Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-535
Changcun Pan, Tian Li, Liping Jiang, Hai Yan, Liwei Zhang
Background: Brainstem gliomas are heterogeneous diseases, many of which are difficult to safely resect and have limited treatment options due to their location. These constraints pose challenges to biopsy, which limits the use of routine molecular profiling and identification of personalized therapies. Here, we explored the potential of sequencing of circulating tumor DNA (ctDNA) isolated from the cerebrospinal fluid (CSF) of brainstem glioma patients as a less invasive approach for tumor molecular profiling. Cohorts and Methods:A retrospective analysis of brainstem glioma patients with CSF and tumor tissue available was completed. CSF was obtained from patients either intraoperatively (91.2%, 52/57), from ventricular-peritoneal shunt (3.5%, 2/57), or by lumbar puncture (5.3%, 3/57), all prior to surgical manipulation of the tumor. Deep panel sequencing of glioma-associated genes was performed on CSF-derived ctDNA and, where available, matched blood and tumor DNA from 57 patients, including nine medullary and 23 diffuse intrinsic pontine gliomas (DIPG). In addition, we have now completed a prospective study, in which 12 preoperative CSF samples were obtained from lumbar puncture and used to isolate and characterize ctDNA. Results: In the retrospective analysis, at least one tumor-specific mutation was detected in over 82.5% of CSF ctDNA samples (47/57). In cases with primary tumors harboring at least one mutation, alterations were identified in the CSF ctDNA of 97.3% of cases (36/37). In over 83% (31/37) of cases, all primary tumor alterations were detected in the CSF, and in 91.9% (34/37) of cases, at least half of the alterations were identified. Among ten patients found to have primary tumors negative for mutations, 30% (3/10) had detectable somatic alterations in the CSF. Finally, mutation detection using plasma ctDNA was less sensitive than sequencing the CSF ctDNA (38% vs. 100%, respectively). In the prospective study, at least one tumor-specific mutation was detected in over 83.3% of CSF ctDNA samples (10/12), which is consistent with the data from the retrospective cohort. Conclusion: Our study indicates that deep sequencing of CSF ctDNA is a reliable technique for detecting tumor-specific alterations in brainstem tumors. This approach may offer an alternative approach to stereotactic biopsy for molecular profiling of brainstem tumors. Citation Format: Changcun Pan, Tian Li, Liping Jiang, Hai Yan, Liwei Zhang. Molecular profiling of brainstem gliomas by liquid biopsy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 535.
{"title":"Abstract 535: Molecular profiling of brainstem gliomas by liquid biopsy","authors":"Changcun Pan, Tian Li, Liping Jiang, Hai Yan, Liwei Zhang","doi":"10.1158/1538-7445.AM2021-535","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-535","url":null,"abstract":"Background: Brainstem gliomas are heterogeneous diseases, many of which are difficult to safely resect and have limited treatment options due to their location. These constraints pose challenges to biopsy, which limits the use of routine molecular profiling and identification of personalized therapies. Here, we explored the potential of sequencing of circulating tumor DNA (ctDNA) isolated from the cerebrospinal fluid (CSF) of brainstem glioma patients as a less invasive approach for tumor molecular profiling. Cohorts and Methods:A retrospective analysis of brainstem glioma patients with CSF and tumor tissue available was completed. CSF was obtained from patients either intraoperatively (91.2%, 52/57), from ventricular-peritoneal shunt (3.5%, 2/57), or by lumbar puncture (5.3%, 3/57), all prior to surgical manipulation of the tumor. Deep panel sequencing of glioma-associated genes was performed on CSF-derived ctDNA and, where available, matched blood and tumor DNA from 57 patients, including nine medullary and 23 diffuse intrinsic pontine gliomas (DIPG). In addition, we have now completed a prospective study, in which 12 preoperative CSF samples were obtained from lumbar puncture and used to isolate and characterize ctDNA. Results: In the retrospective analysis, at least one tumor-specific mutation was detected in over 82.5% of CSF ctDNA samples (47/57). In cases with primary tumors harboring at