Pub Date : 2024-07-21DOI: 10.1101/2024.07.19.24310726
Xuefeng Wang, Tingyi Li, Islam Eljilany, Vineeth Sukrithan, Aakrosh Ratan, Martin Mccarter, John Carpten, Howard Colman, Alexandra P. Ikeguchi, Igor Puzanov, Susanne Arnold, Michelle Churchman, Patrick Hwu, Paulo C. Rodriguez, William S. Dalton, George J. Weiner, Ahmad A. Tarhini
Background: Cancer initiation, progression, and immune evasion depend on the tumor microenvironment (TME). Thus, understanding the TME immune architecture is essential for understanding tumor metastasis and therapy response. This study aimed to create an immune cell states (CSs) atlas using bulk RNA-seq data enriched by eco-type analyses to resolve the complex immune architectures in the TME. Methods: We employed EcoTyper, a machine-learning (ML) framework, to study the real-world prognostic significance of immune CSs and multicellular ecosystems, utilizing molecular data from 1,610 patients with multiple malignancies who underwent immune checkpoint inhibitor (ICI) therapy within the ORIEN Avatar cohort, a well-annotated real-world dataset. Results: Our analysis revealed consistent ICI-specific prognostic TME carcinoma ecotypes (CEs) (including CE1, CE9, CE10) across our pan-cancer dataset, where CE1 being more lymphocyte-deficient and CE10 being more proinflammatory. Also, the analysis of specific immune CSs across different cancers showed consistent CD8+ and CD4+ T cell CS distribution patterns. Furthermore, survival analysis of the ORIEN ICI cohort demonstrated that ecotype CE9 is associated with the most favorable survival outcomes, while CE2 is linked to the least favorable outcomes. Notably, the melanoma-specific prognostic EcoTyper model confirmed that lower predicted risk scores are associated with improved survival and better response to immunotherapy. Finally, de novo discovery of ecotypes in the ORIEN ICI dataset identified Ecotype E3 as significantly associated with poorer survival outcomes. Conclusion: Our findings offer important insights into refining the patient selection process for immunotherapy in real-world practice and guiding the creation of novel therapeutic strategies to target specific ecotypes within the TME.
{"title":"Multicellular immune ecotypes within solid tumors predict real-world therapeutic benefits with immune checkpoint inhibitors","authors":"Xuefeng Wang, Tingyi Li, Islam Eljilany, Vineeth Sukrithan, Aakrosh Ratan, Martin Mccarter, John Carpten, Howard Colman, Alexandra P. Ikeguchi, Igor Puzanov, Susanne Arnold, Michelle Churchman, Patrick Hwu, Paulo C. Rodriguez, William S. Dalton, George J. Weiner, Ahmad A. Tarhini","doi":"10.1101/2024.07.19.24310726","DOIUrl":"https://doi.org/10.1101/2024.07.19.24310726","url":null,"abstract":"Background: Cancer initiation, progression, and immune evasion depend on the tumor microenvironment (TME). Thus, understanding the TME immune architecture is essential for understanding tumor metastasis and therapy response. This study aimed to create an immune cell states (CSs) atlas using bulk RNA-seq data enriched by eco-type analyses to resolve the complex immune architectures in the TME. Methods: We employed EcoTyper, a machine-learning (ML) framework, to study the real-world prognostic significance of immune CSs and multicellular ecosystems, utilizing molecular data from 1,610 patients with multiple malignancies who underwent immune checkpoint inhibitor (ICI) therapy within the ORIEN Avatar cohort, a well-annotated real-world dataset. Results: Our analysis revealed consistent ICI-specific prognostic TME carcinoma ecotypes (CEs) (including CE1, CE9, CE10) across our pan-cancer dataset, where CE1 being more lymphocyte-deficient and CE10 being more proinflammatory. Also, the analysis of specific immune CSs across different cancers showed consistent CD8+ and CD4+ T cell CS distribution patterns. Furthermore, survival analysis of the ORIEN ICI cohort demonstrated that ecotype CE9 is associated with the most favorable survival outcomes, while CE2 is linked to the least favorable outcomes. Notably, the melanoma-specific prognostic EcoTyper model confirmed that lower predicted risk scores are associated with improved survival and better response to immunotherapy. Finally, de novo discovery of ecotypes in the ORIEN ICI dataset identified Ecotype E3 as significantly associated with poorer survival outcomes.\u0000Conclusion: Our findings offer important insights into refining the patient selection process for immunotherapy in real-world practice and guiding the creation of novel therapeutic strategies to target specific ecotypes within the TME.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"50 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141742472","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 : 2024-07-12DOI: 10.1101/2024.07.12.24310333
Douglas Daoudlarian, Amandine Segot, Sofiya Latifyan, Robin Bartolini, Victor Joo, Nuria Mederos, Hasna Bouchaab, Rita Demicheli, Karim Abdelhamid, Nabila Ferahta, Jacqueline Doms, Gregoire Stalder, Alessandra Noto, Lucrezia Mencarelli, Valerie Mosimann, Dominik Berthold, Athina Stravodimou, Sartori Claudio, Keyvan Shabafrouz, John A. Thompson, Yinghong Wang, Solange Peters, Giuseppe Pantaleo, Michel Obeid
Immune-related cytokine release syndrome (irCRS) frequently occurs during immune checkpoint inhibitor (ICI) therapy. In the present study, we have attempted to identify biomarkers in oncology patients experiencing irCRS-like symptoms (n=35), including 9 patients with hemophagocytic lymphohistiocytosis (irHLH)-like manifestations (8 classified as Grade (G) 4 irCRS and 1 as G3 irCRS) and 8 with sepsis, differentiating between irCRS, irHLH and sepsis. Patients grouped in three clusters based on distinct cytokine profiles and survival outcomes. We identified 24 biomarkers that significantly discriminated between irHLH and irCRS G3 (P < 0.0455 to < 0.0027). Notably, HGF and ferritin demonstrated superior predictive values over the traditional HScore, with a positive predictive value (PPV) and negative predictive value (NPV) of 100%. Furthermore, CXCL9 not only distinguished between irHLH and irCRS G3, but was also a predictor of treatment intensification with tocilizumab (TCZ) with a PPV of 90% and a NPV of 100%. Other parameters, such as leukocyte count, neutrophils, ferritin, IL-6, IL-7, EGF, fibrinogen, and GM-CSF, were effective in discriminating sepsis from high-grade irCRS with a PPV of 75-80% and an NPV of 100%. In comparison to sepsis, the frequencies of CXCR5+ or CCR4+ CD8 memory, CD38+ ITM monocytes, and CD62L+ neutrophils were observed to be higher in high-Grade irCRS. Of note, TCZ treatment led to complete resolution of clinical symptoms in 12 patients with high-grade irCRS refractory to corticosteroids (CS). These findings demonstrate the power of unique immunologic biomarkers in determining the severity of irCRS, in predicting survival, and distinguishing between high-grade irCRS, irHLH and sepsis. Therefore, these distinct unique signatures are instrumental for the optimal development of personalized clinical and therapeutic management in patients experiencing irCRS patient.
