland, K. Nahum, K. Burke, J. Dar, Z. Fleming, N. Gibb, R. Guirguis, A. Herzog, T. John, V. Kumar, S. Kamat, A. Kassar, M. Leitao, M. Levine, L. Mendez, L. Patel, D. Berry, E. Warshal, D. Wolf, J. Zarwan, C. Collins, Y. Spitzer, G. Miller, B. Einstein, M. TRINOVA-3/ENGOT-ov2/GOG-3001 investigators

Abstract

Background: Angiopoietin 1 and 2 regulate angiogenesis and vascular remodelling by interacting with the tyrosine kinase receptor Tie2, and inhibition of angiogenesis has shown promise in the treatment of ovarian cancer. We aimed to assess whether trebananib, a peptibody that inhibits binding of angiopoietin 1 and 2 to Tie2, improved progression-free survival when added to carboplatin and paclitaxel as first-line therapy in advanced epithelial ovarian, primary fallopian tube, or peritoneal cancer in a phase 3 clinical trial. Methods: TRINOVA-3, a multicentre, multinational, phase 3, double-blind study, was done at 206 investigational sites (hospitals and cancer centres)in 14 countries. Eligible patients were aged 18 years or older with biopsy-confirmed International Federation of Gynecology and Obstetrics (FIGO)stage III to IV epithelial ovarian, primary peritoneal, or fallopian tube cancers, and an ECOG performance status of 0 or 1. Eligible patients were randomly assigned (2:1)using a permuted block method (block size of six patients)to receive six cycles of paclitaxel (175 mg/m2)and carboplatin (area under the serum concentration-time curve 5 or 6)every 3 weeks, plus weekly intravenous trebananib 15 mg/kg or placebo. Maintenance therapy with trebananib or placebo continued for up to 18 additional months. The primary endpoint was progression-free survival, as assessed by the investigators, in the intention-to-treat population. Safety analyses included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01493505, and is complete. Findings: Between Jan 30, 2012, and Feb 25, 2014, 1164 patients were screened and 1015 eligible patients were randomly allocated to treatment (678 to trebananib and 337 to placebo). After a median follow-up of 27·4 months (IQR 17·7–34·2), 626 patients had progression-free survival events (405 [60%]of 678 in the trebananib group and 221 [66%]of 337 in the placebo group). Median progression-free survival did not differ between the trebananib group (15·9 months [15·0–17·6])and the placebo group (15·0 months [12·6–16·1])groups (hazard ratio 0·93 [95% CI 0·79–1·09]; p=0·36). 512 (76%)of 675 patients in the trebananib group and 237 (71%)of 336 in the placebo group had grade 3 or worse treatment-emergent adverse events; of which the most common events were neutropenia (trebananib 238 [35%]vs placebo 126 [38%])anaemia (76 [11%]vs 40 [12%]), and leucopenia (81 [12%]vs 35 [10%]). 269 (40%)patients in the trebananib group and 104 (31%)in the placebo group had serious adverse events. Two fatal adverse events in the trebananib group were considered related to trebananib, paclitaxel, and carboplatin (lung infection and neutropenic colitis); two were considered to be related to paclitaxel and carboplatin (general physical health deterioration and platelet count decreased). No treatment-related fatal adverse events occurred in the placebo group. Interpretation: Trebananib plus carboplatin and paclitaxel did not improve progression-free survival as first-line treatment for advanced ovarian cancer. The combination of trebananib plus carboplatin and paclitaxel did not produce new safety signals. These results show that trebananib in combination with carboplatin and paclitaxel is minimally effective in this patient population. Funding: Amgen. © 2019 Elsevier Ltd