least one mutation, alterations were identified in the CSF ctDNA of 97.3% of cases (36/37). In over 83% (31/37) of cases, all primary tumor alterations were detected in the CSF, and in 91.9% (34/37) of cases, at least half of the alterations were identified. Among ten patients found to have primary tumors negative for mutations, 30% (3/10) had detectable somatic alterations in the CSF. Finally, mutation detection using plasma ctDNA was less sensitive than sequencing the CSF ctDNA (38% vs. 100%, respectively). In the prospective study, at least one tumor-specific mutation was detected in over 83.3% of CSF ctDNA samples (10/12), which is consistent with the data from the retrospective cohort. Conclusion: Our study indicates that deep sequencing of CSF ctDNA is a reliable technique for detecting tumor-specific alterations in brainstem tumors. This approach may offer an alternative approach to stereotactic biopsy for molecular profiling of brainstem tumors. Citation Format: Changcun Pan, Tian Li, Liping Jiang, Hai Yan, Liwei Zhang. Molecular profiling of brainstem gliomas by liquid biopsy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 535.","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"40 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73761321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-LB041
F. Janku, R. Abdul-Karim, A. Azad, J. Bendell, G. Falchook, H. Gan, T. Tan, Judy S. Wang, C. Chee, Lina Ma, J. Mooney, N. Marina, G. Abbadessa, M. Milla, T. Meniawy
THOR-707 (SAR444245) is a recombinant human IL-2 molecule that includes a PEG moiety irreversibly bound to a novel amino acid via click chemistry to block the alpha-binding domain while retaining near-native affinity for the beta/gamma subunits. In animal models, THOR-707 improved the anti-tumor benefits of aldesleukin, but without its severe side effects, both as single agent and combined with anti-PD1. Here we report safety, PK/PD, and preliminary anti-tumor activity for THOR-707 as monotherapy and combined with pembrolizumab in the ongoing HAMMER Phase 1/2 trial. THOR-707 was administered via IV infusion as monotherapy Q2W (Cohort A), Q3W (Cohort B), or combined with pembrolizumab 200 mg IV Q3W (Cohort C); escalation follows a 3 + 3 schema to identify the maximum tolerated dose and/or the recommended Phase 2 dose. As of 16 November 2020, 28 pts were enrolled: ECOG 0-1; median age 62 (37-76) yrs; median lines of prior therapies were 3 (1-9; 11 pts had prior anti-PD1). Most common tumor types: colorectal (n=5), melanoma (n=4). Cohort enrollment was A: 8 µg/kg (n=4); B: 8 µg/kg (n=4), 16 µg/kg (n=6), 24 µg/kg (n=7); C: 8 µg/kg (n=4), 16 µg/kg (n=3). No dose-limiting toxicity (DLT) or vascular leak syndrome (VLS) was observed. Most common treatment-emergent adverse events (TEAEs) were flu-like symptoms (46.4%), fever (46.4%), vomiting/nausea (35.7%), chills (32.1%), following the first dose and resolved with standard supportive care. No cumulative toxicity, end organ toxicity, QTc prolongation, or other cardiac toxicity was observed. Grade (G) 3-4 related toxicities in B: 1 G3 rash (8 µg/kg); 1 G4 AST increase, 2 G3 increase in AST/ALT & 1 G4 decrease in lymphocytes (16 µg/kg); 2 G4 decrease in lymphocytes, 1 G4 CRS with G3 hypertension (led to discontinuation), and 1 G3 acute kidney injury (24 µg/kg); C: 1 G3 & 1G4 decrease in lymphocytes (16 µg/kg). CD8 cells (effector & memory) and NK cells increased in Cycle 1 by a median (range) respectively of 3.1 (1.04 - 5.91) and 7.93 (1.71 - 26.85) fold and were sustained until next cycle. There was no meaningful increase in CD4 Tregs or eosinophil counts (a marker of potential VLS), 1.89 (0.86- 5.36) and 1.77 (0.47- 3.65) fold. No anti-drug antibodies (IL-2 or PEG) and no meaningful IL-5 elevations were found. One IL-6 increase at 24 hrs (to 1,000 pg/mL) was observed. Half-life is ~ 10 hours. Three pts have confirmed partial responses: 1 PD-1-naive basal cell carcinoma; 1 head & neck squamous cell carcinoma with progression after a prior anti-PD-1, ongoing for 9+ mos in C (8 µg/kg); 1 squamous cellular carcinoma of unknown origin, unresponsive to prior anti-PD-1, ongoing for 3+ mos in B (24 µg/kg). Two pts had stable disease for 9 and 6 mos, respectively, with pancreatic (in A, 8 µg/kg) and prostate cancer (in B, 16 µg/kg); 11 pts remained on treatment for ≥5 cycles. Preliminary encouraging results with THOR-707 monotherapy and in combination with pembrolizumab support IL-2 not-alpha preferential activit
