Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer

M. Ambrosini; B. Rousseau; P. Manca; O. Artz; A. Marabelle; T. André; G. Maddalena; G. Mazzoli; R. Intini; R. Cohen; A. Cercek; N. H. Segal; L. Saltz; A. M. Varghese; R. Yaeger; M. Nusrat; Z. Goldberg; G. Y. Ku; I. El Dika; O. Margalit; A. Grinshpun; P. Murtaza Kasi; R. Schilsky; A. Lutfi; E. Shacham-Shmueli; M. Khan Afghan; L. Weiss; C. B. Westphalen; V. Conca; B. Decker; G. Randon; E. Elez; M. Fakih; A. B. Schrock; C. Cremolini; P. Jayachandran; M. J. Overman; S. Lonardi; F. Pietrantonio

doi:10.1016/j.annonc.2024.03.009

Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer

M. Ambrosini, B. Rousseau, P. Manca, O. Artz, A. Marabelle, T. André, G. Maddalena, G. Mazzoli, R. Intini, R. Cohen, A. Cercek, N. H. Segal, L. Saltz, A. M. Varghese, R. Yaeger, M. Nusrat, Z. Goldberg, G. Y. Ku, I. El Dika, O. MargalitA. Grinshpun, P. Murtaza Kasi, R. Schilsky, A. Lutfi, E. Shacham-Shmueli, M. Khan Afghan, L. Weiss, C. B. Westphalen, V. Conca, B. Decker, G. Randon, E. Elez, M. Fakih, A. B. Schrock, C. Cremolini, P. Jayachandran, M. J. Overman, S. Lonardi, F. Pietrantonio

Research output: Contribution to journal › Article › peer-review

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Abstract

Background: POLE and POLD1 proofreading deficiency (POLE/D1pd) define a rare subtype of ultramutated metastatic colorectal cancer (mCRC; over 100 mut/Mb). Disease-specific data about the activity and efficacy of immune checkpoint inhibitors (ICIs) in POLE/D1pd mCRC are lacking and it is unknown whether outcomes may be different from mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRCs treated with ICIs. Patients and methods: In this global study, we collected 27 patients with mCRC harboring POLE/D1 mutations leading to proofreading deficiency and treated with anti-programmed cell death-ligand 1 alone +/− anti-cytotoxic T-lymphocyte antigen-4 agents. We collected clinicopathological and genomic characteristics, response, and survival outcomes after ICIs of POLE/D1pd mCRC and compared them with a cohort of 610 dMMR/MSI-H mCRC patients treated with ICIs. Further genomic analyses were carried out in an independent cohort of 7241 CRCs to define POLE and POLD1pd molecular profiles and mutational signatures. Results: POLE/D1pd was associated with younger age, male sex, fewer RAS/BRAF driver mutations, and predominance of right-sided colon cancers. Patients with POLE/D1pd mCRC showed a significantly higher overall response rate (ORR) compared to dMMR/MSI-H mCRC (89% versus 54%; P = 0.01). After a median follow-up of 24.9 months (interquartile range: 11.3-43.0 months), patients with POLE/D1pd showed a significantly superior progression-free survival (PFS) compared to dMMR/MSI-H mCRC [hazard ratio (HR) = 0.24, 95% confidence interval (CI) 0.08-0.74, P = 0.01] and superior overall survival (OS) (HR = 0.38, 95% CI 0.12-1.18, P = 0.09). In multivariable analyses including the type of DNA repair defect, POLE/D1pd was associated with significantly improved PFS (HR = 0.17, 95% CI 0.04-0.69, P = 0.013) and OS (HR = 0.24, 95% CI 0.06-0.98, P = 0.047). Molecular profiling showed that POLE/D1pd tumors have higher tumor mutational burden (TMB). Responses were observed in both subtypes and were associated with the intensity of POLE/D1pd signature. Conclusions: Patients with POLE/D1pd mCRC showed more favorable outcomes compared to dMMR/MSI-H mCRC to treatment with ICIs in terms of tumor response and survival.