Published
2019

34. Gynecologic cancers in pregnancy: Guidelines based on a third international consensus meeting

Author

Amant, F, Berveiller, P, Boere, I, Cardonick, E, Fruscio, R, Fumagalli, M, Halaska, M, Hasenburg, A, Johansson, A, Lambertini, M, Lok, C, Maggen, C, Morice, P, Peccatori, F, Poortmans, P, Van Calsteren, K, Vandenbroucke, T, van Gerwen, M, van den Heuvel-Eibrink, M, Zagouri, F, Zapardiel, I, Amant, Frédéric, Berveiller, Paul, Boere, Ingrid, Cardonick, Elyce, Fruscio, Robert, Fumagalli, Monica, Halaska, Michael J, Hasenburg, Annette, Johansson, Anna L V, Lambertini, Matteo, Lok, Christianne, Maggen, Charlotte, Morice, Philippe, Peccatori, Fedro, Poortmans, Philip, Van Calsteren, Kristel, Vandenbroucke, Tineke, van Gerwen, Mathilde, van den Heuvel-Eibrink, Marry, Zagouri, Flora, Zapardiel, Ignacio, Amant, F, Berveiller, P, Boere, I, Cardonick, E, Fruscio, R, Fumagalli, M, Halaska, M, Hasenburg, A, Johansson, A, Lambertini, M, Lok, C, Maggen, C, Morice, P, Peccatori, F, Poortmans, P, Van Calsteren, K, Vandenbroucke, T, van Gerwen, M, van den Heuvel-Eibrink, M, Zagouri, F, Zapardiel, I, Amant, Frédéric, Berveiller, Paul, Boere, Ingrid, Cardonick, Elyce, Fruscio, Robert, Fumagalli, Monica, Halaska, Michael J, Hasenburg, Annette, Johansson, Anna L V, Lambertini, Matteo, Lok, Christianne, Maggen, Charlotte, Morice, Philippe, Peccatori, Fedro, Poortmans, Philip, Van Calsteren, Kristel, Vandenbroucke, Tineke, van Gerwen, Mathilde, van den Heuvel-Eibrink, Marry, Zagouri, Flora, and Zapardiel, Ignacio

Abstract

We aimed to provide comprehensive protocols and promote effective management of pregnant women with gynecological cancers. New insights and more experience have been gained since the previous guidelines were published in 2014. Members of the International Network on Cancer, Infertility and Pregnancy (INCIP), in collaboration with other international experts, reviewed existing literature on their respective areas of expertise. Summaries were subsequently merged into a manuscript that served as a basis for discussion during the consensus meeting. Treatment of gynecological cancers during pregnancy is attainable if management is achieved by collaboration of a multidisciplinary team of health care providers. This allows further optimization of maternal treatment, while considering fetal development and providing psychological support and long-term follow-up of the infants. Nonionizing imaging procedures are preferred diagnostic procedures, but limited ionizing imaging methods can be allowed if indispensable for treatment plans. In contrast to other cancers, standard surgery for gynecological cancers often needs to be adapted according to cancer type and gestational age. Most standard regimens of chemotherapy can be administered after 14 weeks gestational age but are not recommended beyond 35 weeks. C-section is recommended for most cervical and vulvar cancers, whereas vaginal delivery is allowed in most ovarian cancers. Breast-feeding should be avoided with ongoing chemotherapeutic, endocrine or targeted treatment. More studies that focus on the long-term toxic effects of gynecologic cancer treatments are needed to provide a full understanding of their fetal impact. In particular, data on targeted therapies that are becoming standard of care in certain gynecological malignancies is still limited. Furthermore, more studies aimed at the definition of the exact prognosis of patients after antenatal cancer treatment are warranted. Participation in existing registries (www.c

Published
2019

35. A rare cause of dysregulated metabolic syndrome: cortisol-producing adrenocortical carcinoma

Author

Saes, L, Boere, I A, Hofland, J, Mulder, M, Feelders, R A, Medical Oncology, and Internal Medicine

Abstract

Adrenocortical carcinoma is a rare and highly malignant disease which can cause hypercortisolism leading to dysregulation of blood pressure and glucose levels. Most patients present with advanced disease. We describe the classic presentation of a functional adrenocortical carcinoma in a patient with metabolic syndrome.

