Validation of the DNA damage immune response signature in patients with triple-negative breast cancer from the SWOG 9313c trial

Priyanka Sharma, William E. Barlow, Andrew K. Godwin, Eileen E. Parkes, Laura A. Knight, Steven M. Walker, Richard D. Kennedy, Denis P. Harkin, Gemma E. Logan, Christopher J. Steele, Shauna M. Lambe, Sunil Badve, Yesim Gökmen-Polar, Harsh B. Pathak, Kamilla Isakova, Hannah M. Linden, Peggy Porter, Lajos Pusztai, Alastair M. Thompson, Debu TripathyGabriel N. Hortobagyi, Daniel F. Hayes

Research output: Contribution to journalArticle

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Abstract

PURPOSE To independently validate two biomarkers, a 44-gene DNA damage immune response (DDIR) signature and stromal tumor-infiltrating lymphocytes (sTILs), as prognostic markers in patients with triple-negative breast cancer (TNBC) treated with adjuvant doxorubicin (A) and cyclophosphamide (C) in SWOG 9313. METHODS Four hundred twenty-five centrally determined patient cases with TNBC from S9313 were identified. DDIR signature was performed on RNA isolated from formalin-fixed paraffin-embedded tumor tissue, and samples were classified as DDIR negative or positive using predefined cutoffs. Evaluation of sTILs was performed as described previously. Markers were tested for prognostic value for disease-free survival (DFS) and overall survival (OS) using Cox regression models adjusted for treatment assignment, nodal status, and tumor size. RESULTS Among 425 patients with TNBC, 33% were node positive. DDIR was tested successfully in 90% of patients (381 of 425), 62% of which were DDIR signature positive. DDIR signature positivity was associated with improved DFS (hazard ratio [HR], 0.67; 95% CI, 0.48 to 0.92; P = .015) and OS (HR, 0.61; 95% CI, 0.43 to 0.89; P = .010). sTILs density assessment was available in 99% of patients and was associated with improved DFS (HR, 0.70; 95% CI, 0.51 to 0.96; P = .026 for sTILs density≥20% v,20%) and OS (HR, 0.59; 95% CI, 0.41 to 0.85; P = .004 for sTILs density ≥ 20% v <20%). DDIR signature score and sTILs density were moderately correlated (r = 0.60), which precluded statistical significance for DFS in a joint model. Three-year DFS and OS in a subgroup of patients with DDIR positivity and T1c/T2N0 disease were 88% and 94%, respectively. CONCLUSION The prognostic role of sTILs and DDIR in early-stage TNBC was confirmed. DDIR signature conferred improved prognosis in two thirds of patients with TNBC treated with adjuvant AC. DDIR signature has the potential to stratify outcome and to identify patients with less projected benefit after AC chemotherapy.

Original languageEnglish (US)
Pages (from-to)3484-3492
Number of pages9
JournalJournal of Clinical Oncology
Volume37
Issue number36
DOIs
StatePublished - Jan 1 2019

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Triple Negative Breast Neoplasms
DNA Damage
Tumor-Infiltrating Lymphocytes
Disease-Free Survival
Survival
Proportional Hazards Models
Paraffin
Doxorubicin
Cyclophosphamide
Formaldehyde
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Sharma, P., Barlow, W. E., Godwin, A. K., Parkes, E. E., Knight, L. A., Walker, S. M., ... Hayes, D. F. (2019). Validation of the DNA damage immune response signature in patients with triple-negative breast cancer from the SWOG 9313c trial. Journal of Clinical Oncology, 37(36), 3484-3492. https://doi.org/10.1200/JCO.19.00693

Validation of the DNA damage immune response signature in patients with triple-negative breast cancer from the SWOG 9313c trial. / Sharma, Priyanka; Barlow, William E.; Godwin, Andrew K.; Parkes, Eileen E.; Knight, Laura A.; Walker, Steven M.; Kennedy, Richard D.; Harkin, Denis P.; Logan, Gemma E.; Steele, Christopher J.; Lambe, Shauna M.; Badve, Sunil; Gökmen-Polar, Yesim; Pathak, Harsh B.; Isakova, Kamilla; Linden, Hannah M.; Porter, Peggy; Pusztai, Lajos; Thompson, Alastair M.; Tripathy, Debu; Hortobagyi, Gabriel N.; Hayes, Daniel F.

In: Journal of Clinical Oncology, Vol. 37, No. 36, 01.01.2019, p. 3484-3492.