Original language	English
Pages (from-to)	643-655
Number of pages	13
Journal	Annals of Oncology
Volume	35
Issue number	7
DOIs	https://doi.org/10.1016/j.annonc.2024.03.009
Publication status	Published - 1 Jul 2024

Keywords

POLD1 mutations
POLE mutations
immune checkpoint inhibitors
metastatic colorectal cancer
proofreading deficiency

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10.1016/j.annonc.2024.03.009

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Ambrosini, M., Rousseau, B., Manca, P., Artz, O., Marabelle, A., André, T., Maddalena, G., Mazzoli, G., Intini, R., Cohen, R., Cercek, A., Segal, N. H., Saltz, L., Varghese, A. M., Yaeger, R., Nusrat, M., Goldberg, Z., Ku, G. Y., El Dika, I., ... Pietrantonio, F. (2024). Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer. Annals of Oncology, 35(7), 643-655. https://doi.org/10.1016/j.annonc.2024.03.009

@article{9630e3c969fc41b4aed51b581147db33,

title = "Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer",

abstract = "Background: POLE and POLD1 proofreading deficiency (POLE/D1pd) define a rare subtype of ultramutated metastatic colorectal cancer (mCRC; over 100 mut/Mb). Disease-specific data about the activity and efficacy of immune checkpoint inhibitors (ICIs) in POLE/D1pd mCRC are lacking and it is unknown whether outcomes may be different from mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRCs treated with ICIs. Patients and methods: In this global study, we collected 27 patients with mCRC harboring POLE/D1 mutations leading to proofreading deficiency and treated with anti-programmed cell death-ligand 1 alone +/− anti-cytotoxic T-lymphocyte antigen-4 agents. We collected clinicopathological and genomic characteristics, response, and survival outcomes after ICIs of POLE/D1pd mCRC and compared them with a cohort of 610 dMMR/MSI-H mCRC patients treated with ICIs. Further genomic analyses were carried out in an independent cohort of 7241 CRCs to define POLE and POLD1pd molecular profiles and mutational signatures. Results: POLE/D1pd was associated with younger age, male sex, fewer RAS/BRAF driver mutations, and predominance of right-sided colon cancers. Patients with POLE/D1pd mCRC showed a significantly higher overall response rate (ORR) compared to dMMR/MSI-H mCRC (89% versus 54%; P = 0.01). After a median follow-up of 24.9 months (interquartile range: 11.3-43.0 months), patients with POLE/D1pd showed a significantly superior progression-free survival (PFS) compared to dMMR/MSI-H mCRC [hazard ratio (HR) = 0.24, 95% confidence interval (CI) 0.08-0.74, P = 0.01] and superior overall survival (OS) (HR = 0.38, 95% CI 0.12-1.18, P = 0.09). In multivariable analyses including the type of DNA repair defect, POLE/D1pd was associated with significantly improved PFS (HR = 0.17, 95% CI 0.04-0.69, P = 0.013) and OS (HR = 0.24, 95% CI 0.06-0.98, P = 0.047). Molecular profiling showed that POLE/D1pd tumors have higher tumor mutational burden (TMB). Responses were observed in both subtypes and were associated with the intensity of POLE/D1pd signature. Conclusions: Patients with POLE/D1pd mCRC showed more favorable outcomes compared to dMMR/MSI-H mCRC to treatment with ICIs in terms of tumor response and survival.",

keywords = "POLD1 mutations, POLE mutations, immune checkpoint inhibitors, metastatic colorectal cancer, proofreading deficiency",

author = "M. Ambrosini and B. Rousseau and P. Manca and O. Artz and A. Marabelle and T. Andr{\'e} and G. Maddalena and G. Mazzoli and R. Intini and R. Cohen and A. Cercek and Segal, {N. H.} and L. Saltz and Varghese, {A. M.} and R. Yaeger and M. Nusrat and Z. Goldberg and Ku, {G. Y.} and {El Dika}, I. and O. Margalit and A. Grinshpun and {Murtaza Kasi}, P. and R. Schilsky and A. Lutfi and E. Shacham-Shmueli and {Khan Afghan}, M. and L. Weiss and Westphalen, {C. B.} and V. Conca and B. Decker and G. Randon and E. Elez and M. Fakih and Schrock, {A. B.} and C. Cremolini and P. Jayachandran and Overman, {M. J.} and S. Lonardi and F. Pietrantonio",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s)",