{"title":"Distinct immune signatures are a potent tool in the clinical management of cytokine-related syndrome during immune checkpoint therapy","authors":"Douglas Daoudlarian, Amandine Segot, Sofiya Latifyan, Robin Bartolini, Victor Joo, Nuria Mederos, Hasna Bouchaab, Rita Demicheli, Karim Abdelhamid, Nabila Ferahta, Jacqueline Doms, Gregoire Stalder, Alessandra Noto, Lucrezia Mencarelli, Valerie Mosimann, Dominik Berthold, Athina Stravodimou, Sartori Claudio, Keyvan Shabafrouz, John A. Thompson, Yinghong Wang, Solange Peters, Giuseppe Pantaleo, Michel Obeid","doi":"10.1101/2024.07.12.24310333","DOIUrl":"https://doi.org/10.1101/2024.07.12.24310333","url":null,"abstract":"Immune-related cytokine release syndrome (irCRS) frequently occurs during immune checkpoint inhibitor (ICI) therapy. In the present study, we have attempted to identify biomarkers in oncology patients experiencing irCRS-like symptoms (n=35), including 9 patients with hemophagocytic lymphohistiocytosis (irHLH)-like manifestations (8 classified as Grade (G) 4 irCRS and 1 as G3 irCRS) and 8 with sepsis, differentiating between irCRS, irHLH and sepsis. Patients grouped in three clusters based on distinct cytokine profiles and survival outcomes. We identified 24 biomarkers that significantly discriminated between irHLH and irCRS G3 (P < 0.0455 to < 0.0027). Notably, HGF and ferritin demonstrated superior predictive values over the traditional HScore, with a positive predictive value (PPV) and negative predictive value (NPV) of 100%. Furthermore, CXCL9 not only distinguished between irHLH and irCRS G3, but was also a predictor of treatment intensification with tocilizumab (TCZ) with a PPV of 90% and a NPV of 100%. Other parameters, such as leukocyte count, neutrophils, ferritin, IL-6, IL-7, EGF, fibrinogen, and GM-CSF, were effective in discriminating sepsis from high-grade irCRS with a PPV of 75-80% and an NPV of 100%. In comparison to sepsis, the frequencies of CXCR5+ or CCR4+ CD8 memory, CD38+ ITM monocytes, and CD62L+ neutrophils were observed to be higher in high-Grade irCRS. Of note, TCZ treatment led to complete resolution of clinical symptoms in 12 patients with high-grade irCRS refractory to corticosteroids (CS). These findings demonstrate the power of unique immunologic biomarkers in determining the severity of irCRS, in predicting survival, and distinguishing between high-grade irCRS, irHLH and sepsis. Therefore, these distinct unique signatures are instrumental for the optimal development of personalized clinical and therapeutic management in patients experiencing irCRS patient.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141608209","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 : 2024-07-12DOI: 10.1101/2024.07.11.24310290
Eric M Nickels, Naying Zhou, Joseph L Wiemels
We assessed cancer concordance, cancer incidence in the healthy twin of cancer probands, and cancer risk in relation to birth order in pediatric and adolescent/young adult twins via a population-based study in California from 1982-2022. Twin subjects born in California between 1982-2017 who were diagnosed with leukemia from 0-39 years of age were identified through linked birth and California Cancer Registry (1988-2022) data. Two concordant-twin leukemias cases were identified across 255 total twin pairs with leukemia for an overall rate of leukemia concordance of 0.9%. One concordant twin pair was identified among 199 pairs with lymphoid leukemia (0.5%) and one within 34 pairs with acute myeloid leukemia (2.9%). A significant association was identified between twin plurality birth order and development of leukemia (OR 1.18, 95% CI 1-1.39, P=0.049), an effect which was strongest in lymphoid leukemias (2.21, 1.44-3.39, P=1.65e-4). Assessment of DNA methylation markers associated with birth order showed significantly reduced methylation in first-born twin cases compared to second-born (P=8.53e-12) in a subset of 41 twins discordant for lymphoid leukemia. Overall cancer concordance in twins was comparable to the lower range of previous estimates from different world regions. Concordance in lymphoid leukemias was quite lower than expected, indicating concordant leukemia is rarer than previously appreciated. We identified a strong association between twin plurality birth order and development of pediatric cancer. While the underlying cause of this finding is uncertain, we identified significant differences in DNA methylation at previously described sites associated with birth order, suggesting a similar biological mechanism.
