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1. Clinicopathologic and Genomic Factors Impacting Efficacy of First-Line Chemoimmunotherapy in Advanced NSCLC

Author

Joao V. Alessi, Arielle Elkrief, Biagio Ricciuti, Xinan Wang, Alessio Cortellini, Victor R. Vaz, Giuseppe Lamberti, Rosa L. Frias, Deepti Venkatraman, Claudia A.M. Fulgenzi, Federica Pecci, Gonzalo Recondo, Alessandro Di Federico, Adriana Barrichello, Hyesun Park, Mizuki Nishino, Grace M. Hambelton, Jacklynn V. Egger, Marc Ladanyi, Subba Digumarthy, Bruce E. Johnson, David C. Christiani, Xihong Lin, Justin F. Gainor, Jessica J. Lin, David J. Pinato, Adam J. Schoenfeld, and Mark M. Awad

Subjects
Pulmonary and Respiratory Medicine, Oncology
Published
2023

2. Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Biagio Ricciuti, Arielle Elkrief, Joao Alessi, Xinan Wang, Yvonne Li, Hersh Gupta, Daniel M. Muldoon, Arrien A. Bertram, Federica Pecci, Giuseppe Lamberti, Alessandro Di Federico, Adriana Barrichello, Victor R. Vaz, Malini Gandhi, Elinton Lee, Geoffrey I. Shapiro, Hyesun Park, Mizuki Nishino, James Lindsay, Kristen D. Felt, Bijaya Sharma, Andrew D. Cherniack, Scott Rodig, Daniel R. Gomez, Narek Shaverdian, Mehrdad Rakaee, Chaitanya Bandlamudi, Marc Ladanyi, Pasi A. Janne, Adam J. Schoenfeld, Lynette M. Sholl, Mark M. Awad, and Michael L. Cheng

Subjects
Cancer Research, Oncology
Abstract

Purpose: ATM is the most commonly mutated DNA damage and repair gene in non–small cell lung cancer (NSCLC); however, limited characterization has been pursued. Experimental Design: Clinicopathologic, genomic, and treatment data were collected for 5,172 patients with NSCLC tumors which underwent genomic profiling. ATM IHC was performed on 182 NSCLCs with ATM mutations. Multiplexed immunofluorescence was performed on a subset of 535 samples to examine tumor-infiltrating immune cell subsets. Results: A total of 562 deleterious ATM mutations were identified in 9.7% of NSCLC samples. ATM-mutant (ATMMUT) NSCLC was significantly associated with female sex (P = 0.02), ever smoking status (P < 0.001), non-squamous histology (P = 0.004), and higher tumor mutational burden (DFCI, P < 0.0001; MSK, P < 0.0001) compared with ATM–wild-type (ATMWT) cases. Among 3,687 NSCLCs with comprehensive genomic profiling, co-occurring KRAS, STK11, and ARID2 oncogenic mutations were significantly enriched among ATMMUT NSCLCs (Q < 0.05), while TP53 and EGFR mutations were enriched in ATMWT NSCLCs. Among 182 ATMMUT samples with ATM IHC, tumors with nonsense, insertions/deletions, or splice site mutations were significantly more likely to display ATM loss by IHC (71.4% vs. 28.6%; P < 0.0001) compared with tumors with only predicted pathogenic missense mutations. Clinical outcomes to PD-(L)1 monotherapy (N = 1,522) and chemo-immunotherapy (N = 951) were similar between ATMMUT and ATMWT NSCLCs. Patients with concurrent ATM/TP53 mutations had significantly improved response rate and progression-free survival with PD-(L)1 monotherapy. Conclusions: Deleterious ATM mutations defined a subset of NSCLC with unique clinicopathologic, genomic, and immunophenotypic features. Our data may serve as resource to guide interpretation of specific ATM mutations in NSCLC.

Published
2023

4. Peripheral nervous system adverse events associated with immune checkpoint inhibitors

Author

Simone Rossi, Francesco Gelsomino, Rita Rinaldi, Lorenzo Muccioli, Francesca Comito, Alessandro Di Federico, Andrea De Giglio, Giuseppe Lamberti, Elisa Andrini, Veronica Mollica, Roberto D’Angelo, Flavia Baccari, Corrado Zenesini, Pierandrea Madia, Emanuel Raschi, Pietro Cortelli, Andrea Ardizzoni, and Maria Guarino