Published
2018

36. Oncological management and obstetric and neonatal outcomes for women diagnosed with cancer during pregnancy: a 20-year international cohort study of 1170 patients

Author

de Haan, J, Verheecke, M, Van Calsteren, K, Van Calster, B, Shmakov, R, Mhallem Gziri, M, Halaska, M, Fruscio, R, Lok, C, Boere, I, Zola, P, Ottevanger, P, de Groot, C, Peccatori, F, Dahl Steffensen, K, Cardonick, E, Polushkina, E, Rob, L, Ceppi, L, Sukhikh, G, Han, S, Amant, F, de Haan, Jorine, Verheecke, Magali, Van Calsteren, Kristel, Van Calster, Ben, Shmakov, Roman G, Mhallem Gziri, Mina, Halaska, Michael J, Fruscio, Robert, Lok, Christianne A R, Boere, Ingrid A, Zola, Paolo, Ottevanger, Petronella B, de Groot, Christianne J M, Peccatori, Fedro A, Dahl Steffensen, Karina, Cardonick, Elyce H, Polushkina, Evgeniya, Rob, Lukas, Ceppi, Lorenzo, Sukhikh, Gennady T, Han, Sileny N, Amant, Frédéric, de Haan, J, Verheecke, M, Van Calsteren, K, Van Calster, B, Shmakov, R, Mhallem Gziri, M, Halaska, M, Fruscio, R, Lok, C, Boere, I, Zola, P, Ottevanger, P, de Groot, C, Peccatori, F, Dahl Steffensen, K, Cardonick, E, Polushkina, E, Rob, L, Ceppi, L, Sukhikh, G, Han, S, Amant, F, de Haan, Jorine, Verheecke, Magali, Van Calsteren, Kristel, Van Calster, Ben, Shmakov, Roman G, Mhallem Gziri, Mina, Halaska, Michael J, Fruscio, Robert, Lok, Christianne A R, Boere, Ingrid A, Zola, Paolo, Ottevanger, Petronella B, de Groot, Christianne J M, Peccatori, Fedro A, Dahl Steffensen, Karina, Cardonick, Elyce H, Polushkina, Evgeniya, Rob, Lukas, Ceppi, Lorenzo, Sukhikh, Gennady T, Han, Sileny N, and Amant, Frédéric

Abstract

Background: Awareness is growing that cancer can be treated during pregnancy, but the effect of this change on maternal and neonatal outcomes is unknown. The International Network on Cancer, Infertility and Pregnancy (INCIP) registers the incidence and maternal, obstetric, oncological, and neonatal outcomes of cancer occurring during pregnancy. We aimed to describe the oncological management and obstetric and neonatal outcomes of patients registered in INCIP and treated in the past 20 years, and assess associations between cancer type or treatment modality and obstetric and neonatal outcomes. Methods: This descriptive cohort study included pregnant patients with cancer registered from all 37 centres (from 16 countries) participating in the INCIP registry. Oncological, obstetric, and neonatal outcome data of consecutive patients diagnosed with primary invasive cancer during pregnancy between Jan 1, 1996, and Nov 1, 2016, were retrospectively and prospectively collected. We analysed changes over time in categorical patient characteristics, outcomes, and treatment methods with log-binomial regression. We used multiple logistic regression to analyse preterm, prelabour rupture of membranes (PPROM) or preterm contractions, small for gestational age, and admission to the neonatal intensive care unit (NICU). The INCIP registry study is registered with ClinicalTrials.gov, number NCT00330447, and is ongoing. Findings: 1170 patients were included in the analysis and 779 (67%) received treatment during pregnancy. Breast cancer was the most common malignant disease (462 [39%]). Every 5 years, the likelihood of receiving treatment during pregnancy increased (relative risk [RR] 1·10, 95% CI 1·05–1·15), mainly related to an increase of chemotherapeutic treatment (1·31, 1·20–1·43). Overall, 955 (88%) of 1089 singleton pregnancies ended in a livebirth, of which 430 (48%) of 887 pregnancies ended preterm. Each 5 years, we observed more livebirths (RR 1·04, 95% CI 1·01–1·06) and fewer

Published
2018

37. Corrigendum to ‘Genetic and microscopic assessment of the human chemotherapy-exposed placenta reveals possible pathways contributive to fetal growth restriction’[YPLAC 64C (2018) 61–70]