{"title":"First-born twin has a higher risk of acute leukemia in a population-based assessment of cancer in twins in California, and lower than anticipated rate of twin concordance.","authors":"Eric M Nickels, Naying Zhou, Joseph L Wiemels","doi":"10.1101/2024.07.11.24310290","DOIUrl":"https://doi.org/10.1101/2024.07.11.24310290","url":null,"abstract":"We assessed cancer concordance, cancer incidence in the healthy twin of cancer probands, and cancer risk in relation to birth order in pediatric and adolescent/young adult twins via a population-based study in California from 1982-2022. Twin subjects born in California between 1982-2017 who were diagnosed with leukemia from 0-39 years of age were identified through linked birth and California Cancer Registry (1988-2022) data. Two concordant-twin leukemias cases were identified across 255 total twin pairs with leukemia for an overall rate of leukemia concordance of 0.9%. One concordant twin pair was identified among 199 pairs with lymphoid leukemia (0.5%) and one within 34 pairs with acute myeloid leukemia (2.9%). A significant association was identified between twin plurality birth order and development of leukemia (OR 1.18, 95% CI 1-1.39, P=0.049), an effect which was strongest in lymphoid leukemias (2.21, 1.44-3.39, P=1.65e-4). Assessment of DNA methylation markers associated with birth order showed significantly reduced methylation in first-born twin cases compared to second-born (P=8.53e-12) in a subset of 41 twins discordant for lymphoid leukemia. Overall cancer concordance in twins was comparable to the lower range of previous estimates from different world regions. Concordance in lymphoid leukemias was quite lower than expected, indicating concordant leukemia is rarer than previously appreciated. We identified a strong association between twin plurality birth order and development of pediatric cancer. While the underlying cause of this finding is uncertain, we identified significant differences in DNA methylation at previously described sites associated with birth order, suggesting a similar biological mechanism.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141608285","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 : 2024-07-12DOI: 10.1101/2024.07.12.24310284
Patricia Pedregal-Pascual, Carlos Guarner-Argente, Eng Hooi Tan, Asieh Golozar, Talita Duarte-Salles, Andreas Weinberger Rosen, Antonella Delmestri, Wai Yi Man, Edward Burn, DANIEL PRIETO-ALHAMBRA, Danielle Newby
Background: The management of colorectal cancer (CRC) is evolving, with advances in screening and treatment. We leveraged population-based data to generate up-to-date UK estimates of age and sex-specific incidence and prevalence and overall survival for the period 2000-2021. Methods: We analysed nationally representative primary care records from Clinical Practice Research Datalink (CPRD) GOLD, and replicated in CPRD Aurum. We calculated incidence rates, prevalence, and short- and long-term survival stratified by age, sex, and diagnosis year. Results: Unadjusted prevalence increased in the study period, from 15.6 to 46.4/10,000. Overall incidence was 61.5/100,000 person years, increasing in 2000-2011 to drop slightly in 2011-2014, and then plateauing. In contrast, early-onset CRC raised uninterruptedly throughout the study period, from 8.33 to 19.07/100,000 person-years. Overall survival was 78.3%, 51.4% and 38.5% at 1-, 5-, and 10-years respectively, lower in men compared to women. Modest improvements in survival were observed over the study period, particularly for 60-69 year old patients. Conclusion: The overall prevalence of CRC in the UK has tripled in the last 20 years, leading to increased healthcare resource needs and with slight survival improvements. A worrying increasing trend of early-onset CRC is observed, warranting further research into its diagnosis and management.
{"title":"Incidence, prevalence, and survival of colorectal cancer in the United Kingdom from 2000-2021: a population-based cohort study","authors":"Patricia Pedregal-Pascual, Carlos Guarner-Argente, Eng Hooi Tan, Asieh Golozar, Talita Duarte-Salles, Andreas Weinberger Rosen, Antonella Delmestri, Wai Yi Man, Edward Burn, DANIEL PRIETO-ALHAMBRA, Danielle Newby","doi":"10.1101/2024.07.12.24310284","DOIUrl":"https://doi.org/10.1101/2024.07.12.24310284","url":null,"abstract":"Background: The management of colorectal cancer (CRC) is evolving, with advances in screening and treatment. We leveraged population-based data to generate up-to-date UK estimates of age and sex-specific incidence and prevalence and overall survival for the period 2000-2021.\u0000Methods: We analysed nationally representative primary care records from Clinical Practice Research Datalink (CPRD) GOLD, and replicated in CPRD Aurum. We calculated incidence rates, prevalence, and short- and long-term survival stratified by age, sex, and diagnosis year. Results: Unadjusted prevalence increased in the study period, from 15.6 to 46.4/10,000. Overall incidence was 61.5/100,000 person years, increasing in 2000-2011 to drop slightly in 2011-2014, and then plateauing. In contrast, early-onset CRC raised uninterruptedly throughout the study period, from 8.33 to 19.07/100,000 person-years.\u0000Overall survival was 78.3%, 51.4% and 38.5% at 1-, 5-, and 10-years respectively, lower in men compared to women. Modest improvements in survival were observed over the study period, particularly for 60-69 year old patients.\u0000Conclusion: The overall prevalence of CRC in the UK has tripled in the last 20 years, leading to increased healthcare resource needs and with slight survival improvements. A worrying increasing trend of early-onset CRC is observed, warranting further research into its diagnosis and management.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"42 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141608278","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 : 2024-07-12DOI: 10.1101/2024.07.12.24310208
Pierre-Florent Petit, Douglas Daoudlarian, Sofiya Latifyan, Hasna Bouchaab, Nuria Mederos, Jacqueline Doms, Karim Abdelhamid, Nabila Ferahta, Lucrezia Mencarelli, Victor Joo, Robin Bartolini, Athina Stravodimou, Keyvan Shabafrouz, Giuseppe Pantaleo, Solange Peters, Michel Obeid