Subjects
Neurology, Neurology (clinical)
Abstract

Background Immune checkpoint inhibitors (ICIs) represent an effective cancer immunotherapy yet are associated with immune-related adverse events (irAEs). The aim of this study was to characterize irAEs involving the peripheral nervous system (PNS-irAEs) in a real-world cohort of ICI-treated patients. Methods Cancer patients treated with ICIs between January 2014 and March 2022 were included. Patients with PNS-irAEs were identified and divided into two groups: (1) cranial/peripheral neuropathies and (2) myasthenia gravis (MG) and/or myositis. Clinical characteristics and outcomes, measured with the modified Rankin Scale (mRS), were compared among the two groups. Results Among 920 ICI-treated patients, 20 patients (2.17%) developed a PNS-irAEs. The median latency from ICI exposure was 8.8 weeks and the median time from onset to clinical nadir was 3.5 weeks. Eleven patients developed a neuropathy: polyneuropathy (n = 4), cranial neuropathy (n = 3), small-fiber neuropathy (n = 3), brachial plexopathy (n = 1). Nine patients presented MG and/or myositis: concomitant MG and myositis (n = 6), isolated myositis (n = 2), exacerbation of MG (n = 1). Immunosuppressive treatment and/or ICI withdrawal determined a significant clinical improvement, expressed by a mRS reduction, in the neuropathy group (p = 0.004), but not in the MG/myositis group (p = 0.11). Overall, death due to irAEs occurred in four patients (20%), all with MG/myositis. Compared to patients with neuropathies, those with MG/myositis had a shorter latency onset (p = 0.036), developed more frequently concomitant non-neurologic irAEs (p = 0.028) and showed a higher mortality rate (p = 0.026). Conclusions In our large cohort of ICI-treated patients, 2.17% developed PNS-irAEs. Compared to ir-neuropathies, ir-MG/myositis tend to occur earlier from ICI exposure and present a worse response to treatment and a higher mortality.

Published
2023

5. Prospective Evaluation of MGMT-Promoter Methylation Status and Correlations with Outcomes to Temozolomide-Based Chemotherapy in Well-Differentiated Neuroendocrine Tumors

Author

Nicole Brighi, Giuseppe Lamberti, Elisa Andrini, Cristina Mosconi, Lisa Manuzzi, Giada Donati, Andrea Lisotti, Davide Campana, Nicole Brighi, Giuseppe Lamberti, Elisa Andrini, Cristina Mosconi, Lisa Manuzzi, Giada Donati, Andrea Lisotti, and Davide Campana

Subjects
neuroendocrine neoplasm, neuroendocrine neoplasms, chemotherapy, biomarkers, epigenetic, gastroenteropancreatic, biomarker
Abstract

Temozolomide (TEM) as a single agent or in combination with capecitabine (CAPTEM) is active in well-differentiated advanced neuroendocrine tumors (NETs) of gastro-entero-pancreatic and thoracic origin. The predictive role of MGMT-promoter methylation in this setting is controversial. We sought to prospectively evaluate the MGMT-promoter methylation status ability to predict outcomes to TEM-based chemotherapy in patients with NET. A single-center, prospective, observational study has been conducted at the ENETS Center-of-Excellence Outpatient Clinic of the IRCCS Policlinico Sant’Orsola-Malpighi in Bologna, Italy. Patients with advanced, gastro-entero-pancreatic or lung well-differentiated NETs candidate to TEM-based chemotherapy and with available tumor samples for MGMT-promoter methylation assessment were included. The MGMT-promoter methylation status was analyzed by using pyrosequencing. The primary endpoint was progression-free survival (PFS) by the MGMT-promoter methylation status. Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Survival outcomes were compared by restricted mean survival time (RMST) difference. Of 26 screened patients, 22 were finally enrolled in the study. The most frequent NET primary sites were the pancreas (64%) and the lung (23%). MGMT promoter was methylated in five tumors (23%). At a median follow-up time of 47.2 months (95%CI 29.3–89.7), the median PFS was 32.8 months (95%CI 17.2–NA), while the median OS was not reached. Patients in the methylated MGMT group, when compared to those in the unmethylated MGMT group, had longer PFS (median not reached [95%CI NA–NA] vs. 30.2 months [95%CI 15.2–NA], respectively; RMST p = 0.005) and OS (median not reached [95%CI NA–NA] vs. not reached [40.1–NA], respectively; RMST p = 0.019). After adjusting for confounding factors, the MGMT-promoter methylation status was independently associated to the PFS. Numerically higher ORR (60% vs. 24%; p = 0.274) and DCR (100% vs. 88%; p = 1.00) were observed in the methylated vs. unmethylated MGMT group. TEM-based chemotherapy was well-tolerated (adverse events grade ≥3 < 10%). In this prospective study, MGMT-promoter methylation predicted better outcomes to TEM-based chemotherapy in patients with NET.

