Immune and genomic biomarkers of immunotherapy response in cancer of unknown primary
Background Cancer of unknown primary (CUP) is a heterogeneous group of metastatic cancers where a primary tissue of origin (TOO) is uncertain. Most patients with CUP have limited treatment options and poor survival outcomes. Immune checkpoint inhibitors (ICIs) can be efficacious in some patients wit...
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BMJ Publishing Group
2023-01-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/1/e005809.full |
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| author | Madhu Singh Linda Mileshkin Penelope Schofield Bo Gao Gary Richardson Andrew Pattison Rodney J Hicks Niko Thio Mark Warren Colin Wood Stephen B Fox Anna DeFazio Andrew Fellowes Christopher Steer David Bowtell Nicholas Wilcken Tharani Sivakumaran Atara Posner Dariush Etemadmoghadam Krista Fisher Samantha Webb Christos S Karapetis Ian M Collins Narayan Karanth Owen W J Prall Richard William Tothill |
| author_facet | Madhu Singh Linda Mileshkin Penelope Schofield Bo Gao Gary Richardson Andrew Pattison Rodney J Hicks Niko Thio Mark Warren Colin Wood Stephen B Fox Anna DeFazio Andrew Fellowes Christopher Steer David Bowtell Nicholas Wilcken Tharani Sivakumaran Atara Posner Dariush Etemadmoghadam Krista Fisher Samantha Webb Christos S Karapetis Ian M Collins Narayan Karanth Owen W J Prall Richard William Tothill |
| author_sort | Madhu Singh |
| collection | DOAJ |
| description | Background Cancer of unknown primary (CUP) is a heterogeneous group of metastatic cancers where a primary tissue of origin (TOO) is uncertain. Most patients with CUP have limited treatment options and poor survival outcomes. Immune checkpoint inhibitors (ICIs) can be efficacious in some patients with CUP, but the optimal predictive biomarkers are unknown. We therefore assessed immune and genomic biomarkers as well as predicted TOO in patients with CUP, including a subset treated with ICIs.Methods Patients with CUP were subject to gene-expression profiling (GEP) and DNA panel sequencing. Immune and stromal-related gene expression was explored by NanoString, including genes associated with immunotherapy response (IR) in other solid malignancies. ICI responsive cancer types were assigned based on Food and Drug Administration-approved indications, and either detection of a latent primary tumor or the TOO was suspected based on genomics informed pathology review. Tumor mutation burden (TMB) and gene mutations were also assessed.Results A total of 219 patients with CUP were included, 215 assessed for TOO in a previous study, with the majority (163) receiving both RNA and DNA tests. Of GEP profiled cases, 33% (59/175) had a high IR gene-expression score. Of the DNA sequenced cases, 16% (32/203) had high TMB (>10 mutations/Mb), including two with mismatch repair deficiency. Low correlation was observed between TMB and an IR score (R=0.26, p<0.001). Among 110 CUPs with a latent primary or suspected TOO, 47% (52/110) belonged to ICI-responsive cancer types. More than half of the CUPs had at least one feature that may predict ICI response (high IR score, high TMB, ICI-responsive cancer type). Among patients with CUP treated with ICIs, 8/28 (29%) responded (2 complete responses and 6 partial responses). Among non-responders, 9 had stable and 11 had progressive disease. All responders had a high IR score (7/8) and/or high TMB (3/8), while most (5/8) belonged to ICI-responsive cancer types. These features were detected at a lower frequency in non-responders and mostly in patients with stable disease.Conclusions A significant fraction of CUP tumors had genomic features previously associated with ICI response. High IR score was the most sensitive predictive feature of ICI response, warranting evaluation in a larger patient series. |
| format | Article |
| id | doaj-art-62a3f3bb406f4f688c1bd4d184af4202 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2023-01-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-62a3f3bb406f4f688c1bd4d184af42022025-01-29T12:10:10ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-01-0111110.1136/jitc-2022-005809Immune and genomic biomarkers of immunotherapy response in cancer of unknown primaryMadhu Singh0Linda Mileshkin1Penelope Schofield2Bo Gao3Gary Richardson4Andrew Pattison5Rodney J Hicks6Niko Thio7Mark Warren8Colin Wood9Stephen B Fox10Anna DeFazio11Andrew Fellowes12Christopher Steer13David Bowtell14Nicholas Wilcken15Tharani Sivakumaran16Atara Posner17Dariush Etemadmoghadam18Krista Fisher19Samantha Webb20Christos S Karapetis21Ian M Collins22Narayan Karanth23Owen W J Prall24Richard William Tothill25Department of Medical Oncology, Barwon Health Cancer Services, Geelong, Victoria, AustraliaSir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, AustraliaSir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, AustraliaDepartment of Clinical Nutrition, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, Jiangsu, ChinaMedical Oncology, Cabrini Health, Malvern, Victoria, AustraliaDepartment of Clinical Pathology and Centre for Cancer Research, The University of Melbourne, Melbourne, Victoria, AustraliaDepartment of Radiology, University of Melbourne, Melbourne, Victoria, Australia1Peter