{"title":"Abstract LB041: THOR-707 (SAR444245), a novel not-alpha IL-2 as monotherapy and in combination with pembrolizumab in advanced/metastatic solid tumors: Interim results from HAMMER, an open-label, multicenter phase 1/2 Study","authors":"F. Janku, R. Abdul-Karim, A. Azad, J. Bendell, G. Falchook, H. Gan, T. Tan, Judy S. Wang, C. Chee, Lina Ma, J. Mooney, N. Marina, G. Abbadessa, M. Milla, T. Meniawy","doi":"10.1158/1538-7445.AM2021-LB041","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-LB041","url":null,"abstract":"THOR-707 (SAR444245) is a recombinant human IL-2 molecule that includes a PEG moiety irreversibly bound to a novel amino acid via click chemistry to block the alpha-binding domain while retaining near-native affinity for the beta/gamma subunits. In animal models, THOR-707 improved the anti-tumor benefits of aldesleukin, but without its severe side effects, both as single agent and combined with anti-PD1. Here we report safety, PK/PD, and preliminary anti-tumor activity for THOR-707 as monotherapy and combined with pembrolizumab in the ongoing HAMMER Phase 1/2 trial. THOR-707 was administered via IV infusion as monotherapy Q2W (Cohort A), Q3W (Cohort B), or combined with pembrolizumab 200 mg IV Q3W (Cohort C); escalation follows a 3 + 3 schema to identify the maximum tolerated dose and/or the recommended Phase 2 dose. As of 16 November 2020, 28 pts were enrolled: ECOG 0-1; median age 62 (37-76) yrs; median lines of prior therapies were 3 (1-9; 11 pts had prior anti-PD1). Most common tumor types: colorectal (n=5), melanoma (n=4). Cohort enrollment was A: 8 µg/kg (n=4); B: 8 µg/kg (n=4), 16 µg/kg (n=6), 24 µg/kg (n=7); C: 8 µg/kg (n=4), 16 µg/kg (n=3). No dose-limiting toxicity (DLT) or vascular leak syndrome (VLS) was observed. Most common treatment-emergent adverse events (TEAEs) were flu-like symptoms (46.4%), fever (46.4%), vomiting/nausea (35.7%), chills (32.1%), following the first dose and resolved with standard supportive care. No cumulative toxicity, end organ toxicity, QTc prolongation, or other cardiac toxicity was observed. Grade (G) 3-4 related toxicities in B: 1 G3 rash (8 µg/kg); 1 G4 AST increase, 2 G3 increase in AST/ALT & 1 G4 decrease in lymphocytes (16 µg/kg); 2 G4 decrease in lymphocytes, 1 G4 CRS with G3 hypertension (led to discontinuation), and 1 G3 acute kidney injury (24 µg/kg); C: 1 G3 & 1G4 decrease in lymphocytes (16 µg/kg). CD8 cells (effector & memory) and NK cells increased in Cycle 1 by a median (range) respectively of 3.1 (1.04 - 5.91) and 7.93 (1.71 - 26.85) fold and were sustained until next cycle. There was no meaningful increase in CD4 Tregs or eosinophil counts (a marker of potential VLS), 1.89 (0.86- 5.36) and 1.77 (0.47- 3.65) fold. No anti-drug antibodies (IL-2 or PEG) and no meaningful IL-5 elevations were found. One IL-6 increase at 24 hrs (to 1,000 pg/mL) was observed. Half-life is ~ 10 hours. Three pts have confirmed partial responses: 1 PD-1-naive basal cell carcinoma; 1 head & neck squamous cell carcinoma with progression after a prior anti-PD-1, ongoing for 9+ mos in C (8 µg/kg); 1 squamous cellular carcinoma of unknown origin, unresponsive to prior anti-PD-1, ongoing for 3+ mos in B (24 µg/kg). Two pts had stable disease for 9 and 6 mos, respectively, with pancreatic (in A, 8 µg/kg) and prostate cancer (in B, 16 µg/kg); 11 pts remained on treatment for ≥5 cycles. Preliminary encouraging results with THOR-707 monotherapy and in combination with pembrolizumab support IL-2 not-alpha preferential activit","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73991830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-28
G. Bregni, Elena Trevisi, C. Senti, A. Pretta, C. Vandeputte, P. Kehagias, E. Reina, A. Deleporte, P. Gkolfakis, J. Laethem, P. Vergauwe, M. Eynde, G. Deboever, J. Janssens, G. Demolin, S. Holbrechts, M. Clausse, Thierry De Grez, M. Peeters, L. D'Hondt, K. Geboes, T. besse-Hammer, A. Buggenhout, F. Rothé, P. Flamen, A. Hendlisz, F. Sclafani