Published
2023

6. Chemotherapy in Well Differentiated Neuroendocrine Tumors (NET) G1, G2, and G3: A Narrative Review

Author

Arianna Zappi, Irene Persano, Linda Galvani, Elena Parlagreco, Elisa Andrini, Davide Campana, Maria Pia Brizzi, Giuseppe Lamberti, Anna La Salvia, Arianna Zappi, irene persano, Linda Galvani, Elena Parlagreco, Elisa Andrini, Davide Campana, Maria Pia Brizzi, Giuseppe Lamberti, and ANNA LA SALVIA

Subjects
treatment, General Medicine, chemotherapy, neuroendocrine tumor, well differentiated neuroendocrine neoplasms
Abstract

Neuroendocrine tumors (NETs) are rare neoplasms with a wide spectrum of clinical behavior, from the long survival of well-differentiated NETs to the dismal prognosis of high-grade neuroendocrine carcinomas (NECs), being G3 NETs a recently recognized intermediate entity. While the role of chemotherapy is well established in NECs, data on NETs mostly derives from small studies, experts’ opinions, and extrapolating results from small-cell lung cancer studies. This narrative review aims to summarize available evidence about the use of chemotherapy in the setting of G1-2 NETs and G3 NETs. We performed literature research in PubMed Library for all articles published up to September 2022 about the efficacy of chemotherapy in NETs. Treatment regimens with STZ-5FU, CAPTEM, and anti-metabolite-based treatment are the most active and tolerated in gastroenteropancreatic NETs (GEP-NETs) G1-G2, while platinum-based regimens (FOLFOX/XELOX) and TEM/CAPTEM showed the best activity in thoracic NETs. Solid evidence about chemotherapy efficacy in G3 NETs is still lacking. Literature data support the use of chemotherapy in low-intermediate grade NETs after the failure of other therapies or if tumor shrinkage is needed. Studies assessing G3 NETs independently from NECs are needed to better understand the role of chemotherapy in this setting.

Published
2023

10. Supplementary Figure 8 from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Supplementary Figure 8. Oncoprint plot showing the distribution of the most commonly mutated genes in NSCLCs with complete ATM loss by IHC (ATMLOST), intact ATM expression (ATMINTACT), and ATM heterogeneous loss (ATMHET LOST) by IHC.

Published
2023

11. Supplementary Figure 25 from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Supplementary Figure 25. (A) Intratumoral, (B) tumor-stroma interface, and (C) total CD8+ PD1+ T cells according to ATM/TP53 co-mutation status. (D) Intratumoral, (E) tumor-stroma interface, and (F) total FOXP3+ immune cells according to ATM/TP53 co-mutation status.

Published
2023

12. Supplementary Table 6 from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Supplementary Table 6. Baseline clinicopathologic features of patients with ATM mutated NSCLC according ATM protein expression by immunohistochemistry.

Published
2023

13. Supplementary Figure 15 from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Supplementary Figure 15. (A) Objective response rate, (B) progression-free survival, and (C) overall survival to chemo-immunotherapy among patients with advanced/metastatic PD-L1 negative (

Published
2023

14. Supplementary Figure 16 from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Supplementary Figure 16. (A) Objective response rate, (B) progression-free survival, and (C) overall survival to PD-(L)1 inhibition monotherapy among patients with advanced/metastatic NSCLC, according to ATM/TP53 co-mutation status. (D) Objective response rate, (E) progression-free survival, and (F) overall survival to PD-(L)1 inhibition in combination with chemotherapy among patients with advanced NSCLC, according to ATM/TP53 co-mutation status.

Published
2023

15. Supplementary Figure 1. from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Supplementary Figure 1. (A) ATM mutation classification schema (B) Lollipop plot of all 714 mutations in the ATM gene identified in the combined DFCI/MSK cohort. (C) Lollipop plot of all 152 benign mutations in the ATM gene identified in the combined DFCI/MSK cohort.

Published
2023

16. Supplementary Figure 11 from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Supplementary Figure 11. Overall survival since the date of initial diagnosis among patients with stage IV NSCLC according to ATM mutation status.

Published
2023

17. Supplementary Figure 28 from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Supplementary Figure 28. (A) Box-plot showing the distribution of tumor-infiltrating lymphocytes assessed using computational pathology algorithm in ATMMUT and ATMWT NSCLCs. (B) Box-plot showing the distribution of tumor-infiltrating lymphocytes assessed using computational pathology algorithm in according to ATM/TP53 co-mutation status in NSCLC.

Published
2023

18. Supplementary Figure 12 from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Supplementary Figure 12. Disease-free survival and overall survival among patients with (A) stage I, (B) stage II, and (C) stage III NSCLC according to ATM expression by immunohistochemistry.