Background. Immune checkpoint inhibitor (ICI)-associated arthritis (ICI-AR) significantly affects quality of life and often requires discontinuation of ICI therapy and initiation of immunosuppressive treatment. The aim of this retrospective study was to evaluate the dual efficacy of tocilizumab (TCZ), an anti-IL-6R agent, in the treatment of ICI-AR and the prevention of relapses after ICI rechallenge. Methods. This retrospective single-center study was conducted at our institution from 2020 to the end of 2023. We identified 26 patients who developed ICI-AR. The primary objectives were to evaluate the therapeutic efficacy of TCZ in the treatment of ICI-AR in 26 patients and to evaluate the potential of TCZ as secondary prophylaxis during ICI rechallenge in 11 of them. For the treatment of ICI-AR, patients received prednisone (CS) at a low dose of 0.3 mg/kg tapered at 0.05 mg/kg weekly for six weeks until discontinuation. TCZ was administered at a dose of 8 mg/kg every two weeks. In the subgroup receiving secondary prophylaxis (rechallenge n=11, in 10 patients), TCZ was reintroduced at the same dosage of 8 mg/kg bi-weekly concurrently with ICI rechallenge, and without the addition of CS. A control group of patients (rechallenge n=5, in 3 patients) was rechallenged without TCZ. Secondary endpoints included post rechallenge evaluation of ICI duration, reintroduction of CS > 0.1 mg/kg/day, ICI-RA flares, and disease control rate (DCR). An additional explanatory endpoint was the identification of biomarkers predictive of response to TCZ. Results. The median age of the patients was 70 years. The median follow-up from ICI initiation was 864 days. ICI regimens included anti-PD-(L)1 monotherapy in 17 patients (63%), anti-PD-1 combined with anti-CTLA4 therapy in 8 patients (31%), and anti-PD-1 combined with anti-LAG3 therapy in 1 patient (4%). Among the 20 patients treated with TCZ for ICI-AR, all (100%) achieved an ACR70 response rate, defined as greater than 70% improvement, at 10 weeks. Additionally, 81% of these patients achieved steroid-free remission after 24 weeks on TCZ. The median follow-up period was 552 days in rechallenged patients. The ICI rechallenge regimens (n=16) included anti-PD-(L)1 monotherapy in thirteen cases (81%) and combination therapy in three cases (19%). The results demonstrated a reduction in ICI-AR relapses upon ICI rechallenge in patients receiving TCZ prophylaxis as compared to patients who did not receive prophylaxis (17% vs 40%). In addition, the requirement for CS at doses exceeding 0.1 mg/kg/day was completely abolished with prophylaxis (0% vs 20%), and the mean duration of ICI treatment was notably extended from 113 days to 206 days. The 12-month post-rechallenge outcomes showed a disease control rate (DCR) of 77%. Importantly, during TCZ prophylaxis, CXCL9 levels remained elevated, showing no decline from their levels at the onset of ICI-AR. Additionally, elevations of IL-6 and CXCL10 levels were exclusively observed
{"title":"Tocilizumab provides dual benefits in treating immune checkpoint inhibitor-associated arthritis and preventing relapse during ICI rechallenge: the TAPIR study","authors":"Pierre-Florent Petit, Douglas Daoudlarian, Sofiya Latifyan, Hasna Bouchaab, Nuria Mederos, Jacqueline Doms, Karim Abdelhamid, Nabila Ferahta, Lucrezia Mencarelli, Victor Joo, Robin Bartolini, Athina Stravodimou, Keyvan Shabafrouz, Giuseppe Pantaleo, Solange Peters, Michel Obeid","doi":"10.1101/2024.07.12.24310208","DOIUrl":"https://doi.org/10.1101/2024.07.12.24310208","url":null,"abstract":"Background. Immune checkpoint inhibitor (ICI)-associated arthritis (ICI-AR) significantly affects quality of life and often requires discontinuation of ICI therapy and initiation of immunosuppressive treatment. The aim of this retrospective study was to evaluate the dual efficacy of tocilizumab (TCZ), an anti-IL-6R agent, in the treatment of ICI-AR and the prevention of relapses after ICI rechallenge.\u0000Methods. This retrospective single-center study was conducted at our institution from 2020 to the end of 2023. We identified 26 patients who developed ICI-AR. The primary objectives were to evaluate the therapeutic efficacy of TCZ in the treatment of ICI-AR in 26 patients and to evaluate the potential of TCZ as secondary prophylaxis during ICI rechallenge in 11 of them. For the treatment of ICI-AR, patients received prednisone (CS) at a low dose of 0.3 mg/kg tapered at 0.05 mg/kg weekly for six weeks until discontinuation. TCZ was administered at a dose of 8 mg/kg every two weeks. In the subgroup receiving secondary prophylaxis (rechallenge n=11, in 10 patients), TCZ was reintroduced at the same dosage of 8 mg/kg bi-weekly concurrently with ICI rechallenge, and without the addition of CS. A control group of patients (rechallenge n=5, in 3 patients) was rechallenged without TCZ. Secondary endpoints included post rechallenge evaluation of ICI duration, reintroduction of CS > 0.1 mg/kg/day, ICI-RA flares, and disease control rate (DCR). An additional explanatory endpoint was the identification of biomarkers predictive of response to TCZ.\u0000Results. The median age of the patients was 70 years. The median follow-up from ICI initiation was 864 days. ICI regimens included anti-PD-(L)1 monotherapy in 17 patients (63%), anti-PD-1 combined with anti-CTLA4 therapy in 8 patients (31%), and anti-PD-1 combined with anti-LAG3 therapy in 1 patient (4%). Among the 20 patients treated with TCZ for ICI-AR, all (100%) achieved an ACR70 response rate, defined as greater than 70% improvement, at 10 weeks. Additionally, 81% of these patients achieved steroid-free remission after 24 weeks on TCZ. The median follow-up period was 552 days in rechallenged patients. The ICI rechallenge regimens (n=16) included anti-PD-(L)1 monotherapy in thirteen cases (81%) and combination therapy in three cases (19%). The results demonstrated a reduction in ICI-AR relapses upon ICI rechallenge in patients receiving TCZ prophylaxis as compared to patients who did not receive prophylaxis (17% vs 40%). In addition, the requirement for CS at doses exceeding 0.1 mg/kg/day was completely abolished with prophylaxis (0% vs 20%), and the mean duration of ICI treatment was notably extended from 113 days to 206 days. The 12-month post-rechallenge outcomes showed a disease control rate (DCR) of 77%. Importantly, during TCZ prophylaxis, CXCL9 levels remained elevated, showing no decline from their levels at the onset of ICI-AR. Additionally, elevations of IL-6 and CXCL10 levels were exclusively observed","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"43 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141608281","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 : 2024-07-11DOI: 10.1101/2024.07.10.24310238
Annette Lasham, Reenadevi Ramsaroop, Abbey Wrigley, Nicholas Knowlton
Aim: To perform the first national analysis of demographic and clinicopathological features associated with the HER2 positive, HER2-low and HER2-zero invasive breast cancers in New Zealand. The study will inform the proportion of women who benefit from new HER2-targeted antibody drug conjugate (ADC) therapies. Methods: Utilising data from Te Rehita Mate Utaetae (Breast Cancer Foundation NZ National Register), the study analysed data from women diagnosed with invasive breast cancer over a 21-year period. The HER2 status of tumours was classified into three categories: HER2-zero, -low, -positive. Results: From 2009-2021, 94% of women underwent HER2 testing, with 14% diagnosed with HER2-positive breast cancer. For advanced-stage disease, 38% formerly classified as HER2-negative were reclassified as HER2-low. Including HER2-positive breast cancers, this indicates 60% of women with advanced breast cancer would be eligible for the new HER2-directed ADCs (approximately 120 women per year). In future, these therapies may provide a targeted option for 40% of women with early-stage triple negative breast cancer now classified as HER2-low. Conclusion: The findings suggest a significant proportion of women with invasive breast cancer in New Zealand could benefit from new HER2-targeted treatments. There is a need to standardise HER2 testing to enhance personalised treatment and improve outcomes.
