Merkel cell carcinoma patients presenting without a primary lesion have elevated markers of immunity, higher tumor mutation burden, and improved survival

Natalie Vandeven, Christopher W. Lewis, Vladimir Makarov, Nadeem Riaz, Kelly G. Paulson, Daniel Hippe, Amy Bestick, Ryan Doumani, Tessa Marx, Seesha Takagishi, Timothy A. Chan, Jaehyuk Choi, Paul Nghiem*

*Corresponding author for this work

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Purpose: Patients presenting with nodal Merkel cell carcinoma without an identifiable (unknown) primary lesion (MCC-UP) are nearly twice as likely to survive compared with similarly staged patients with known primary lesions (MCC-KP). The basis of this previously reported finding is unclear. Experimental Design: Survival analyses and markers of immunity were evaluated in 123 patients with advanced MCC. Whole-exome sequence data were analyzed from 16 tumors. Results: As in prior studies, patients with nodal MCC-UP had strikingly improved MCC-specific survival as compared with MCC-KP patients (HR, 0.297; P < 0.001). Surprisingly, patients presenting with distant metastatic MCC-UP also had significantly improved survival (HR, 0.296; P ¼ 0.038). None of the 72 patients with MCC-UP were immunosuppressed as compared to 12 of the 51 (24%) patients with MCC-KP (P < 0.001). Merkel polyomavirus oncoprotein antibody median titer was higher in MCC-UP patients (26,229) than MCC-KP patients (3,492; P < 0.001). In addition, the median number of nonsynonymous exome mutations in MCC-UP tumors (688 mutations) was markedly higher than MCC-KP tumors (10 mutations, P ¼ 0.016). Conclusions: This is the first study to our knowledge to explore potential underlying immune-mediated mechanisms of MCC-UP presentation. In this cohort, MCC-UP patients were never immune suppressed, had higher oncoprotein antibody titers, and higher tumor mutational burdens. In addition, we show that nodal tumors identified in MCC-UP patients did indeed arise from primary skin lesions as they contained abundant UV-signature mutations. These findings suggest that stronger underlying immunity against MCC contributes to primary lesion elimination and improved survival.

Original languageEnglish (US)
Pages (from-to)963-971
Number of pages9
JournalClinical Cancer Research
Volume24
Issue number4
DOIs
StatePublished - Feb 15 2018

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Merkel Cell Carcinoma
Tumor Burden
Immunity
Mutation
Survival
Exome
Oncogene Proteins
Neoplasms
Polyomavirus
Antibodies
Survival Analysis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Vandeven, Natalie ; Lewis, Christopher W. ; Makarov, Vladimir ; Riaz, Nadeem ; Paulson, Kelly G. ; Hippe, Daniel ; Bestick, Amy ; Doumani, Ryan ; Marx, Tessa ; Takagishi, Seesha ; Chan, Timothy A. ; Choi, Jaehyuk ; Nghiem, Paul. / Merkel cell carcinoma patients presenting without a primary lesion have elevated markers of immunity, higher tumor mutation burden, and improved survival. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 4. pp. 963-971.
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title = "Merkel cell carcinoma patients presenting without a primary lesion have elevated markers of immunity, higher tumor mutation burden, and improved survival",
abstract = "Purpose: Patients presenting with nodal Merkel cell carcinoma without an identifiable (unknown) primary lesion (MCC-UP) are nearly twice as likely to survive compared with similarly staged patients with known primary lesions (MCC-KP). The basis of this previously reported finding is unclear. Experimental Design: Survival analyses and markers of immunity were evaluated in 123 patients with advanced MCC. Whole-exome sequence data were analyzed from 16 tumors. Results: As in prior studies, patients with nodal MCC-UP had strikingly improved MCC-specific survival as compared with MCC-KP patients (HR, 0.297; P < 0.001). Surprisingly, patients presenting with distant metastatic MCC-UP also had significantly improved survival (HR, 0.296; P ¼ 0.038). None of the 72 patients with MCC-UP were immunosuppressed as compared to 12 of the 51 (24{\%}) patients with MCC-KP (P < 0.001). Merkel polyomavirus oncoprotein antibody median titer was higher in MCC-UP patients (26,229) than MCC-KP patients (3,492; P < 0.001). In addition, the median number of nonsynonymous exome mutations in MCC-UP tumors (688 mutations) was markedly higher than MCC-KP tumors (10 mutations, P ¼ 0.016). Conclusions: This is the first study to our knowledge to explore potential underlying immune-mediated mechanisms of MCC-UP presentation. In this cohort, MCC-UP patients were never immune suppressed, had higher oncoprotein antibody titers, and higher tumor mutational burdens. In addition, we show that nodal tumors identified in MCC-UP patients did indeed arise from primary skin lesions as they contained abundant UV-signature mutations. These findings suggest that stronger underlying immunity against MCC contributes to primary lesion elimination and improved survival.",
author = "Natalie Vandeven and Lewis, {Christopher W.} and Vladimir Makarov and Nadeem Riaz and Paulson, {Kelly G.} and Daniel Hippe and Amy Bestick and Ryan Doumani and Tessa Marx and Seesha Takagishi and Chan, {Timothy A.} and Jaehyuk Choi and Paul Nghiem",
year = "2018",
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doi = "10.1158/1078-0432.CCR-17-1678",
language = "English (US)",
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Vandeven, N, Lewis, CW, Makarov, V, Riaz, N, Paulson, KG, Hippe, D, Bestick, A, Doumani, R, Marx, T, Takagishi, S, Chan, TA, Choi, J & Nghiem, P 2018, 'Merkel cell carcinoma patients presenting without a primary lesion have elevated markers of immunity, higher tumor mutation burden, and improved survival', Clinical Cancer Research, vol. 24, no. 4, pp. 963-971. https://doi.org/10.1158/1078-0432.CCR-17-1678