Research output: Contribution to journalArticle

Sharma, P, Barlow, WE, Godwin, AK, Parkes, EE, Knight, LA, Walker, SM, Kennedy, RD, Harkin, DP, Logan, GE, Steele, CJ, Lambe, SM, Badve, S, Gökmen-Polar, Y, Pathak, HB, Isakova, K, Linden, HM, Porter, P, Pusztai, L, Thompson, AM, Tripathy, D, Hortobagyi, GN & Hayes, DF 2019, 'Validation of the DNA damage immune response signature in patients with triple-negative breast cancer from the SWOG 9313c trial', Journal of Clinical Oncology, vol. 37, no. 36, pp. 3484-3492. https://doi.org/10.1200/JCO.19.00693
Sharma, Priyanka ; Barlow, William E. ; Godwin, Andrew K. ; Parkes, Eileen E. ; Knight, Laura A. ; Walker, Steven M. ; Kennedy, Richard D. ; Harkin, Denis P. ; Logan, Gemma E. ; Steele, Christopher J. ; Lambe, Shauna M. ; Badve, Sunil ; Gökmen-Polar, Yesim ; Pathak, Harsh B. ; Isakova, Kamilla ; Linden, Hannah M. ; Porter, Peggy ; Pusztai, Lajos ; Thompson, Alastair M. ; Tripathy, Debu ; Hortobagyi, Gabriel N. ; Hayes, Daniel F. / Validation of the DNA damage immune response signature in patients with triple-negative breast cancer from the SWOG 9313c trial. In: Journal of Clinical Oncology. 2019 ; Vol. 37, No. 36. pp. 3484-3492.
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title = "Validation of the DNA damage immune response signature in patients with triple-negative breast cancer from the SWOG 9313c trial",
abstract = "PURPOSE To independently validate two biomarkers, a 44-gene DNA damage immune response (DDIR) signature and stromal tumor-infiltrating lymphocytes (sTILs), as prognostic markers in patients with triple-negative breast cancer (TNBC) treated with adjuvant doxorubicin (A) and cyclophosphamide (C) in SWOG 9313. METHODS Four hundred twenty-five centrally determined patient cases with TNBC from S9313 were identified. DDIR signature was performed on RNA isolated from formalin-fixed paraffin-embedded tumor tissue, and samples were classified as DDIR negative or positive using predefined cutoffs. Evaluation of sTILs was performed as described previously. Markers were tested for prognostic value for disease-free survival (DFS) and overall survival (OS) using Cox regression models adjusted for treatment assignment, nodal status, and tumor size. RESULTS Among 425 patients with TNBC, 33{\%} were node positive. DDIR was tested successfully in 90{\%} of patients (381 of 425), 62{\%} of which were DDIR signature positive. DDIR signature positivity was associated with improved DFS (hazard ratio [HR], 0.67; 95{\%} CI, 0.48 to 0.92; P = .015) and OS (HR, 0.61; 95{\%} CI, 0.43 to 0.89; P = .010). sTILs density assessment was available in 99{\%} of patients and was associated with improved DFS (HR, 0.70; 95{\%} CI, 0.51 to 0.96; P = .026 for sTILs density≥20{\%} v,20{\%}) and OS (HR, 0.59; 95{\%} CI, 0.41 to 0.85; P = .004 for sTILs density ≥ 20{\%} v <20{\%}). DDIR signature score and sTILs density were moderately correlated (r = 0.60), which precluded statistical significance for DFS in a joint model. Three-year DFS and OS in a subgroup of patients with DDIR positivity and T1c/T2N0 disease were 88{\%} and 94{\%}, respectively. CONCLUSION The prognostic role of sTILs and DDIR in early-stage TNBC was confirmed. DDIR signature conferred improved prognosis in two thirds of patients with TNBC treated with adjuvant AC. DDIR signature has the potential to stratify outcome and to identify patients with less projected benefit after AC chemotherapy.",
author = "Priyanka Sharma and Barlow, {William E.} and Godwin, {Andrew K.} and Parkes, {Eileen E.} and Knight, {Laura A.} and Walker, {Steven M.} and Kennedy, {Richard D.} and Harkin, {Denis P.} and Logan, {Gemma E.} and Steele, {Christopher J.} and Lambe, {Shauna M.} and Sunil Badve and Yesim G{\"o}kmen-Polar and Pathak, {Harsh B.} and Kamilla Isakova and Linden, {Hannah M.} and Peggy Porter and Lajos Pusztai and Thompson, {Alastair M.} and Debu Tripathy and Hortobagyi, {Gabriel N.} and Hayes, {Daniel F.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1200/JCO.19.00693",
language = "English (US)",
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TY - JOUR

T1 - Validation of the DNA damage immune response signature in patients with triple-negative breast cancer from the SWOG 9313c trial

AU - Sharma, Priyanka

AU - Barlow, William E.

AU - Godwin, Andrew K.

AU - Parkes, Eileen E.

AU - Knight, Laura A.

AU - Walker, Steven M.

