Six-year absolute invasive disease-free survival benefit of adding adjuvant pertuzumab to trastuzumab and chemotherapy for patients with early HER2-positive breast cancer: A Subpopulation Treatment Effect Pattern Plot (STEPP) analysis of the APHINITY (BIG 4-11) trial

Richard D Gelber; Xin V Wang; Bernard F Cole; David Cameron; Fatima Cardoso; Vivianne Tjan-Heijnen; Ian Krop; Sherene Loi; Roberto Salgado; Astrid Kiermaier; Elizabeth Frank; Debora Fumagalli; Carmela Caballero; Evandro de Azambuja; Marion Procter; Emma Clark; Eleonora Restuccia; Sarah Heeson; Jose Bines; Sibylle Loibl; Martine Piccart-Gebhart; APHINITY Steering Committee and Investigators

doi:10.1016/j.ejca.2022.01.031

Six-year absolute invasive disease-free survival benefit of adding adjuvant pertuzumab to trastuzumab and chemotherapy for patients with early HER2-positive breast cancer: A Subpopulation Treatment Effect Pattern Plot (STEPP) analysis of the APHINITY (BIG 4-11) trial

Richard D Gelber^*, Xin V Wang, Bernard F Cole, David Cameron, Fatima Cardoso, Vivianne Tjan-Heijnen, Ian Krop, Sherene Loi, Roberto Salgado, Astrid Kiermaier, Elizabeth Frank, Debora Fumagalli, Carmela Caballero, Evandro de Azambuja, Marion Procter, Emma Clark, Eleonora Restuccia, Sarah Heeson, Jose Bines, Sibylle LoiblMartine Piccart-Gebhart, APHINITY Steering Committee and Investigators

^*Corresponding author for this work

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

Abstract

AIM: The APHINITY trial showed that adding adjuvant pertuzumab (P) to trastuzumab and chemotherapy, compared with adding placebo (Pla), significantly improved invasive disease-free survival (IDFS) for patients with HER2+ early breast cancer both overall and for the node-positive (N+) cohort. We explored whether adding P could benefit some N- subpopulations and whether to consider de-escalation for some N+ subpopulations.

METHODS: Subpopulation Treatment Effect Pattern Plot (STEPP) is an exploratory, graphical method that plots estimates of treatment effect for overlapping patient subpopulations defined by a covariate of interest. We used STEPP to estimate Kaplan-Meier differences in 6-year IDFS percentages (P minus Pla: Δ ± standard error [SE]), both overall and by nodal status, for overlapping subpopulations defined by (1) a clinical composite risk score, (2) tumour infiltrating lymphocytes (TILs) percentage, and (3) human epidermal growth factor receptor 2 (HER2) FISH copy number. Because of multiplicity, a Δ of at least three SE is required to warrant attention.

RESULTS: The average absolute gains in 6-year IDFS percentages were 2.8 ± 0.9 overall; 4.5 ± 1.2 for N+ and 0.1 ± 1.1 for N-. Largest gains were for patients with intermediate clinical composite risk (5.3 ± 1.9 overall; 6.9 ± 2.3 N+; 4.0 ± 3.0 N-), highest TILs percentage (6.3 ± 1.7 overall; 7.4 ± 2.4 N+; 3.2 ± 1.7 N-), and intermediate HER2 copy number (2.8 ± 1.9 overall; 7.4 ± 2.5 N+; -1.3 ± 1.9 N-), but clear evidence indicating a pattern of differential subpopulation treatment effects was lacking.

CONCLUSIONS: STEPP plots for N- did not identify subpopulations clearly benefiting from adding P, and those for N+ did not identify subpopulations warranting de-escalation. TILs percentage appeared to be more predictive of P treatment effect than clinical composite risk score.

TRIAL REGISTRATION: clinicaltrials.gov Identifier NCT01358877.