{"title":"Analysis of HER2-low breast cancer in Aotearoa New Zealand: a nationwide retrospective cohort study","authors":"Annette Lasham, Reenadevi Ramsaroop, Abbey Wrigley, Nicholas Knowlton","doi":"10.1101/2024.07.10.24310238","DOIUrl":"https://doi.org/10.1101/2024.07.10.24310238","url":null,"abstract":"Aim:\u0000To perform the first national analysis of demographic and clinicopathological features associated with the HER2 positive, HER2-low and HER2-zero invasive breast cancers in New Zealand. The study will inform the proportion of women who benefit from new HER2-targeted antibody drug conjugate (ADC) therapies. Methods:\u0000Utilising data from Te Rehita Mate Utaetae (Breast Cancer Foundation NZ National Register), the study analysed data from women diagnosed with invasive breast cancer over a 21-year period. The HER2 status of tumours was classified into three categories: HER2-zero, -low, -positive. Results:\u0000From 2009-2021, 94% of women underwent HER2 testing, with 14% diagnosed with HER2-positive breast cancer. For advanced-stage disease, 38% formerly classified as HER2-negative were reclassified as HER2-low. Including HER2-positive breast cancers, this indicates 60% of women with advanced breast cancer would be eligible for the new HER2-directed ADCs (approximately 120 women per year). In future, these therapies may provide a targeted option for 40% of women with early-stage triple negative breast cancer now classified as HER2-low. Conclusion:\u0000The findings suggest a significant proportion of women with invasive breast cancer in New Zealand could benefit from new HER2-targeted treatments. There is a need to standardise HER2 testing to enhance personalised treatment and improve outcomes.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"78 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141608282","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 : 2024-07-10DOI: 10.1101/2024.07.09.24310145
Saed Sayad, Mark Hiatt, Hazem Mustafa
Background. Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer (NSCLC) and frequently affects non-smokers, especially women. It is characterized by a complex genetic profile and interactions with its microenvironment, which contribute to its aggressive and adaptable nature. Early symptoms are often subtle, leading to late diagnoses. Treatment approaches have advanced with targeted therapies and immunotherapy supplementing traditional chemotherapy and radiation. Despite these advancements, the prognosis remains variable, highlighting the need for continued research into new treatment strategies to improve outcomes. Method. In this study, we employed Single-cell RNA Sequencing (scRNA-seq) to comprehensively analyze the impact of chemotherapy on lung adenocarcinoma at the individual cell level. By comparing before and after treatment samples, we assessed the differential expression of genes and pathways, revealing insights into how different cell types within the tumour respond to chemotherapy. This approach enabled us to pinpoint specific mechanisms of drug resistance and highlight potential therapeutic targets for overcoming these challenges. Results. Our analysis uncovered substantial changes in gene expression between primary tumour cells and metastatic cells following chemotherapy. Notably, we observed that 45 pathways were shared between the top 50 upregulated pathways in the primary tumour and the top 50 downregulated pathways in the metastatic tumour post-chemotherapy. Conversely, there was no overlap between the top 50 downregulated pathways in the primary tumour and the top 50 upregulated pathways in the metastatic tumour after chemotherapy. This suggests that chemotherapy effectively downregulated the major upregulated pathways but did not upregulate the key downregulated pathways in metastatic tumours. Conclusions. Integrating single-cell transcriptomics into LUAD research offers detailed insights into the tumour's response to chemotherapy and its interaction with the immune system. This approach enhances our understanding of LUAD and aids in developing targeted and effective treatments. Based on our analysis, we hypothesize that combining chemotherapy with drugs designed to upregulate the downregulated pathways in primary tumour cells could significantly enhance treatment efficacy and improve patient outcomes.