Merkel cell carcinoma patients presenting without a primary lesion have elevated markers of immunity, higher tumor mutation burden, and improved survival. / Vandeven, Natalie; Lewis, Christopher W.; Makarov, Vladimir; Riaz, Nadeem; Paulson, Kelly G.; Hippe, Daniel; Bestick, Amy; Doumani, Ryan; Marx, Tessa; Takagishi, Seesha; Chan, Timothy A.; Choi, Jaehyuk; Nghiem, Paul.

In: Clinical Cancer Research, Vol. 24, No. 4, 15.02.2018, p. 963-971.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Merkel cell carcinoma patients presenting without a primary lesion have elevated markers of immunity, higher tumor mutation burden, and improved survival

AU - Vandeven, Natalie

AU - Lewis, Christopher W.

AU - Makarov, Vladimir

AU - Riaz, Nadeem

AU - Paulson, Kelly G.

AU - Hippe, Daniel

AU - Bestick, Amy

AU - Doumani, Ryan

AU - Marx, Tessa

AU - Takagishi, Seesha

AU - Chan, Timothy A.

AU - Choi, Jaehyuk

AU - Nghiem, Paul

PY - 2018/2/15

Y1 - 2018/2/15

N2 - Purpose: Patients presenting with nodal Merkel cell carcinoma without an identifiable (unknown) primary lesion (MCC-UP) are nearly twice as likely to survive compared with similarly staged patients with known primary lesions (MCC-KP). The basis of this previously reported finding is unclear. Experimental Design: Survival analyses and markers of immunity were evaluated in 123 patients with advanced MCC. Whole-exome sequence data were analyzed from 16 tumors. Results: As in prior studies, patients with nodal MCC-UP had strikingly improved MCC-specific survival as compared with MCC-KP patients (HR, 0.297; P < 0.001). Surprisingly, patients presenting with distant metastatic MCC-UP also had significantly improved survival (HR, 0.296; P ¼ 0.038). None of the 72 patients with MCC-UP were immunosuppressed as compared to 12 of the 51 (24%) patients with MCC-KP (P < 0.001). Merkel polyomavirus oncoprotein antibody median titer was higher in MCC-UP patients (26,229) than MCC-KP patients (3,492; P < 0.001). In addition, the median number of nonsynonymous exome mutations in MCC-UP tumors (688 mutations) was markedly higher than MCC-KP tumors (10 mutations, P ¼ 0.016). Conclusions: This is the first study to our knowledge to explore potential underlying immune-mediated mechanisms of MCC-UP presentation. In this cohort, MCC-UP patients were never immune suppressed, had higher oncoprotein antibody titers, and higher tumor mutational burdens. In addition, we show that nodal tumors identified in MCC-UP patients did indeed arise from primary skin lesions as they contained abundant UV-signature mutations. These findings suggest that stronger underlying immunity against MCC contributes to primary lesion elimination and improved survival.

AB - Purpose: Patients presenting with nodal Merkel cell carcinoma without an identifiable (unknown) primary lesion (MCC-UP) are nearly twice as likely to survive compared with similarly staged patients with known primary lesions (MCC-KP). The basis of this previously reported finding is unclear. Experimental Design: Survival analyses and markers of immunity were evaluated in 123 patients with advanced MCC. Whole-exome sequence data were analyzed from 16 tumors. Results: As in prior studies, patients with nodal MCC-UP had strikingly improved MCC-specific survival as compared with MCC-KP patients (HR, 0.297; P < 0.001). Surprisingly, patients presenting with distant metastatic MCC-UP also had significantly improved survival (HR, 0.296; P ¼ 0.038). None of the 72 patients with MCC-UP were immunosuppressed as compared to 12 of the 51 (24%) patients with MCC-KP (P < 0.001). Merkel polyomavirus oncoprotein antibody median titer was higher in MCC-UP patients (26,229) than MCC-KP patients (3,492; P < 0.001). In addition, the median number of nonsynonymous exome mutations in MCC-UP tumors (688 mutations) was markedly higher than MCC-KP tumors (10 mutations, P ¼ 0.016). Conclusions: This is the first study to our knowledge to explore potential underlying immune-mediated mechanisms of MCC-UP presentation. In this cohort, MCC-UP patients were never immune suppressed, had higher oncoprotein antibody titers, and higher tumor mutational burdens. In addition, we show that nodal tumors identified in MCC-UP patients did indeed arise from primary skin lesions as they contained abundant UV-signature mutations. These findings suggest that stronger underlying immunity against MCC contributes to primary lesion elimination and improved survival.

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U2 - 10.1158/1078-0432.CCR-17-1678

DO - 10.1158/1078-0432.CCR-17-1678

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