MacCallum Cancer Centre, Melbourne, VIC, AustraliaMedical Oncology, Bendigo Health, Bendigo, Victoria, AustraliaPeter MacCallum Cancer Centre, Melbourne, Victoria, AustraliaSir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia5The Westmead Institute for Medical Research, Sydney, AustraliaDepartment of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, AustraliaBorder Medical Oncology, Albury Wodonga Regional Cancer Centre, Albury, Victoria, AustraliaPeter MacCallum Cancer Centre, Melbourne, Victoria, AustraliaDepartment of Medical Oncology, Westmead Hospital The Crown Princess Mary Cancer Centre, Sydney, New South Wales, AustraliaDepartment of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, AustraliaDepartment of Clinical Pathology and Centre for Cancer Research, The University of Melbourne, Melbourne, Victoria, AustraliaPeter MacCallum Cancer Centre, Melbourne, Victoria, AustraliaPeter MacCallum Cancer Centre, Melbourne, Victoria, AustraliaPeter MacCallum Cancer Centre, Melbourne, Victoria, AustraliaDepartment of Medical Oncology and Flinders Medical Centre, Flinders University, Adelaide, South Australia, AustraliaDepartment of Medical Oncology and SouthWest HealthCare, Deakin University - Warrnambool Campus, Warrnambool, Victoria, AustraliaDivision of Medicine, Top End Health and Hospital Services, Alan Walker Cancer Centre, Darwin, Northern Territory, AustraliaDepartment of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, AustraliaDepartment of Clinical Pathology and Centre for Cancer Research, The University of Melbourne, Melbourne, Victoria, AustraliaBackground Cancer of unknown primary (CUP) is a heterogeneous group of metastatic cancers where a primary tissue of origin (TOO) is uncertain. Most patients with CUP have limited treatment options and poor survival outcomes. Immune checkpoint inhibitors (ICIs) can be efficacious in some patients with CUP, but the optimal predictive biomarkers are unknown. We therefore assessed immune and genomic biomarkers as well as predicted TOO in patients with CUP, including a subset treated with ICIs.Methods Patients with CUP were subject to gene-expression profiling (GEP) and DNA panel sequencing. Immune and stromal-related gene expression was explored by NanoString, including genes associated with immunotherapy response (IR) in other solid malignancies. ICI responsive cancer types were assigned based on Food and Drug Administration-approved indications, and either detection of a latent primary tumor or the TOO was suspected based on genomics informed pathology review. Tumor mutation burden (TMB) and gene mutations were also assessed.Results A total of 219 patients with CUP were included, 215 assessed for TOO in a previous study, with the majority (163) receiving both RNA and DNA tests. Of GEP profiled cases, 33% (59/175) had a high IR gene-expression score. Of the DNA sequenced cases, 16% (32/203) had high TMB (>10 mutations/Mb), including two with mismatch repair deficiency. Low correlation was observed between TMB and an IR score (R=0.26, p<0.001). Among 110 CUPs with a latent primary or suspected TOO, 47% (52/110) belonged to ICI-responsive cancer types. More than half of the CUPs had at least one feature that may predict ICI response (high IR score, high TMB, ICI-responsive cancer type). Among patients with CUP treated with ICIs, 8/28 (29%) responded (2 complete responses and 6 partial responses). Among non-responders, 9 had stable and 11 had progressive disease. All responders had a high IR score (7/8) and/or high TMB (3/8), while most (5/8) belonged to ICI-responsive cancer types. These features were detected at a lower frequency in non-responders and mostly in patients with stable disease.Conclusions A significant fraction of CUP tumors had genomic features previously associated with ICI response. High IR score was the most sensitive predictive feature of ICI response, warranting evaluation in a larger patient series.https://jitc.bmj.com/content/11/1/e005809.full |
| spellingShingle | Madhu Singh Linda Mileshkin Penelope Schofield Bo Gao Gary Richardson Andrew Pattison Rodney J Hicks Niko Thio Mark Warren Colin Wood Stephen B Fox Anna DeFazio Andrew Fellowes Christopher Steer David Bowtell Nicholas Wilcken Tharani Sivakumaran Atara Posner Dariush Etemadmoghadam Krista Fisher Samantha Webb Christos S Karapetis Ian M Collins Narayan Karanth Owen W J Prall Richard William Tothill Immune and genomic biomarkers of immunotherapy response in cancer of unknown primary Journal for ImmunoTherapy of Cancer |
| title | Immune and genomic biomarkers of immunotherapy response in cancer of unknown primary |
| title_full | Immune and genomic biomarkers of immunotherapy response in cancer of unknown primary |
| title_fullStr | Immune and genomic biomarkers of immunotherapy response in cancer of unknown primary |
| title_full_unstemmed | Immune and genomic biomarkers of immunotherapy response in cancer of unknown primary |
| title_short | Immune and genomic biomarkers of immunotherapy response in cancer of unknown primary |
| title_sort | immune and genomic biomarkers of immunotherapy response in cancer of unknown primary |
| url | https://jitc.bmj.com/content/11/1/e005809.full |
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