Published
2023

19. Data from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Purpose:ATM is the most commonly mutated DNA damage and repair gene in non–small cell lung cancer (NSCLC); however, limited characterization has been pursued.Experimental Design:Clinicopathologic, genomic, and treatment data were collected for 5,172 patients with NSCLC tumors which underwent genomic profiling. ATM IHC was performed on 182 NSCLCs with ATM mutations. Multiplexed immunofluorescence was performed on a subset of 535 samples to examine tumor-infiltrating immune cell subsets.Results:A total of 562 deleterious ATM mutations were identified in 9.7% of NSCLC samples. ATM-mutant (ATMMUT) NSCLC was significantly associated with female sex (P = 0.02), ever smoking status (P < 0.001), non-squamous histology (P = 0.004), and higher tumor mutational burden (DFCI, P < 0.0001; MSK, P < 0.0001) compared with ATM–wild-type (ATMWT) cases. Among 3,687 NSCLCs with comprehensive genomic profiling, co-occurring KRAS, STK11, and ARID2 oncogenic mutations were significantly enriched among ATMMUT NSCLCs (Q < 0.05), while TP53 and EGFR mutations were enriched in ATMWT NSCLCs. Among 182 ATMMUT samples with ATM IHC, tumors with nonsense, insertions/deletions, or splice site mutations were significantly more likely to display ATM loss by IHC (71.4% vs. 28.6%; P < 0.0001) compared with tumors with only predicted pathogenic missense mutations. Clinical outcomes to PD-(L)1 monotherapy (N = 1,522) and chemo-immunotherapy (N = 951) were similar between ATMMUT and ATMWT NSCLCs. Patients with concurrent ATM/TP53 mutations had significantly improved response rate and progression-free survival with PD-(L)1 monotherapy.Conclusions:Deleterious ATM mutations defined a subset of NSCLC with unique clinicopathologic, genomic, and immunophenotypic features. Our data may serve as resource to guide interpretation of specific ATM mutations in NSCLC.

Published
2023

20. Supplementary Table 1 from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Supplementary Table 1. Baseline clinicopathologic features of the 5172 patients with NSCLC which underwent comprehensive tumor genomic profiling at the Dana-Farber Cancer Institute and Memorial Sloan Kettering Cancer Center.

Published
2023

21. Supplementary Figure 6 from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Supplementary Figure 6. (A) Tumor mutational burden and (B) PD-L1 tumor proportion score distributions according to ATM protein expression by IHC (lost versus intact).

Published
2023

22. Supplementary Figure 13 from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Supplementary Figure 13. Overall survival since the date of initial diagnosis among patients with stage IV NSCLC according to ATM expression by immunohistochemistry.

Published
2023

23. Supplementary Figure 24 from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Supplementary Figure 24. (A) Intratumoral, (B) tumor-stroma interface, and (C) total CD8+ T cells according to ATM/TP53 co-mutation status. (D) Intratumoral, (E) tumor-stroma interface, and (F) total PD1+ immune cells according to ATM/TP53 co-mutation status.

Published
2023

24. Supplementary Figure 14 from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Supplementary Figure 14. (A) Objective response rate, (B) progression-free survival, and (C) overall survival to PD-(L)1 immune checkpoint blockade monotherapy among patients with advanced/metastatic PD-L1 negative (

Published
2023

25. Supplementary Figure 29 from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Supplementary Figure 29. Box plot showing immune cell subsets significantly enriched among ATMMUT versus ATMWT NSCLC as assessed by deconvoluting bulky RNAseq data from the TCGA-NSCLC dataset. Non-significant results are not shown.

Published
2023

26. Supplementary Figure 9 from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Supplementary Figure 9. (A) Disease free- and overall survival among patients with (A) stage I, and (B) stage II NSCLC according to ATM mutation status.

Published
2023

27. Supplementary Figure 18 from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Supplementary Figure 18. (A) Objective response rate, (B) progression-free survival, and (C) overall survival to PD-(L)1 immune checkpoint blockade monotherapy among patients with ATMMUT NSCLC, according to STK11 mutation. (D) Objective response rate, (E) progression-free survival, and (F) overall survival to PD-(L)1 immune checkpoint blockade in combination with platinum doublet chemotherapy among patients with ATMMUT NSCLC, according to STK11 mutation.

Published
2023

28. Supplementary Figure 27 from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Supplementary Figure 27. Tumor mutational burden in NSCLC samples which underwent NGS at the DFCI and MSK according to ATM/TP53 co-mutation status.

Published
2023

29. Supplementary Figure 3 from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Supplementary Figure 3. Co-mutation plot showing co-occurrent and mutual exclusive mutations among (A) ATMMUT and (B) ATMWT NSCLCs.