Author

Verheecke, M., primary, Cortès Calabuig, A., additional, Finalet Ferreiro, J., additional, Brys, V., additional, Van Bree, R., additional, Verbist, G., additional, Everaert, T., additional, Leemans, L., additional, Gziri, M.M., additional, Boere, I., additional, Halaska, M.J., additional, Van Houdt, J., additional, Amant, F., additional, and Van Calsteren, K., additional

Published
2018
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38. Genetic and microscopic assessment of the human chemotherapy-exposed placenta reveals possible pathways contributive to fetal growth restriction

Author

Verheecke, M., primary, Cortès Calabuig, A., additional, Finalet Ferreiro, J., additional, Brys, V., additional, Van Bree, R., additional, Verbist, G., additional, Everaert, T., additional, Leemans, L., additional, Gziri, M.M., additional, Boere, I., additional, Halaska, M.J., additional, Vanhoudt, J., additional, Amant, F., additional, and Van Calsteren, K., additional

Published
2018
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39. Melanoma during pregnancy: A report of 60 pregnancies complicated by melanoma

Author

De Haan, J, Lok, C, De Groot, C, Crijns, M, Van Calsteren, K, Dahl Steffensen, K, Halaska, M, Altintas, S, Boere, I, Fruscio, R, Kolawa, W, Witteveen, P, Amant, F, Amant, F., FRUSCIO, ROBERT, De Haan, J, Lok, C, De Groot, C, Crijns, M, Van Calsteren, K, Dahl Steffensen, K, Halaska, M, Altintas, S, Boere, I, Fruscio, R, Kolawa, W, Witteveen, P, Amant, F, Amant, F., and FRUSCIO, ROBERT

Abstract

The management of melanoma during pregnancy is challenging as maternal benefits and fetal risks need to be balanced. Here, we present an overview of the incidence, the demographic and clinical characteristics and the treatment modalities used. After analysis of obstetric, fetal and maternal outcome, recommendations for clinical practice are provided. From the 'International Network on Cancer, Infertility and Pregnancy' database, pregnant patients with melanoma were identified and analysed. Sixty pregnancies were eligible for analysis. Fifty percent of the patients presented with advanced melanoma during pregnancy (14 stage III and 16 stage IV), and 27% were diagnosed with recurrent melanoma. Surgery was the main therapeutic strategy during pregnancy. Only four patients with advanced melanoma were treated during pregnancy with systemic therapy (n=1) or radiotherapy (n=3). Premature delivery was observed in 18% of the ongoing pregnancies, all which were induced and 78% of which involved patients with advanced melanoma. Thirty-nine percent of the patients died within 5 years; all had been diagnosed with stage III or IV disease during pregnancy. Melanoma can present in a more advanced stage during pregnancy. New systemic therapies may be beneficial for patients with metastatic melanoma but may not be pregnancy compatible. In these patients, preterm induction of labour need to be discussed, despite the short-term and long-term negative effects on the child.

Published
2017

40. Pediatric Outcome After Maternal Cancer Diagnosed During Pregnancy

Author

Amant, F, Vandenbroucke, T, Verheecke, M, Fumagalli, M, Halaska, M, Boere, I, Han, S, Gziri, M, Peccatori, F, Rob, L, Lok, C, Witteveen, P, Voigt, J, Naulaers, G, Vallaeys, L, Van den Heuvel, F, Lagae, L, Mertens, L, Claes, L, Van Calsteren, K, Pregn, I, Medical Oncology, and Other departments