year = "2024",

month = jul,

day = "1",

doi = "10.1016/j.annonc.2024.03.009",

language = "English",

volume = "35",

pages = "643--655",

journal = "Annals of Oncology",

issn = "0923-7534",

number = "7",

}

Ambrosini, M, Rousseau, B, Manca, P, Artz, O, Marabelle, A, André, T, Maddalena, G, Mazzoli, G, Intini, R, Cohen, R, Cercek, A, Segal, NH, Saltz, L, Varghese, AM, Yaeger, R, Nusrat, M, Goldberg, Z, Ku, GY, El Dika, I, Margalit, O, Grinshpun, A, Murtaza Kasi, P, Schilsky, R, Lutfi, A, Shacham-Shmueli, E, Khan Afghan, M, Weiss, L, Westphalen, CB, Conca, V, Decker, B, Randon, G, Elez, E, Fakih, M, Schrock, AB, Cremolini, C, Jayachandran, P, Overman, MJ, Lonardi, S & Pietrantonio, F 2024, 'Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer', Annals of Oncology, vol. 35, no. 7, pp. 643-655. https://doi.org/10.1016/j.annonc.2024.03.009

TY - JOUR

T1 - Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer

AU - Ambrosini, M.

AU - Rousseau, B.

AU - Manca, P.

AU - Artz, O.

AU - Marabelle, A.

AU - André, T.

AU - Maddalena, G.

AU - Mazzoli, G.

AU - Intini, R.

AU - Cohen, R.

AU - Cercek, A.

AU - Segal, N. H.

AU - Saltz, L.

AU - Varghese, A. M.

AU - Yaeger, R.

AU - Nusrat, M.

AU - Goldberg, Z.

AU - Ku, G. Y.

AU - El Dika, I.

AU - Margalit, O.

AU - Grinshpun, A.

AU - Murtaza Kasi, P.

AU - Schilsky, R.

AU - Lutfi, A.

AU - Shacham-Shmueli, E.

AU - Khan Afghan, M.

AU - Weiss, L.

AU - Westphalen, C. B.

AU - Conca, V.

AU - Decker, B.

AU - Randon, G.

AU - Elez, E.

AU - Fakih, M.

AU - Schrock, A. B.

AU - Cremolini, C.

AU - Jayachandran, P.

AU - Overman, M. J.

AU - Lonardi, S.

AU - Pietrantonio, F.

PY - 2024/7/1

Y1 - 2024/7/1

N2 - Background: POLE and POLD1 proofreading deficiency (POLE/D1pd) define a rare subtype of ultramutated metastatic colorectal cancer (mCRC; over 100 mut/Mb). Disease-specific data about the activity and efficacy of immune checkpoint inhibitors (ICIs) in POLE/D1pd mCRC are lacking and it is unknown whether outcomes may be different from mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRCs treated with ICIs. Patients and methods: In this global study, we collected 27 patients with mCRC harboring POLE/D1 mutations leading to proofreading deficiency and treated with anti-programmed cell death-ligand 1 alone +/− anti-cytotoxic T-lymphocyte antigen-4 agents. We collected clinicopathological and genomic characteristics, response, and survival outcomes after ICIs of POLE/D1pd mCRC and compared them with a cohort of 610 dMMR/MSI-H mCRC patients treated with ICIs. Further genomic analyses were carried out in an independent cohort of 7241 CRCs to define POLE and POLD1pd molecular profiles and mutational signatures. Results: POLE/D1pd was associated with younger age, male sex, fewer RAS/BRAF driver mutations, and predominance of right-sided colon cancers. Patients with POLE/D1pd mCRC showed a significantly higher overall response rate (ORR) compared to dMMR/MSI-H mCRC (89% versus 54%; P = 0.01). After a median follow-up of 24.9 months (interquartile range: 11.3-43.0 months), patients with POLE/D1pd showed a significantly superior progression-free survival (PFS) compared to dMMR/MSI-H mCRC [hazard ratio (HR) = 0.24, 95% confidence interval (CI) 0.08-0.74, P = 0.01] and superior overall survival (OS) (HR = 0.38, 95% CI 0.12-1.18, P = 0.09). In multivariable analyses including the type of DNA repair defect, POLE/D1pd was associated with significantly improved PFS (HR = 0.17, 95% CI 0.04-0.69, P = 0.013) and OS (HR = 0.24, 95% CI 0.06-0.98, P = 0.047). Molecular profiling showed that POLE/D1pd tumors have higher tumor mutational burden (TMB). Responses were observed in both subtypes and were associated with the intensity of POLE/D1pd signature. Conclusions: Patients with POLE/D1pd mCRC showed more favorable outcomes compared to dMMR/MSI-H mCRC to treatment with ICIs in terms of tumor response and survival.