{"title":"Unveiling Chemotherapy's Impact on Lung Cancer through Single-Cell Transcriptomics","authors":"Saed Sayad, Mark Hiatt, Hazem Mustafa","doi":"10.1101/2024.07.09.24310145","DOIUrl":"https://doi.org/10.1101/2024.07.09.24310145","url":null,"abstract":"Background. Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer (NSCLC) and frequently affects non-smokers, especially women. It is characterized by a complex genetic profile and interactions with its microenvironment, which contribute to its aggressive and adaptable nature. Early symptoms are often subtle, leading to late diagnoses. Treatment approaches have advanced with targeted therapies and immunotherapy supplementing traditional chemotherapy and radiation. Despite these advancements, the prognosis remains variable, highlighting the need for continued research into new treatment strategies to improve outcomes.\u0000Method. In this study, we employed Single-cell RNA Sequencing (scRNA-seq) to comprehensively analyze the impact of chemotherapy on lung adenocarcinoma at the individual cell level. By comparing before and after treatment samples, we assessed the differential expression of genes and pathways, revealing insights into how different cell types within the tumour respond to chemotherapy. This approach enabled us to pinpoint specific mechanisms of drug resistance and highlight potential therapeutic targets for overcoming these challenges.\u0000Results. Our analysis uncovered substantial changes in gene expression between primary tumour cells and metastatic cells following chemotherapy. Notably, we observed that 45 pathways were shared between the top 50 upregulated pathways in the primary tumour and the top 50 downregulated pathways in the metastatic tumour post-chemotherapy. Conversely, there was no overlap between the top 50 downregulated pathways in the primary tumour and the top 50 upregulated pathways in the metastatic tumour after chemotherapy. This suggests that chemotherapy effectively downregulated the major upregulated pathways but did not upregulate the key downregulated pathways in metastatic tumours.\u0000Conclusions. Integrating single-cell transcriptomics into LUAD research offers detailed insights into the tumour's response to chemotherapy and its interaction with the immune system. This approach enhances our understanding of LUAD and aids in developing targeted and effective treatments. Based on our analysis, we hypothesize that combining chemotherapy with drugs designed to upregulate the downregulated pathways in primary tumour cells could significantly enhance treatment efficacy and improve patient outcomes.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141577394","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 : 2024-07-10DOI: 10.1101/2024.07.09.24310101
Jessie JF Medeiros, Andy Zeng, Michelle Chan-Seng-Yue, Tristan Woo, Suraj Bansal, Hyerin Kim, Jessica L McLeod, Andrea Arruda, Hubert Tsui, Jaime O Claudio, Dawn Maze, Hassan Sibai, Mark D Minden, James A Kennedy, Jean CY Wang, John E Dick, Vikas Gupta
Purpose. Myelofibrosis (MF) is the most severe myeloproliferative neoplasm (MPN) where there remains a need for improved risk stratification methods to better inform patient management. Since MF is a stem cell driven disease and stem cell informed transcriptomic information has been shown to be prognostic across other clinical settings we sought to use this information to generate novel transcriptomic-based risk stratification models that could complement current approaches. Patients and Methods. We identified 358 MF patients from the MPN registry at the Princess Margaret Cancer Centre (ClinicalTrials.gov Identifier: NCT02760238) from whom peripheral blood mononuclear cells were collected and clinical data was available. We randomly split our cohort into a 250-patient training set and a 108-patient test set to train and validate prognostic models, respectively. Results. Within the training set we used repeated nested cross validation together with LASSO regression from various starting gene sets and found that the best prognostic models were consistently derived from transcriptomic variation among MF stem cells. From this gene set we trained our final model, a 24-gene weighted expression score (termed, MPN24) that is prognostic for overall survival in MF patients. Importantly, MPN24 was validated in the test set patients. MPN24 captures unique prognostic information to current risk stratification models such as DIPSS, MIPSS70 and the Genomic-Personalized Risk scores. Therefore, we present a novel 3-tier risk stratification approach that integrates DIPSS and MPN24 to more effectively risk stratify MF patients. Finally, from MPN24 we derived a 13-gene subsignature (termed, MPN13) from the training set patients that was validated to predict time-to-transformation in the test set patients. Conclusions. Transcriptomic information informed by MF stem cells offer novel and unique prognostic potential in MF that significantly complements current approaches. Future work will be needed to validate the robustness of the approach in external cohorts and identify how patient management can be optimized with these novel transcriptomic biomarkers.
目的。骨髓纤维化（MF）是最严重的骨髓增生性肿瘤（MPN），目前仍需要改进风险分层方法，为患者管理提供更好的信息。由于骨髓纤维化是一种干细胞驱动的疾病，而干细胞信息转录组信息已被证明在其他临床环境中具有预后作用，因此我们试图利用这些信息生成基于转录组的新型风险分层模型，以补充当前的方法。我们从玛格丽特公主癌症中心（Princess Margaret Cancer Centre）的骨髓增生性疾病登记处（ClinicalTrials.gov Identifier: NCT02760238）确定了358名采集了外周血单个核细胞并提供了临床数据的中风患者。我们将队列随机分为250名患者的训练集和108名患者的测试集，分别用于训练和验证预后模型。在训练集中，我们使用了重复嵌套交叉验证和LASSO回归法，从不同的起始基因集出发，发现最佳预后模型始终来自中频干细胞的转录组变异。从这个基因集中，我们训练出了最终模型--24 个基因的加权表达评分（称为 MPN24），它是 MF 患者总生存期的预后指标。重要的是，MPN24 在测试集患者中得到了验证。与目前的风险分层模型（如 DIPSS、MIPSS70 和基因组个性化风险评分）相比，MPN24 能捕捉到独特的预后信息。因此，我们提出了一种整合了 DIPSS 和 MPN24 的新型三层风险分层方法，以更有效地对中风患者进行风险分层。最后，我们从MPN24中得出了训练集患者的13个基因子特征（称为MPN13），并对其进行了验证，以预测测试集患者的转归时间。中风干细胞提供的转录组信息为中风提供了新颖独特的预后潜力，极大地补充了当前的方法。未来的工作需要在外部队列中验证该方法的稳健性，并确定如何利用这些新型转录组生物标志物优化患者管理。