AU - Kennedy, Richard D.

AU - Harkin, Denis P.

AU - Logan, Gemma E.

AU - Steele, Christopher J.

AU - Lambe, Shauna M.

AU - Badve, Sunil

AU - Gökmen-Polar, Yesim

AU - Pathak, Harsh B.

AU - Isakova, Kamilla

AU - Linden, Hannah M.

AU - Porter, Peggy

AU - Pusztai, Lajos

AU - Thompson, Alastair M.

AU - Tripathy, Debu

AU - Hortobagyi, Gabriel N.

AU - Hayes, Daniel F.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - PURPOSE To independently validate two biomarkers, a 44-gene DNA damage immune response (DDIR) signature and stromal tumor-infiltrating lymphocytes (sTILs), as prognostic markers in patients with triple-negative breast cancer (TNBC) treated with adjuvant doxorubicin (A) and cyclophosphamide (C) in SWOG 9313. METHODS Four hundred twenty-five centrally determined patient cases with TNBC from S9313 were identified. DDIR signature was performed on RNA isolated from formalin-fixed paraffin-embedded tumor tissue, and samples were classified as DDIR negative or positive using predefined cutoffs. Evaluation of sTILs was performed as described previously. Markers were tested for prognostic value for disease-free survival (DFS) and overall survival (OS) using Cox regression models adjusted for treatment assignment, nodal status, and tumor size. RESULTS Among 425 patients with TNBC, 33% were node positive. DDIR was tested successfully in 90% of patients (381 of 425), 62% of which were DDIR signature positive. DDIR signature positivity was associated with improved DFS (hazard ratio [HR], 0.67; 95% CI, 0.48 to 0.92; P = .015) and OS (HR, 0.61; 95% CI, 0.43 to 0.89; P = .010). sTILs density assessment was available in 99% of patients and was associated with improved DFS (HR, 0.70; 95% CI, 0.51 to 0.96; P = .026 for sTILs density≥20% v,20%) and OS (HR, 0.59; 95% CI, 0.41 to 0.85; P = .004 for sTILs density ≥ 20% v <20%). DDIR signature score and sTILs density were moderately correlated (r = 0.60), which precluded statistical significance for DFS in a joint model. Three-year DFS and OS in a subgroup of patients with DDIR positivity and T1c/T2N0 disease were 88% and 94%, respectively. CONCLUSION The prognostic role of sTILs and DDIR in early-stage TNBC was confirmed. DDIR signature conferred improved prognosis in two thirds of patients with TNBC treated with adjuvant AC. DDIR signature has the potential to stratify outcome and to identify patients with less projected benefit after AC chemotherapy.

AB - PURPOSE To independently validate two biomarkers, a 44-gene DNA damage immune response (DDIR) signature and stromal tumor-infiltrating lymphocytes (sTILs), as prognostic markers in patients with triple-negative breast cancer (TNBC) treated with adjuvant doxorubicin (A) and cyclophosphamide (C) in SWOG 9313. METHODS Four hundred twenty-five centrally determined patient cases with TNBC from S9313 were identified. DDIR signature was performed on RNA isolated from formalin-fixed paraffin-embedded tumor tissue, and samples were classified as DDIR negative or positive using predefined cutoffs. Evaluation of sTILs was performed as described previously. Markers were tested for prognostic value for disease-free survival (DFS) and overall survival (OS) using Cox regression models adjusted for treatment assignment, nodal status, and tumor size. RESULTS Among 425 patients with TNBC, 33% were node positive. DDIR was tested successfully in 90% of patients (381 of 425), 62% of which were DDIR signature positive. DDIR signature positivity was associated with improved DFS (hazard ratio [HR], 0.67; 95% CI, 0.48 to 0.92; P = .015) and OS (HR, 0.61; 95% CI, 0.43 to 0.89; P = .010). sTILs density assessment was available in 99% of patients and was associated with improved DFS (HR, 0.70; 95% CI, 0.51 to 0.96; P = .026 for sTILs density≥20% v,20%) and OS (HR, 0.59; 95% CI, 0.41 to 0.85; P = .004 for sTILs density ≥ 20% v <20%). DDIR signature score and sTILs density were moderately correlated (r = 0.60), which precluded statistical significance for DFS in a joint model. Three-year DFS and OS in a subgroup of patients with DDIR positivity and T1c/T2N0 disease were 88% and 94%, respectively. CONCLUSION The prognostic role of sTILs and DDIR in early-stage TNBC was confirmed. DDIR signature conferred improved prognosis in two thirds of patients with TNBC treated with adjuvant AC. DDIR signature has the potential to stratify outcome and to identify patients with less projected benefit after AC chemotherapy.

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DO - 10.1200/JCO.19.00693

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