Subjects
Male, Pediatrics, medicine.medical_treatment, Growth, Bayley Scales of Infant Development, 0302 clinical medicine, Child Development, Cognition, Pregnancy, Birth Weight, 030212 general & internal medicine, Non-U.S. Gov't, Obstetrics, Research Support, Non-U.S. Gov't, Gestational age, Obstetrics and Gynecology, Heart, General Medicine, Multicenter Study, 030220 oncology & carcinogenesis, Child, Preschool, Prenatal Exposure Delayed Effects, Female, medicine.symptom, Pregnancy Complications, Neoplastic, Infant, Premature, medicine.medical_specialty, Birth weight, Antineoplastic Agents, Gestational Age, Research Support, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, Journal Article, Humans, Comparative Study, Chemotherapy, Radiotherapy, business.industry, Case-control study, Infant, Newborn, Cancer, Infant, Infant, Low Birth Weight, medicine.disease, Radiation therapy, Low birth weight, Case-Control Studies, General health, Health questionnaire, business
Abstract

BACKGROUND Data on the long-term outcome of children who are exposed to maternal cancer with or without treatment during pregnancy are lacking. METHODS In this multicenter case–control study, we compared children whose mothers received a diagnosis of cancer during the pregnancy with matched children of women without a cancer diagnosis. We used a health questionnaire and medical files to collect data regarding neonatal and general health. All children were prospectively assessed (by means of a neurologic examination and the Bayley Scales of Infant Development) at 18 months, 36 months, or both. A cardiac assessment was performed at 36 months. RESULTS A total of 129 children (median age, 22 months; range, 12 to 42) were included in the group whose mother had cancer (prenatal-exposure group) with a matching number in the control group. During pregnancy, 96 children (74.4%) were exposed to chemotherapy (alone or in combination with other treatments), 11 (8.5%) to radiotherapy (alone or in combination), 13 (10.1%) to surgery alone, 2 (1.6%) to other drug treatments, and 14 (10.9%) to no treatment. Birth weight was below the 10th percentile in 28 of 127 children (22.0%) in the prenatal-exposure group and in 19 of 125 children (15.2%) in the control group (P=0.16). There was no significant between-group difference in cognitive development on the basis of the Bayley score (P=0.08) or in subgroup analyses. The gestational age at birth was correlated with the cognitive outcome in the two study groups. Cardiologic evaluation among 47 children at 36 months of age showed normal cardiac findings. CONCLUSIONS Prenatal exposure to maternal cancer with or without treatment did not impair the cognitive, cardiac, or general development of children in early childhood. Prematurity was correlated with a worse cognitive outcome, but this effect was independent of cancer treatment. (Funded by Research Foundation–Flanders and others; ClinicalTrials.gov number, NCT00330447. opens in new tab.)

Published
2016

41. Pediatric Outcome after Maternal Cancer Diagnosed during Pregnancy

Author

Amant, F., Vandenbroucke, T., Verheecke, M., Fumagalli, M., Halaska, M. J., Boere, I., Han, S., Gziri, M. M., Peccatori, F., Rob, L., Lok, C., Witteveen, P., Voigt, J-U, Naulaers, G., Vallaeys, L., Van den Heuvel, F., Lagae, L., Mertens, L., Claes, L., Van Calsteren, K., Amant, F., Vandenbroucke, T., Verheecke, M., Fumagalli, M., Halaska, M. J., Boere, I., Han, S., Gziri, M. M., Peccatori, F., Rob, L., Lok, C., Witteveen, P., Voigt, J-U, Naulaers, G., Vallaeys, L., Van den Heuvel, F., Lagae, L., Mertens, L., Claes, L., and Van Calsteren, K.

Published
2015

42. Pediatric Outcome after Maternal Cancer Diagnosed during Pregnancy

Author

Divisie Beeld & Oncologie, Cancer, MS MOD, Amant, F., Vandenbroucke, T., Verheecke, M., Fumagalli, M., Halaska, M. J., Boere, I., Han, S., Gziri, M. M., Peccatori, F., Rob, L., Lok, C., Witteveen, P., Voigt, J-U, Naulaers, G., Vallaeys, L., Van den Heuvel, F., Lagae, L., Mertens, L., Claes, L., Van Calsteren, K., Divisie Beeld & Oncologie, Cancer, MS MOD, Amant, F., Vandenbroucke, T., Verheecke, M., Fumagalli, M., Halaska, M. J., Boere, I., Han, S., Gziri, M. M., Peccatori, F., Rob, L., Lok, C., Witteveen, P., Voigt, J-U, Naulaers, G., Vallaeys, L., Van den Heuvel, F., Lagae, L., Mertens, L., Claes, L., and Van Calsteren, K.