{"title":"Stem Cell-Derived Gene Expression Scores Predict Survival and Blastic Transformation in Myelofibrosis","authors":"Jessie JF Medeiros, Andy Zeng, Michelle Chan-Seng-Yue, Tristan Woo, Suraj Bansal, Hyerin Kim, Jessica L McLeod, Andrea Arruda, Hubert Tsui, Jaime O Claudio, Dawn Maze, Hassan Sibai, Mark D Minden, James A Kennedy, Jean CY Wang, John E Dick, Vikas Gupta","doi":"10.1101/2024.07.09.24310101","DOIUrl":"https://doi.org/10.1101/2024.07.09.24310101","url":null,"abstract":"Purpose. Myelofibrosis (MF) is the most severe myeloproliferative neoplasm (MPN) where there remains a need for improved risk stratification methods to better inform patient management. Since MF is a stem cell driven disease and stem cell informed transcriptomic information has been shown to be prognostic across other clinical settings we sought to use this information to generate novel transcriptomic-based risk stratification models that could complement current approaches.\u0000Patients and Methods. We identified 358 MF patients from the MPN registry at the Princess Margaret Cancer Centre (ClinicalTrials.gov Identifier: NCT02760238) from whom peripheral blood mononuclear cells were collected and clinical data was available. We randomly split our cohort into a 250-patient training set and a 108-patient test set to train and validate prognostic models, respectively.\u0000Results. Within the training set we used repeated nested cross validation together with LASSO regression from various starting gene sets and found that the best prognostic models were consistently derived from transcriptomic variation among MF stem cells. From this gene set we trained our final model, a 24-gene weighted expression score (termed, MPN24) that is prognostic for overall survival in MF patients. Importantly, MPN24 was validated in the test set patients. MPN24 captures unique prognostic information to current risk stratification models such as DIPSS, MIPSS70 and the Genomic-Personalized Risk scores. Therefore, we present a novel 3-tier risk stratification approach that integrates DIPSS and MPN24 to more effectively risk stratify MF patients. Finally, from MPN24 we derived a 13-gene subsignature (termed, MPN13) from the training set patients that was validated to predict time-to-transformation in the test set patients.\u0000Conclusions. Transcriptomic information informed by MF stem cells offer novel and unique prognostic potential in MF that significantly complements current approaches. Future work will be needed to validate the robustness of the approach in external cohorts and identify how patient management can be optimized with these novel transcriptomic biomarkers.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"49 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141566767","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 : 2024-07-10DOI: 10.1101/2024.07.09.24310044
Charles J. Rayner, David B. Bartlett, Sophie K. Allen, Tyler Woolridge, Tadd Seymour, Sunny Sunshine, Julie Hunt, David King, Izhar Bagwan, Javed Sultan, Shaun R. Preston, Adam E. Frampton, Nicola E. Annels, Nima Abbassi-Ghadi
INTRODUCTION: For patients with locally advanced oesophagogastric cancer, the standard of care in the UK is neoadjuvant chemotherapy (NAC) followed by surgery. Prehabilitation exercise can improve physiological function and fitness. As no studies have assessed tumour infiltrating lymphocyte (TIL) responses in humans during NAC undergoing prehabilitation, we aimed to determine whether prehabilitation increased TILs. METHODS: We enrolled 22 patients with locally advanced oesophageal cancer on a randomised control trial comparing 16 weeks of low-to-moderate intensity twice weekly supervised and thrice weekly home-based exercise (Prehab: N=11) to no prehabilitation (Control: N=11). We analysed peak cardiorespiratory fitness (VO2peak) before NAC, after 8 weeks of NAC (Post-NAC) and following 8 weeks of NAC recovery before surgery (Pre-Surgery). We assessed tumours by high-resolution multispectral immunohistochemistry (mIHC) and NanoString spatial transcriptomics. RESULTS: We observed a main effect of time [F(2,40) = 6.394, p=0.004, n2=.242] and a group x time interaction [F(2,40) = 3.445, p=0.042, n2=.147] for relative VO2peak. This was characterised by a 9.0% +/-10.2% reduction at Post-NAC (p=0.018) for the Controls, while the Prehabilitation group maintained VO2peak at Post-NAC (p=1.000) and increased by 9.4% +/- 7.6% from Post-NAC to Pre-Surgery (p=0.010). Prehabilitation had significantly more CD8+ cells in the tumours (3.2% +/- 3.3% v 1.4% +/- 1.3%, p<0.001) and the stroma (3.2% +/- 2.4% v 1.6% +/- 1.4%, p<0.001) than the Controls. Between Baseline and Post-NAC where the Prehabilitation group maintained VO2peak better than Controls there were significant positive associations with changes in VO2peak and the frequencies of CD8+ TILS (r=.531, p=0.016), PDL1+ cells (r=.566, p=0.009), and GrzB+ TILS (r=.592, p=0.007). When normalised to total numbers of TILs, Prehabilitation was associated with higher levels of CD56+ NK cells (p=0.0274) of which CD56dim NK cells were highest (p=0.0464). Evaluation of the presence and localisation of tumour-associated TLSs in the oesophageal tumours revealed that most TLSs were in the peritumoral regions. Prehabilitation was associated with a higher TLS cell density (p<0.001) and a non-significant smaller, less diffuse surface area (p=0.5134). Additionally, Prehabilitation tumours had more clearly defined germinal centres indicative of mature TLSs. CONCLUSION: We show that exercise training during NAC, which improves cardiorespiratory fitness, is associated with increased frequencies of TILs and maturity of TLS. These data suggest that exercise during NAC enhances the immune system, possibly to be suitable for immunotherapy.