{"title":"Abstract 28: Prognostic value of baseline and early changes of circulating cell-free (cf)DNA in the neoadjuvant setting of early stage colon cancer (CC)","authors":"G. Bregni, Elena Trevisi, C. Senti, A. Pretta, C. Vandeputte, P. Kehagias, E. Reina, A. Deleporte, P. Gkolfakis, J. Laethem, P. Vergauwe, M. Eynde, G. Deboever, J. Janssens, G. Demolin, S. Holbrechts, M. Clausse, Thierry De Grez, M. Peeters, L. D'Hondt, K. Geboes, T. besse-Hammer, A. Buggenhout, F. Rothé, P. Flamen, A. Hendlisz, F. Sclafani","doi":"10.1158/1538-7445.AM2021-28","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-28","url":null,"abstract":"","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75414982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-649
Rohin Patel, A. Robertson, A. Saxena, Mintoo M. Patel
{"title":"Abstract 649: Classics to diagnostics: Assessing EMT biomarkers in colorectal cancer prognosis","authors":"Rohin Patel, A. Robertson, A. Saxena, Mintoo M. Patel","doi":"10.1158/1538-7445.AM2021-649","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-649","url":null,"abstract":"","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"202 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75490477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-357
D. J. Gironda, R. Bergan, R. Alpaugh, D. Danila, Tuan L. Chuang, Brenda Y. Hurtado, T. Ho, Cha-Mei Tang, D. Adams
{"title":"Abstract 357: Cancer associated macrophage like cells predict aggressive disease in local and metastatic prostate cancers","authors":"D. J. Gironda, R. Bergan, R. Alpaugh, D. Danila, Tuan L. Chuang, Brenda Y. Hurtado, T. Ho, Cha-Mei Tang, D. Adams","doi":"10.1158/1538-7445.AM2021-357","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-357","url":null,"abstract":"","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75536781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-632
Diana W. Lone, K. Sadak, B. Miller, Aubrey K. Hubbard, Jeannette M Sample, M. Roesler, J. Poynter
Introduction: Germ cell tumors (GCTs) are a rare heterogenous group of cancers accounting for 3% of childhood cancers and 15% of cancers in adolescents. Cure rates for GCTs exceed 90% and GCTs currently comprise the 3rd largest group of childhood cancer survivors in the United States. Little systematic evidence exists on late effects of cancer treatment in this group. Treatment for GCTs includes some combination of chemotherapy, radiation, and gonadectomy; interventions that place survivors at high risk for developing endocrinopathies. One of the most common endocrinopathies experienced by childhood cancer survivors is growth hormone deficiency (GHD). In this analysis, we evaluated the prevalence of growth hormone deficiency among GCT survivors. Methods: Participants were previously enrolled in the Germ Cell Tumor Epidemiology Study (GaMETES), which is a case parent triad study conducted using the Children9s Oncology Group registry protocols. Data on late effects and outcomes are currently available for a subset of the participants who have provided additional consent for a follow-up study including a self-administered questionnaire and medical record retrieval. GHD was identified via self-report and validated through medical records. Treatment information was abstracted from the medical records. Results: In this interim analysis, 230 participants completed the self-administered questionnaire, including 61 with ovarian tumors, 40 with testicular tumors, 38 extragonadal tumors, and 92 intracranial tumors. Thirty-six of the participants reported having growth hormone deficiency (GHD), all of whom had intracranial germ cell tumors (iGCTs). Thus, the prevalence of GHD among iGCT survivors was 39.1%. We validated 45 questionnaire responses against chart review of iGCT patients. Among these 45, 24 (53.33%) iGCT survivors had GHD. Participants who were treated with high doses of cranial radiation (>30 Gy) were more likely to have GHD (OR = 2.3, 95% CI 0.4-13.1). Conclusions: Growth hormone deficiency is highly prevalent in survivors of childhood intracranial germ cell tumors. The increased prevalence is likely related to the propensity for germ cell tumor involvement of the pituitary stalk, chemotherapy and cranial radiation. Exposure to higher cumulative doses of cranial radiation is associated with higher risk for developing growth hormone deficiency. Citation Format: Diana W. Lone, Karim T. Sadak, Bradley S. Miller, Aubrey K. Hubbard, Jeannette Sample, Michelle Roesler, Jenny N. Poynter. Growth hormone deficiency in childhood germ cell tumor survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 632.