AB - Background: POLE and POLD1 proofreading deficiency (POLE/D1pd) define a rare subtype of ultramutated metastatic colorectal cancer (mCRC; over 100 mut/Mb). Disease-specific data about the activity and efficacy of immune checkpoint inhibitors (ICIs) in POLE/D1pd mCRC are lacking and it is unknown whether outcomes may be different from mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRCs treated with ICIs. Patients and methods: In this global study, we collected 27 patients with mCRC harboring POLE/D1 mutations leading to proofreading deficiency and treated with anti-programmed cell death-ligand 1 alone +/− anti-cytotoxic T-lymphocyte antigen-4 agents. We collected clinicopathological and genomic characteristics, response, and survival outcomes after ICIs of POLE/D1pd mCRC and compared them with a cohort of 610 dMMR/MSI-H mCRC patients treated with ICIs. Further genomic analyses were carried out in an independent cohort of 7241 CRCs to define POLE and POLD1pd molecular profiles and mutational signatures. Results: POLE/D1pd was associated with younger age, male sex, fewer RAS/BRAF driver mutations, and predominance of right-sided colon cancers. Patients with POLE/D1pd mCRC showed a significantly higher overall response rate (ORR) compared to dMMR/MSI-H mCRC (89% versus 54%; P = 0.01). After a median follow-up of 24.9 months (interquartile range: 11.3-43.0 months), patients with POLE/D1pd showed a significantly superior progression-free survival (PFS) compared to dMMR/MSI-H mCRC [hazard ratio (HR) = 0.24, 95% confidence interval (CI) 0.08-0.74, P = 0.01] and superior overall survival (OS) (HR = 0.38, 95% CI 0.12-1.18, P = 0.09). In multivariable analyses including the type of DNA repair defect, POLE/D1pd was associated with significantly improved PFS (HR = 0.17, 95% CI 0.04-0.69, P = 0.013) and OS (HR = 0.24, 95% CI 0.06-0.98, P = 0.047). Molecular profiling showed that POLE/D1pd tumors have higher tumor mutational burden (TMB). Responses were observed in both subtypes and were associated with the intensity of POLE/D1pd signature. Conclusions: Patients with POLE/D1pd mCRC showed more favorable outcomes compared to dMMR/MSI-H mCRC to treatment with ICIs in terms of tumor response and survival.

KW - POLD1 mutations

KW - POLE mutations

KW - immune checkpoint inhibitors

KW - metastatic colorectal cancer

KW - proofreading deficiency

UR - http://www.scopus.com/inward/record.url?scp=85195370590&partnerID=8YFLogxK

U2 - 10.1016/j.annonc.2024.03.009

DO - 10.1016/j.annonc.2024.03.009

M3 - Article

C2 - 38777726

AN - SCOPUS:85195370590

SN - 0923-7534

VL - 35

SP - 643

EP - 655

JO - Annals of Oncology

JF - Annals of Oncology

IS - 7

ER -

Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer

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