Published
2023

30. Supplementary Figure 23. from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Supplementary Figure 23. Correlation of intratumoral, tumor-stroma interface, and total CD8+, PD1+, CD8+PD1+, FOXP3+ T cells and tumoral and non-tumoral PD-L1+ cells among ATMMUT NSCLCs.

Published
2023

31. Supplementary Figure 2 from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Supplementary Figure 2. Proportion of samples with PD-L1 TPS ≥1%, ≥50%, ≥90% according to ATM mutation status (ATMMUT versus ATMWT).

Published
2023

32. Supplementary Figure 4. from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Supplementary Figure 4. (A) Volcano plot showing gene mutations significantly enriched among NSCLCs harboring ATM missense mutations that were predicted to benign in silico versus NSCLCs without any ATM mutation. (B) Volcano plot showing gene mutations significantly enriched among ATMWT and ATMMUT samples in the TCGA-NSCLC cohort.

Published
2023

33. Supplementary Figure 17 from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Supplementary Figure 17. (A) Objective response rate, (B) progression-free survival, and (C) overall survival to PD-(L)1 inhibition among patients with advanced/metastatic NSCLC, according to ATM expression by immunohistochemistry.

Published
2023

34. Supplementary Figure 7 from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Supplementary Figure 7. (A) Histograms showing the distribution of deleterious class I and class II ATM mutations with lost or intact ATM protein expression by IHC. (B) Histograms showing the distribution of deleterious missense, nonsense, splice site, and insertion/deletion mutations with lost or intact ATM protein expression by IHC. (C) proportion of NSCLCs with predicted benign and predicted pathogenic ATM missense mutations with lost and intact ATM expression by IHC.

Published
2023

35. Supplementary Table 4 from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Supplementary Table 4. Baseline clinicopathologic features of patients with ATM mutated NSCLC according ATM protein expression by immunohistochemistry.

Published
2023

36. Supplementary Figure 20 from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Supplementary Figure 20. (A) Intratumoral, (B) tumor-stroma interface, and (C) total CD8+ T cells in ATMMUT and ATMWT NSCLCs. (D) Intratumoral, (E) tumor-stroma interface, and (F) total PD1+ immune cells in ATMMUT and ATMWT NSCLCs.

Published
2023

37. Supplementary Table 2 from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Supplementary Table 2. List of potential ATM germline variants identified among 3800 patients with NSCLC at the DFCI

Published
2023

38. Supplementary Table 5 from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Supplementary Table 5. List of ATM mutations with matched IHC

Published
2023

39. Supplementary Table 3 from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Supplementary Table 3. Baseline clinicopathologic features of patients with ATMMUT and ATMWT NSCLC at the Dana-Farber Cancer Institute and Memorial Sloan Kettering Cancer Center.

Published
2023

40. Supplementary Figure 10 from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Supplementary Figure 10. (A) Progression-free and (B) overall survival among all patients with stage III NSCLC according to ATM mutation status. (C) Progression-free and (D) overall survival among patients with stage III NSCLC who received concurrent chemoradiotherapy followed by durvalumab maintenance according to ATM mutation status.

Published
2023

41. Supplementary Table 7 from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Supplementary Table 7. Baseline clinicopathologic features of patients with ATM mutated and ATM wild-type NSCLCs which underwent multiplexed immunofluorescence at the DFCI.

Published
2023

42. Supplementary Figure 19 from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Supplementary Figure 19. (A) Objective response rate, (B) progression-free survival, and (C) overall survival to PD-(L)1 immune checkpoint blockade monotherapy among patients with ATMMUT NSCLC, according to KEAP1 mutation. (D) Objective response rate, (E) progression-free survival, and (F) overall survival to PD-(L)1 immune checkpoint blockade in combination with platinum doublet chemotherapy among patients with ATMMUT NSCLC, according to KEAP1 mutation status

Published
2023

43. Supplementary Figure 26 from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Supplementary Figure 26. Proportion of (A) tumor, (B) non-tumor, and (C) total PD-L1+ cells according to ATM/TP53 co-mutation status.

Published
2023

44. Supplementary Figure 21 from Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non–Small Cell Lung Cancer

Author

Michael L. Cheng, Mark M. Awad, Lynette M. Sholl, Adam J. Schoenfeld, Pasi A. Janne, Marc Ladanyi, Chaitanya Bandlamudi, Mehrdad Rakaee, Narek Shaverdian, Daniel R. Gomez, Scott Rodig, Andrew D. Cherniack, Bijaya Sharma, Kristen D. Felt, James Lindsay, Mizuki Nishino, Hyesun Park, Geoffrey I. Shapiro, Elinton Lee, Malini Gandhi, Victor R. Vaz, Adriana Barrichello, Alessandro Di Federico, Giuseppe Lamberti, Federica Pecci, Arrien A. Bertram, Daniel M. Muldoon, Hersh Gupta, Yvonne Li, Xinan Wang, Joao Alessi, Arielle Elkrief, and Biagio Ricciuti

Abstract

Supplementary Figure 21. (A) Intratumoral, (B) tumor-stroma interface, and (C) total CD8+ PD1+ T cells in ATMMUT and ATMWT NSCLCs. (D) Intratumoral, (E) tumor-stroma interface, and (F) total FOXP3+ immune cells in ATMMUT and ATMWT NSCLCs.