生殖细胞肿瘤(gct)是一种罕见的异质性癌症，占儿童癌症的3%和青少年癌症的15%。gct的治愈率超过90%，目前gct是美国儿童癌症幸存者的第三大群体。很少有系统的证据表明癌症治疗对这一群体的晚期影响。gct的治疗包括化疗、放疗和性腺切除术;将幸存者置于患内分泌疾病高风险的干预措施。儿童癌症幸存者最常见的内分泌疾病之一是生长激素缺乏症(GHD)。在本分析中，我们评估了GCT幸存者中生长激素缺乏症的患病率。方法:参与者先前被纳入生殖细胞肿瘤流行病学研究(GaMETES)，这是一项使用儿童肿瘤组注册协议进行的病例父母三方研究。目前可获得关于后期影响和结果的数据，这些数据来自已额外同意进行后续研究的一部分参与者，包括自我管理的问卷调查和医疗记录检索。通过自我报告确定GHD，并通过医疗记录进行验证。从病历中提取治疗信息。结果:在这个中期分析中，230名参与者完成了自我管理的问卷，其中卵巢肿瘤61例，睾丸肿瘤40例，角外肿瘤38例，颅内肿瘤92例。36名参与者报告患有生长激素缺乏症(GHD)，他们都患有颅内生殖细胞肿瘤(igct)。因此，iGCT幸存者中GHD的患病率为39.1%。针对iGCT患者的图表回顾，我们验证了45份问卷回答。在这45例中，24例(53.33%)iGCT幸存者发生了GHD。接受高剂量颅脑辐射(bbb30 Gy)治疗的参与者更有可能发生GHD (OR = 2.3, 95% CI 0.4-13.1)。结论:生长激素缺乏症在儿童颅内生殖细胞瘤幸存者中非常普遍。增加的患病率可能与生殖细胞肿瘤累及垂体柄、化疗和颅脑放疗的倾向有关。暴露于较高累积剂量的颅骨辐射与发生生长激素缺乏症的较高风险相关。引文格式:Diana W. Lone, Karim T. Sadak, Bradley S. Miller, Aubrey K. Hubbard, Jeannette Sample, Michelle Roesler, Jenny N. Poynter。儿童生殖细胞肿瘤幸存者的生长激素缺乏[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志，2021;81(13 -增刊):632。
{"title":"Abstract 632: Growth hormone deficiency in childhood germ cell tumor survivors","authors":"Diana W. Lone, K. Sadak, B. Miller, Aubrey K. Hubbard, Jeannette M Sample, M. Roesler, J. Poynter","doi":"10.1158/1538-7445.AM2021-632","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-632","url":null,"abstract":"Introduction: Germ cell tumors (GCTs) are a rare heterogenous group of cancers accounting for 3% of childhood cancers and 15% of cancers in adolescents. Cure rates for GCTs exceed 90% and GCTs currently comprise the 3rd largest group of childhood cancer survivors in the United States. Little systematic evidence exists on late effects of cancer treatment in this group. Treatment for GCTs includes some combination of chemotherapy, radiation, and gonadectomy; interventions that place survivors at high risk for developing endocrinopathies. One of the most common endocrinopathies experienced by childhood cancer survivors is growth hormone deficiency (GHD). In this analysis, we evaluated the prevalence of growth hormone deficiency among GCT survivors. Methods: Participants were previously enrolled in the Germ Cell Tumor Epidemiology Study (GaMETES), which is a case parent triad study conducted using the Children9s Oncology Group registry protocols. Data on late effects and outcomes are currently available for a subset of the participants who have provided additional consent for a follow-up study including a self-administered questionnaire and medical record retrieval. GHD was identified via self-report and validated through medical records. Treatment information was abstracted from the medical records. Results: In this interim analysis, 230 participants completed the self-administered questionnaire, including 61 with ovarian tumors, 40 with testicular tumors, 38 extragonadal tumors, and 92 intracranial tumors. Thirty-six of the participants reported having growth hormone deficiency (GHD), all of whom had intracranial germ cell tumors (iGCTs). Thus, the prevalence of GHD among iGCT survivors was 39.1%. We validated 45 questionnaire responses against chart review of iGCT patients. Among these 45, 24 (53.33%) iGCT survivors had GHD. Participants who were treated with high doses of cranial radiation (>30 Gy) were more likely to have GHD (OR = 2.3, 95% CI 0.4-13.1). Conclusions: Growth hormone deficiency is highly prevalent in survivors of childhood intracranial germ cell tumors. The increased prevalence is likely related to the propensity for germ cell tumor involvement of the pituitary stalk, chemotherapy and cranial radiation. Exposure to higher cumulative doses of cranial radiation is associated with higher risk for developing growth hormone deficiency. Citation Format: Diana W. Lone, Karim T. Sadak, Bradley S. Miller, Aubrey K. Hubbard, Jeannette Sample, Michelle Roesler, Jenny N. Poynter. Growth hormone deficiency in childhood germ cell tumor survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 632.","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"47 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78392644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-396
Cameron McBride, D. Bottino