{"title":"Prehabilitation during neoadjuvant chemotherapy results in an enhanced immune response in oesophageal adenocarcinoma tumours.","authors":"Charles J. Rayner, David B. Bartlett, Sophie K. Allen, Tyler Woolridge, Tadd Seymour, Sunny Sunshine, Julie Hunt, David King, Izhar Bagwan, Javed Sultan, Shaun R. Preston, Adam E. Frampton, Nicola E. Annels, Nima Abbassi-Ghadi","doi":"10.1101/2024.07.09.24310044","DOIUrl":"https://doi.org/10.1101/2024.07.09.24310044","url":null,"abstract":"INTRODUCTION: For patients with locally advanced oesophagogastric cancer, the standard of care in the UK is neoadjuvant chemotherapy (NAC) followed by surgery. Prehabilitation exercise can improve physiological function and fitness. As no studies have assessed tumour infiltrating lymphocyte (TIL) responses in humans during NAC undergoing prehabilitation, we aimed to determine whether prehabilitation increased TILs. METHODS: We enrolled 22 patients with locally advanced oesophageal cancer on a randomised control trial comparing 16 weeks of low-to-moderate intensity twice weekly supervised and thrice weekly home-based exercise (Prehab: N=11) to no prehabilitation (Control: N=11). We analysed peak cardiorespiratory fitness (VO2peak) before NAC, after 8 weeks of NAC (Post-NAC) and following 8 weeks of NAC recovery before surgery (Pre-Surgery). We assessed tumours by high-resolution multispectral immunohistochemistry (mIHC) and NanoString spatial transcriptomics. RESULTS: We observed a main effect of time [F(2,40) = 6.394, p=0.004, n2=.242] and a group x time interaction [F(2,40) = 3.445, p=0.042, n2=.147] for relative VO2peak. This was characterised by a 9.0% +/-10.2% reduction at Post-NAC (p=0.018) for the Controls, while the Prehabilitation group maintained VO2peak at Post-NAC (p=1.000) and increased by 9.4% +/- 7.6% from Post-NAC to Pre-Surgery (p=0.010). Prehabilitation had significantly more CD8+ cells in the tumours (3.2% +/- 3.3% v 1.4% +/- 1.3%, p<0.001) and the stroma (3.2% +/- 2.4% v 1.6% +/- 1.4%, p<0.001) than the Controls. Between Baseline and Post-NAC where the Prehabilitation group maintained VO2peak better than Controls there were significant positive associations with changes in VO2peak and the frequencies of CD8+ TILS (r=.531, p=0.016), PDL1+ cells (r=.566, p=0.009), and GrzB+ TILS (r=.592, p=0.007). When normalised to total numbers of TILs, Prehabilitation was associated with higher levels of CD56+ NK cells (p=0.0274) of which CD56dim NK cells were highest (p=0.0464). Evaluation of the presence and localisation of tumour-associated TLSs in the oesophageal tumours revealed that most TLSs were in the peritumoral regions. Prehabilitation was associated with a higher TLS cell density (p<0.001) and a non-significant smaller, less diffuse surface area (p=0.5134). Additionally, Prehabilitation tumours had more clearly defined germinal centres indicative of mature TLSs. CONCLUSION: We show that exercise training during NAC, which improves cardiorespiratory fitness, is associated with increased frequencies of TILs and maturity of TLS. These data suggest that exercise during NAC enhances the immune system, possibly to be suitable for immunotherapy.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"104 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141588344","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 : 2024-07-10DOI: 10.1101/2024.07.09.24310095
Jessica L. Corredor, Elissa B. Dodd-Eaton, Jacynda Woodman-Ross, Ashley Woodson, Nam H. Nguyen, Gang Peng, Sierra Green, Angelica M. Gutierrez, Banu K. Arun, Wenyi Wang
Purpose Current clinical guidelines for genetic testing for Li-Fraumeni Syndrome (LFS) have many limitations, primarily the criteria don't consider detailed personal and family history information and may miss many individuals with LFS. A personalized risk assessment tool, LFSPRO, was created to estimate a proband's risk for LFS based on personal and family history information. The purpose of this study is to compare LFSPRO to existing clinical criteria to determine if LFSPRO can outperform these tools. Additionally, we gauged genetic counselors' (GCs) experience using LFSPRO for their patients. Methods Between December 2021 and March 2024, GCs identified patients concerning for LFS based on the patients' personal and family history information. This information was entered into LFSPRO to predict the risk to have a pathogenic/pathogenic (LP/P) germline TP53 variant. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) was compared between LFSPRO and Chompret criteria. Select GCs were asked to fill out surveys regarding their experience using LFSPRO following their genetic counseling appointments. Results LFSPRO's sensitivity and specificity were 0.529 and 0.781 compared to Chompret's respective 0.235 and 0.677. Additionally, LFSPRO had a positive predictive value (PPV) of 0.30 compared to Chompret's 0.114. LFSPRO's risk prediction was concordant with genetic testing results in 75% of probands. Eighty-one percent of GC surveys reported LFSPRO being concordant with the GC's expectations and 75% would feel comfortable sharing the results with patients. Conclusion LFSPRO showed improved sensitivity and specificity compared to Chompret criteria and GCs report a positive experience with LFSPRO. LFSPRO can be used to increase access to genetic testing for patients at risk for LFS and could help healthcare providers give more direct risk assessments regarding LFS testing and management for patients.
{"title":"Performance of LFSPRO TP53 germline carrier risk predictions compared to standard genetic counseling practice on prospectively collected probands","authors":"Jessica L. Corredor, Elissa B. Dodd-Eaton, Jacynda Woodman-Ross, Ashley Woodson, Nam H. Nguyen, Gang Peng, Sierra Green, Angelica M. Gutierrez, Banu K. Arun, Wenyi Wang","doi":"10.1101/2024.07.09.24310095","DOIUrl":"https://doi.org/10.1101/2024.07.09.24310095","url":null,"abstract":"Purpose Current clinical guidelines for genetic testing for Li-Fraumeni Syndrome (LFS) have many limitations, primarily the criteria don't consider detailed personal and family history information and may miss many individuals with LFS. A personalized risk assessment tool, LFSPRO, was created to estimate a proband's risk for LFS based on personal and family history information. The purpose of this study is to compare LFSPRO to existing clinical criteria to determine if LFSPRO can outperform these tools. Additionally, we gauged genetic counselors' (GCs) experience using LFSPRO for their patients. Methods Between December 2021 and March 2024, GCs identified patients concerning for LFS based on the patients' personal and family history information. This information was entered into LFSPRO to predict the risk to have a pathogenic/pathogenic (LP/P) germline TP53 variant. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) was compared between LFSPRO and Chompret criteria. Select GCs were asked to fill out surveys regarding their experience using LFSPRO following their genetic counseling appointments. Results LFSPRO's sensitivity and specificity were 0.529 and 0.781 compared to Chompret's respective 0.235 and 0.677. Additionally, LFSPRO had a positive predictive value (PPV) of 0.30 compared to Chompret's 0.114. LFSPRO's risk prediction was concordant with genetic testing results in 75% of probands. Eighty-one percent of GC surveys reported LFSPRO being concordant with the GC's expectations and 75% would feel comfortable sharing the results with patients. Conclusion LFSPRO showed improved sensitivity and specificity compared to Chompret criteria and GCs report a positive experience with LFSPRO. LFSPRO can be used to increase access to genetic testing for patients at risk for LFS and could help healthcare providers give more direct risk assessments regarding LFS testing and management for patients.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141566876","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}
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