Published
2015

43. ASO Visual Abstract: The Role of Adjuvant Use of the PlasmaJet® Device During Cytoreductive Surgery for Advanced-Stage Ovarian Cancer—Results of the PlaComOv-Study, a Randomized, Controlled Trial in the Netherlands.

Author

Nieuwenhuyzen-de Boer, G. M., Hofhuis, W., Reesink-Peters, N., Willemsen, S., Boere, I. A., Schoots, I. G., Piek, J. M. J., Hofman, L. N., Beltman, J. J., van Driel, W. J., Werner, H. M. J., Baalbergen, A., van Haaften-de Jong, A. M. L. D., Dorman, M., Haans, L., Nedelcu, I., Ewing-Graham, P. C., and van Beekhuizen, H. J.

Published
2022
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50. Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer.

Author

Mirza, M. R., Chase, D. M., Slomovitz, B. M., Christensen, R. dePont, Novák, Z., Black, D., Gilbert, L., Sharma, S., Valabrega, G., Landrum, L. M., Hanker, L. C., Stuckey, A., Boere, I., Gold, M. A., Auranen, A., Pothuri, B., Cibula, D., McCourt, C., Raspagliesi, F., and Shahin, M. S.

Subjects
*PROGRAMMED cell death 1 receptors, *ENDOMETRIAL cancer, *IMMUNE checkpoint inhibitors
Abstract

BACKGROUND Dostarlimab is an immune-checkpoint inhibitor that targets the programmed cell death 1 receptor. The combination of chemotherapy and immunotherapy may have synergistic effects in the treatment of endometrial cancer. METHODS We conducted a phase 3, global, double-blind, randomized, placebo-controlled trial. Eligible patients with primary advanced stage III or IV or first recurrent endometrial cancer were randomly assigned in a 1:1 ratio to receive either dostarlimab (500 mg) or placebo, plus carboplatin (area under the concentration-time curve, 5 mg per milliliter per minute) and paclitaxel (175 mg per square meter of body-surface area), every 3 weeks (six cycles), followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. The primary end points were progression-free survival as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, and overall survival. Safety was also assessed. RESULTS Of the 494 patients who underwent randomization, 118 (23.9°/o) had mismatch repair-deficient (dMMR), microsatellite instability-high (MSI-H) tumors. In the dMMR-MSI-H population, estimated progression-free survival at 24 months was 61.4% (95% confidence interval [CI], 46.3 to 73.4) in the dostarlimab group and 15.7°/o (95°/o CI, 7.2 to 27.0) in the placebo group (hazard ratio for progression or death, 0.28; 95% CI, 0.16 to 0.50; P<0.001). In the overall population, progression-free survival at 24 months was 36.1% (95% CI, 29.3 to 42.9) in the dostarlimab group and 18.1% (95% CI, 13.0 to 23.9) in the placebo group (hazard ratio, 0.64; 95% CI, 0.51 to 0.80; PcO.001). Overall survival at 24 months was 71.3% (95% CI, 64.5 to 77.1) with dostarlimab and 56.0% (95% CI, 48.9 to 62.5) with placebo (hazard ratio for death, 0.64; 95% CI, 0.46 to 0.87). The most common adverse events that occurred or worsened during treatment were nausea (53.9% of the patients in the dostarlimab group and 45.9% of those in the placebo group), alopecia (53.5% and 50.0%), and fatigue (51.9% and 54.5%). Severe and serious adverse events were more frequent in the dostarlimab group than in the placebo group. CONCLUSIONS Dostarlimab plus carboplatin-paclitaxel significantly increased progression-free survival among patients with primary advanced or recurrent endometrial cancer, with a substantial benefit in the dMMR-MSI-H population. (Funded by GSK; RUBY ClinicalTrials.gov number, NCT03981796.). [ABSTRACT FROM AUTHOR]

Published
2023
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