The current threshold-based precision medicine paradigm stems in part from the ‘all-or-nothing9 nature of regulatory labeling: a lung cancer patient can access pembrolizumab on-label only if tumor mutational burden (TMB) is at least 10 mutations/megabase, and crizotinib only if at least 15% of their tumor cells have ALK rearrangements (Pembrolizumab and Crizotinib package inserts). However, the drug-centric question - defining the patients most likely to respond to the drug – does not necessarily optimize patient care: in this case, choosing the best drug for a patient with nonzero levels of TMB and ALK. Furthermore, the current paradigm requires the drug sponsor to choose a threshold between a low value, to provide access to as many potentially benefitting patients as possible, and a high value, to maximize probability of success of the pivotal trial. We hypothesize that modeling probability of benefit (PoB) from each drug as a function of continuous biomarker levels (CBLs), and then giving the patient the treatment with the larger PoB not only eliminates the sponsor threshold selection dilemma, it provides better patient care. To test this hypothesis, we developed a simulation study. Given two drug/biomarker pairs, DX/BX and DY/BY, a ‘training9 population of 100 virtual patients responsive to DX, DY, or neither DX nor DY was generated using a ‘ground truth9 model of PoB from DX or DY as a function of patient CBLs of BX and BY, which were drawn from a prespecified random distribution. Logistic regression models were trained to the patients9 benefit outcomes to quantify PoBs as functions of CBLs. The threshold paradigm was simulated by choosing an ‘altruistic9 optimal biomarker threshold (OBT) for each drug which minimizes the net error rate (NER = False Positive + False Negative rate). Then a ‘test9 population of 1000 patients was generated using the same ground truth model used to generate the training population. We then applied the trained PoB model to give each virtual test patient the drug with the highest PoB based on CBLs and applied the threshold method to give each virtual test patient a drug only if the corresponding CBL > OBT. Finally, we compared the NER between PoB and OBT methods. NERs were estimated for three methods: OBT yielded a NER of 20.4%. Maximum univariate PoB, where PoB(DX) is a function of CBL BX alone and PoB(DY) is a function of CBL BY alone, yielded a NER of 14.8%. Maximum bivariate PoB, where PoB(DX) and PoB(DY) are functions of both CBLs BX and BY, yielded a NER of 10.7%. Our analysis predicts that of 100 patients treated according to the OBT method, 20 would either not benefit from the drug they were given or did not get a drug that would have benefited them. In contrast only 10-15 patients would be incorrectly treated using the PoB method, representing a 25-50% lower error rate than OBT. We believe the PoB method warrants consideration in the future of precision oncology. Citation Format: Cameron McBride, Dean Bot
{"title":"Abstract 396: Beyond thresholds in precision oncology: Use of probability of benefit as function of continuous biomarker levels leads to better patient care","authors":"Cameron McBride, D. Bottino","doi":"10.1158/1538-7445.AM2021-396","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-396","url":null,"abstract":"The current threshold-based precision medicine paradigm stems in part from the ‘all-or-nothing9 nature of regulatory labeling: a lung cancer patient can access pembrolizumab on-label only if tumor mutational burden (TMB) is at least 10 mutations/megabase, and crizotinib only if at least 15% of their tumor cells have ALK rearrangements (Pembrolizumab and Crizotinib package inserts). However, the drug-centric question - defining the patients most likely to respond to the drug – does not necessarily optimize patient care: in this case, choosing the best drug for a patient with nonzero levels of TMB and ALK. Furthermore, the current paradigm requires the drug sponsor to choose a threshold between a low value, to provide access to as many potentially benefitting patients as possible, and