Published
2023

45. Safety and Activity of Immune Checkpoint Inhibitors in People Living With HIV and Cancer: A Real-World Report From the Cancer Therapy Using Checkpoint Inhibitors in People Living With HIV-International (CATCH-IT) Consortium

Author

Talal El Zarif, Amin H. Nassar, Elio Adib, Bailey G. Fitzgerald, Jiaming Huang, Tarek H. Mouhieddine, Paul G. Rubinstein, Taylor Nonato, Rana R. McKay, Mingjia Li, Arjun Mittra, Dwight H. Owen, Robert A. Baiocchi, Michael Lorentsen, Christopher Dittus, Nazli Dizman, Adewunmi Falohun, Noha Abdel-Wahab, Adi Diab, Anand Bankapur, Alexandra Reed, Chul Kim, Aakriti Arora, Neil J. Shah, Edward El-Am, Elie Kozaily, Wassim Abdallah, Ahmad Al-Hader, Batool Abu Ghazal, Anwaar Saeed, Claire Drolen, Melissa G. Lechner, Alexandra Drakaki, Javier Baena, Caroline A. Nebhan, Tarek Haykal, Michael A. Morse, Alessio Cortellini, David J. Pinato, Alessia Dalla Pria, Evan Hall, Veli Bakalov, Nathan Bahary, Aarthi Rajkumar, Ankit Mangla, Vishal Shah, Parminder Singh, Frank Aboubakar Nana, Nerea Lopetegui-Lia, Danai Dima, Ryan W. Dobbs, Pauline Funchain, Rabia Saleem, Rachel Woodford, Georgina V. Long, Alexander M. Menzies, Carlo Genova, Giulia Barletta, Sonam Puri, Vaia Florou, Dame Idossa, Maristella Saponara, Paola Queirolo, Giuseppe Lamberti, Alfredo Addeo, Melissa Bersanelli, Dory Freeman, Wanling Xie, Erin G. Reid, Elizabeth Y. Chiao, Elad Sharon, Douglas B. Johnson, Ramya Ramaswami, Mark Bower, Brinda Emu, Thomas U. Marron, Toni K. Choueiri, Lindsey R. Baden, Kathryn Lurain, Guru P. Sonpavde, and Abdul Rafeh Naqash

Subjects
Cancer Research, Oncology
Abstract

PURPOSE Compared with people living without HIV (PWOH), people living with HIV (PWH) and cancer have traditionally been excluded from immune checkpoint inhibitor (ICI) trials. Furthermore, there is a paucity of real-world data on the use of ICIs in PWH and cancer. METHODS This retrospective study included PWH treated with anti–PD-1- or anti–PD-L1-based therapies for advanced cancers. Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Objective response rates (ORRs) were measured per RECIST 1.1 or other tumor-specific criteria, whenever feasible. Restricted mean survival time (RMST) was used to compare OS and PFS between matched PWH and PWOH with metastatic NSCLC (mNSCLC). RESULTS Among 390 PWH, median age was 58 years, 85% (n = 331) were males, 36% (n = 138) were Black; 70% (n = 274) received anti–PD-1/anti–PD-L1 monotherapy. Most common cancers were NSCLC (28%, n = 111), hepatocellular carcinoma ([HCC]; 11%, n = 44), and head and neck squamous cell carcinoma (HNSCC; 10%, n = 39). Seventy percent (152/216) had CD4+ T cell counts ≥200 cells/µL, and 94% (179/190) had HIV viral load CONCLUSION Among PWH, ICIs demonstrated differential activity across cancer types with no excess toxicity. Safety and activity of ICIs were similar between matched cohorts of PWH and PWOH with mNSCLC.