a high value, to maximize probability of success of the pivotal trial. We hypothesize that modeling probability of benefit (PoB) from each drug as a function of continuous biomarker levels (CBLs), and then giving the patient the treatment with the larger PoB not only eliminates the sponsor threshold selection dilemma, it provides better patient care. To test this hypothesis, we developed a simulation study. Given two drug/biomarker pairs, DX/BX and DY/BY, a ‘training9 population of 100 virtual patients responsive to DX, DY, or neither DX nor DY was generated using a ‘ground truth9 model of PoB from DX or DY as a function of patient CBLs of BX and BY, which were drawn from a prespecified random distribution. Logistic regression models were trained to the patients9 benefit outcomes to quantify PoBs as functions of CBLs. The threshold paradigm was simulated by choosing an ‘altruistic9 optimal biomarker threshold (OBT) for each drug which minimizes the net error rate (NER = False Positive + False Negative rate). Then a ‘test9 population of 1000 patients was generated using the same ground truth model used to generate the training population. We then applied the trained PoB model to give each virtual test patient the drug with the highest PoB based on CBLs and applied the threshold method to give each virtual test patient a drug only if the corresponding CBL > OBT. Finally, we compared the NER between PoB and OBT methods. NERs were estimated for three methods: OBT yielded a NER of 20.4%. Maximum univariate PoB, where PoB(DX) is a function of CBL BX alone and PoB(DY) is a function of CBL BY alone, yielded a NER of 14.8%. Maximum bivariate PoB, where PoB(DX) and PoB(DY) are functions of both CBLs BX and BY, yielded a NER of 10.7%. Our analysis predicts that of 100 patients treated according to the OBT method, 20 would either not benefit from the drug they were given or did not get a drug that would have benefited them. In contrast only 10-15 patients would be incorrectly treated using the PoB method, representing a 25-50% lower error rate than OBT. We believe the PoB method warrants consideration in the future of precision oncology. Citation Format: Cameron McBride, Dean Bot","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75918357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-578
A. Wang, Zhixin Zhao, C. Dai, Kemin Zhou, S. Jia, P. Du, Shujun J Luo
Liquid biopsy has become increasingly important in cancer diagnosis, personalized medicine, and disease progression monitoring. Conventional liquid biopsy relies on cancer gene panels which often contain fewer than 500 genes. Despite the revolutionary impact it has brought to the cancer research and cancer patient care, gene panels often miss many key mutations involved in cancer development and drug response. To fully capture the genetic variations embedded in cfDNA, we have developed Predicine-cfWES assay, which expands the features of our existing 152-gene PredicineCARE and 600-gene PredicineATLAS NGS panel with additional coverage of coding regions of the entire human genome. With 2500 x sequencing depth, Predicine-cfWES assay detects common cancer variants at sensitivity of 1% allele frequency and precisely measures copy number variations, such as loss of tumor suppressor genes (PTEN, BRCA2, p53) and gain of oncogenic driver genes (AR, Myc, ERBB2). Variants detected by Predicine-cfWES assay was confirmed by PredicineCARE panel based NGS assay and further used in tumor-agnostic personalized MRD assay. In conclusion, we have developed a comprehensive liquid biopsy solution to profile cfDNA with broad coverage of ~20,000 genes in the whole exome and higher sensitivity in a focused set of clinically actionable cancer variants for more personalized MRD monitoring in cancer patients. Citation Format: Amy Xiaohong Wang, Zhixin Zhao, Chao Dai, Kemin Zhou, Shidong Jia, Pan Du, Shujun Luo. Comparative analysis of cell free DNA with whole-exome sequencing (cfWES) and application to personalized minimal residual disease (MRD) monitoring [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 578.
{"title":"Abstract 578: Comparative analysis of cell free DNA with whole-exome sequencing (cfWES) and application to personalized minimal residual disease (MRD) monitoring","authors":"A. Wang, Zhixin Zhao, C. Dai, Kemin Zhou, S. Jia, P. Du, Shujun J Luo","doi":"10.1158/1538-7445.AM2021-578","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-578","url":null,"abstract":"Liquid biopsy has become increasingly important in cancer diagnosis, personalized medicine, and disease progression monitoring. Conventional liquid biopsy relies on cancer gene panels which often contain fewer than 500 genes. Despite the revolutionary impact it has brought to the cancer research and cancer patient care, gene panels often miss many key mutations involved in cancer development and drug response. To fully capture the genetic variations embedded in cfDNA, we have developed Predicine-cfWES assay, which expands the features of our existing 152-gene PredicineCARE and 600-gene PredicineATLAS NGS panel with additional coverage of coding regions of the entire human genome. With 2500 x sequencing depth, Predicine-cfWES assay detects common cancer variants at sensitivity of 1% allele frequency and precisely measures copy number variations, such as loss of tumor suppressor genes (PTEN, BRCA2, p53) and gain of oncogenic driver genes (AR, Myc, ERBB2). Variants detected by Predicine-cfWES assay was confirmed by PredicineCARE panel based NGS assay and further used in tumor-agnostic personalized MRD assay. In conclusion, we have developed a comprehensive liquid biopsy solution to profile cfDNA with broad coverage of ~20,000 genes in the whole exome and higher sensitivity in a focused set of clinically actionable cancer variants for more personalized MRD monitoring in cancer patients. Citation Format: Amy Xiaohong Wang, Zhixin Zhao, Chao Dai, Kemin Zhou, Shidong Jia, Pan Du, Shujun Luo. Comparative analysis of cell free DNA with whole-exome sequencing (cfWES) and application to personalized minimal residual disease (MRD) monitoring [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 578.","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"30 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77868932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-461
Rama Shankar, Jeremy Haskins, Shreya Paithankar, Bin Chen
Hepatocellular carcinoma (HCC) is the most common form of primary adult liver cancer and the fourth leading cause of cancer-related death worldwide. HCC incidence is highest most often in people with chronic liver diseases, yet the effect of cell composition on the progression of chronic liver diseases to HCC remains unknown. Using gene biomarkers of twenty cell-types identified from healthy liver scRNA-seq data, we estimated cell compositions of six chronic liver diseases and HCC based on their bulk RNA-seq samples. We observed a decrease in the enrichment of various health cells as the progression of liver diseases. Compared to a healthy state, liver fibrosis and HCC present higher enrichment of γδ2 T cells and lower enrichment of central venous liver sinusoidal endothelial cells (LSECs). High enrichment of γδ2 T cells was specifically observed in HCV and/or HBV positive HCC and advanced HCC. γδ2 T cell is one of the nine cell types that are associated with HCC prognosis. The analysis of multiple independent datasets confirmed that γδ2 T cells enrichment is more associated with poor prognosis in patients with lower Alpha-fetoprotein (AFP) level and HCV/HBV positive patients. Following pan-cancer analysis suggested enrichment of γδ2 T cells is associated with poor prognosis in kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, and low grade gliomas. In addition, this type of cells is also enriched in the blood samples of various chronic liver diseases and HCC, indicating the potential of being diagnostic markers. In summary, the integrative bioinformatics analysis identified γδ2 T cells as a marker for HCC progression. Citation Format: Rama Shankar, Jeremy Haskins, Shreya Paithankar, Bin Chen. Pan-liver disease single cell-based deconvolution reveals γδ2 T cells as a marker in hepatocellular carcinoma development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 461.
肝细胞癌(HCC)是成人原发性肝癌最常见的形式，也是全球癌症相关死亡的第四大原因。HCC的发病率在慢性肝病患者中最高，但细胞组成对慢性肝病向HCC发展的影响尚不清楚。利用从健康肝脏scRNA-seq数据中鉴定的20种细胞类型的基因生物标志物，我们根据它们的大量RNA-seq样本估计了6种慢性肝脏疾病和HCC的细胞组成。我们观察到，随着肝脏疾病的进展，各种健康细胞的富集减少。与健康状态相比，肝纤维化和HCC表现为γδ2 T细胞的高富集和中央静脉肝窦内皮细胞(LSECs)的低富集。在HCV和/或HBV阳性HCC和晚期HCC中观察到高富集的γδ2 T细胞。γδ2 T细胞是与HCC预后相关的九种细胞类型之一。多个独立数据集的分析证实，在甲胎蛋白(AFP)水平较低和HCV/HBV阳性的患者中，γδ2 T细胞富集与预后不良的相关性更大。泛癌分析表明，在肾透明细胞癌、肾乳头状细胞癌和低级别胶质瘤中，γδ2 T细胞的富集与预后不良有关。此外，这类细胞在各种慢性肝病和HCC的血液样本中也富集，具有作为诊断标志物的潜力。总之，综合生物信息学分析鉴定出γδ2 T细胞是HCC进展的标志物。引文格式:Rama Shankar, Jeremy Haskins, Shreya Paithankar, Bin Chen。泛肝疾病单细胞反褶积揭示γδ2 T细胞是肝细胞癌发展的标志物[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志，2021;81(13 -增刊):摘要第461期。
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