Published
2023

46. An Update on Appendiceal Neuroendocrine Tumors

Author

Elisa Andrini, Giuseppe Lamberti, Laura Alberici, Claudio Ricci, and Davide Campana

Subjects
Oncology, Pharmacology (medical)
Abstract

The mainstay of appendiceal neuroendocrine neoplasm (aNEN) treatment is surgery, based on simple appendectomy or right-sided hemicolectomy with lymphadenectomy (RHC). The majority of aNENs are adequately treated with appendectomy, but current guidelines have poor accuracy in terms of selecting patients requiring RHC, especially in aNENs 1–2 cm in size. Simple appendectomy is curative for appendiceal NETs (G1–G2) 15 mm or with grading G2 (according to WHO 2010) and/or lympho-vascular invasion should be referred for radicalization with RHC. However, decision-making in these cases should include discussion within a multidisciplinary tumor board at referral centers with the aim of offering each patient a tailored treatment, also considering that relatively young patients with long-life expectancy represent the majority of cases.

Published
2023

47. Impact of aneuploidy and chromosome 9p loss on tumor immune microenvironment and immune checkpoint inhibitor efficacy in non-small cell lung cancer

Author

Joao V. Alessi, Xinan Wang, Arielle Elkrief, Biagio Ricciuti, Yvonne Y. Li, Hersh Gupta, Liam F. Spurr, Hira Rizvi, Jia Luo, Federica Pecci, Giuseppe Lamberti, Gonzalo Recondo, Deepti Venkatraman, Alessandro Di Federico, Malini M. Gandhi, Victor R. Vaz, Mizuki Nishino, Lynette M. Sholl, Andrew D. Cherniack, Marc Ladanyi, Adam Price, Allison L. Richards, Mark Donoghue, James Lindsay, Bijaya Sharma, Madison M. Turner, Kathleen L. Pfaff, Kristen D. Felt, Scott J. Rodig, Xihong Lin, Matthew L. Meyerson, Bruce E. Johnson, David C. Christiani, Adam J. Schoenfeld, and Mark M. Awad

Subjects
Pulmonary and Respiratory Medicine, Oncology
Published
2023

48. Targeted Genomic Profiling and Chemotherapy Outcomes in Grade 3 Gastro-Entero-Pancreatic Neuroendocrine Tumors (G3 GEP-NET)

Author

Giuseppe Lamberti, Natalie Prinzi, Alberto Bongiovanni, Mariangela Torniai, Elisa Andrini, Dario de Biase, Deborah Malvi, Mirta Mosca, Rossana Berardi, Toni Ibrahim, Sara Pusceddu, and Davide Campana

Subjects
Clinical Biochemistry, NET, G3, FOLFOX, XELOX, CAPTEM, NGS, genomic, DAXX, ATRX
Abstract

Background: Grade 3 gastro-entero-pancreatic neuroendocrine tumors (G3 GEP-NET) are poorly characterized in terms of molecular features and response to treatments. Methods: Patients with G3 GEP-NET were included if they received capecitabine and temozolomide (CAPTEM) or oxaliplatin with either 5-fluorouracile (FOLFOX) or capecitabine (XELOX) as first-line treatment (chemotherapy cohort). G3 NET which successfully undergone next-generation sequencing (NGS) were included in the NGS cohort. Results: In total, 49 patients were included in the chemotherapy cohort: 15 received CAPTEM and 34 received FOLFOX/XELOX. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were 42.9%, 9.0 months, and 33.6 months, respectively. Calculating a Ki67 cutoff using ROC curve analysis, tumors with Ki67 ≥ 40% had lower ORR (51.2% vs. 0%; p = 0.007) and shorter PFS (10.6 months vs. 4.4 months; p < 0.001) and OS (49.4 months vs. 10.0 months; p = 0.023). In patients who received FOLFOX/XELOX as a first-line treatment, ORR, PFS, and OS were 38.2%, 7.9 months, and 30.0 months, respectively. In the NGS cohort (N = 13), the most mutated genes were DAXX/ATRX (N = 5, 38%), MEN1 (N = 4, 31%), TP53 (N = 4, 31%), AKT1 (N = 2, 15%), and PIK3CA (N = 1, 8%). Conclusions: FOLFOX/XELOX chemotherapy is active as the first-line treatment of patients with G3 GEP-NET. The mutational landscape of G3 NET is more similar to well-differentiated NETs than NECs.

Published
2023
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49. Co-mutations and KRAS G12C inhibitor efficacy in advanced NSCLC

Author

Marcelo V. Negrao, Haniel A. Araujo, Giuseppe Lamberti, Alissa J. Cooper, Neal S. Akhave, Teng Zhou, Lukas Delasos, J Kevin. Hicks, Mihaela Aldea, Gabriele Minuti, Jacobi Hines, Jacqueline V. Aredo, Michael J. Dennis, Turja Chakrabarti, Susan C. Scott, Paolo Bironzo, Matthias Scheffler, Petros Christopoulos, Albrecht Stenzinger, Jonathan W. Riess, So Yeon Kim, Sarah B. Goldberg, Mingjia Li, Qi Wang, Yun Qing, Ying Ni, Minh Truong Do, Richard Lee, Biagio Ricciuti, Joao Victor. Alessi, Jing Wang, Blerina Resuli, Lorenza Landi, Shu-Chi Tseng, Mizuki Nishino, Subba R. Digumarthy, Waree Rinsurongkawong, Vadeerat Rinsurongkawong, Ara A Vaporciyan, George R. Blumenschein, Jianjun Zhang, Dwight H. Owen, Collin M. Blakely, Giannis Mountzios, Catherine A. Shu, Christine M. Bestvina, Marina Chiara. Garassino, Kristen A. Marrone, Jhanelle E. Gray, Sandip Pravin. Patel, Amy L. Cummings, Heather A. Wakelee, Juergen Wolf, Giorgio Vittorio. Scagliotti, Federico Cappuzzo, Fabrice Barlesi, Pradnya D. Patil, Leylah Drusbosky, Don L. Gibbons, Funda Meric-Bernstam, J. Jack Lee, John V. Heymach, David S. Hong, Rebecca S. Heist, Mark M. Awad, and Ferdinandos Skoulidis

Subjects
Oncology
Abstract

Molecular modifiers of KRAS G12C inhibitor (KRAS G12Ci) efficacy in advanced KRAS G12C-mutant NSCLC are poorly defined. In a large unbiased clinico-genomic analysis of 424 NSCLC patients, we identified and validated co-alterations in KEAP1, SMARCA4 and CDKN2A as major independent determinants of inferior clinical outcomes with KRAS G12Ci monotherapy. Collectively, co-mutations in these three tumor suppressor genes segregated patients into distinct prognostic subgroups and captured ~50% of those with early disease progression (PFS≤3 months) with KRAS G12Ci. Pathway-level integration of less prevalent co-alterations in functionally related genes nominated PI3K/AKT/MTOR pathway and additional baseline RAS gene alterations, including amplifications, as candidate drivers of inferior outcomes with KRAS G12Ci, and revealed a possible association between defective DNA damage response/repair and improved KRAS G12Ci efficacy. Our findings propose a framework for patient stratification and clinical outcome prediction in KRAS G12C-mutant NSCLC that can inform rational selection and appropriate tailoring of emerging combination therapies.

Published
2023

50. Lymph node ratio predicts efficacy of postoperative radiation therapy in nonmetastatic Merkel cell carcinoma: A population‐based analysis

Author

Giuseppe Lamberti, Elisa Andrini, Giambattista Siepe, Cristina Mosconi, Valentina Ambrosini, Claudio Ricci, Paola Valeria Marchese, Gianluca Ricco, Riccardo Casadei, Davide Campana, Lamberti G., Andrini E., Siepe G., Mosconi C., Ambrosini V., Ricci C., Marchese P.V., Ricco G., Casadei R., and Campana D.

Subjects
Male, Cancer Research, Skin Neoplasms, LNR, Radoitherapy, Prognosis, radiation therapy, Carcinoma, Merkel Cell, SEER, Merkel cell carcinoma, lymph node ratio, Oncology, Humans, Lymph Node Excision, Female, Radiology, Nuclear Medicine and imaging, Lymph Nodes, Aged, Neoplasm Staging, Retrospective Studies
Abstract

Background: After radical resection of a nonmetastatic Merkel cell carcinoma (M0 MCC), postoperative radiation therapy (RT) is recommended as it improves survival. However, the role of RT in specific subgroups of M0 MCC is unclear. We sought to identify whether there is a differential survival benefit from RT in specific M0 MCC patient subgroups. Methods: M0 MCC patients from the Surveillance, Epidemiology, and End Results (SEER) database registry were collected. The best prognostic age, tumor size, and lymph node ratio (LNR, ratio between positive lymph nodes and resected lymph nodes) cutoffs were calculated. The primary endpoint was overall survival (OS). Results: A total of 5644 M0 MCC patients (median age 77 years, 62% male) were included: 4022 (71%) node-negative (N0) and 1551 (28%) node-positive (N+). Overall,2682 patients (48%) received RT. Age > 76.5 years, tumor size >13.5 mm, and LNR >0.215 were associated with worse OS. RT was associated with longer OS in the M0 MCC, N0, and N+ group and independently associated with a 25%, 27%, and 26% reduction in the risk for death, respectively. RT benefit on survival was increased in tumor size >13.5 mm in the N0 group and LNR >0.215 in the N+ group. No OS benefit from RT was observed in T4 tumors (N0 and N+ groups). Conclusions: RT was associated with improved survival in M0 MCC, irrespective of the nodal status. LNR >0.215 is a useful prognostic factor for clinical decision-making and for stratification and interpretation of clinical trials.

Published
2022

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