Original language	English
Pages (from-to)	219-228
Number of pages	10
Journal	European Journal of Cancer
Volume	166
Early online date	18 Mar 2022
DOIs	https://doi.org/10.1016/j.ejca.2022.01.031
Publication status	Published - May 2022

Keywords

Adjuvant therapy
HER2-positive early breast cancer
Pertuzumab
STEPP (Subpopulation Treatment Effect Pattern Plot)
SUBGROUP ANALYSES
SUBSETS
TILs (tumour infiltrating lymphocytes)
TREATMENT-COVARIATE INTERACTIONS
Trastuzumab
WOMEN

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Gelber, R. D., Wang, X. V., Cole, B. F., Cameron, D., Cardoso, F., Tjan-Heijnen, V., Krop, I., Loi, S., Salgado, R., Kiermaier, A., Frank, E., Fumagalli, D., Caballero, C., de Azambuja, E., Procter, M., Clark, E., Restuccia, E., Heeson, S., Bines, J., ... APHINITY Steering Committee and Investigators (2022). Six-year absolute invasive disease-free survival benefit of adding adjuvant pertuzumab to trastuzumab and chemotherapy for patients with early HER2-positive breast cancer: A Subpopulation Treatment Effect Pattern Plot (STEPP) analysis of the APHINITY (BIG 4-11) trial. European Journal of Cancer, 166, 219-228. https://doi.org/10.1016/j.ejca.2022.01.031

Gelber, Richard D ; Wang, Xin V ; Cole, Bernard F et al. / Six-year absolute invasive disease-free survival benefit of adding adjuvant pertuzumab to trastuzumab and chemotherapy for patients with early HER2-positive breast cancer : A Subpopulation Treatment Effect Pattern Plot (STEPP) analysis of the APHINITY (BIG 4-11) trial. In: European Journal of Cancer. 2022 ; Vol. 166. pp. 219-228.

@article{e8e83c0c02d343af8d65ac5566556708,

title = "Six-year absolute invasive disease-free survival benefit of adding adjuvant pertuzumab to trastuzumab and chemotherapy for patients with early HER2-positive breast cancer: A Subpopulation Treatment Effect Pattern Plot (STEPP) analysis of the APHINITY (BIG 4-11) trial",

abstract = "AIM: The APHINITY trial showed that adding adjuvant pertuzumab (P) to trastuzumab and chemotherapy, compared with adding placebo (Pla), significantly improved invasive disease-free survival (IDFS) for patients with HER2+ early breast cancer both overall and for the node-positive (N+) cohort. We explored whether adding P could benefit some N- subpopulations and whether to consider de-escalation for some N+ subpopulations.METHODS: Subpopulation Treatment Effect Pattern Plot (STEPP) is an exploratory, graphical method that plots estimates of treatment effect for overlapping patient subpopulations defined by a covariate of interest. We used STEPP to estimate Kaplan-Meier differences in 6-year IDFS percentages (P minus Pla: Δ ± standard error [SE]), both overall and by nodal status, for overlapping subpopulations defined by (1) a clinical composite risk score, (2) tumour infiltrating lymphocytes (TILs) percentage, and (3) human epidermal growth factor receptor 2 (HER2) FISH copy number. Because of multiplicity, a Δ of at least three SE is required to warrant attention.RESULTS: The average absolute gains in 6-year IDFS percentages were 2.8 ± 0.9 overall; 4.5 ± 1.2 for N+ and 0.1 ± 1.1 for N-. Largest gains were for patients with intermediate clinical composite risk (5.3 ± 1.9 overall; 6.9 ± 2.3 N+; 4.0 ± 3.0 N-), highest TILs percentage (6.3 ± 1.7 overall; 7.4 ± 2.4 N+; 3.2 ± 1.7 N-), and intermediate HER2 copy number (2.8 ± 1.9 overall; 7.4 ± 2.5 N+; -1.3 ± 1.9 N-), but clear evidence indicating a pattern of differential subpopulation treatment effects was lacking.CONCLUSIONS: STEPP plots for N- did not identify subpopulations clearly benefiting from adding P, and those for N+ did not identify subpopulations warranting de-escalation. TILs percentage appeared to be more predictive of P treatment effect than clinical composite risk score.TRIAL REGISTRATION: clinicaltrials.gov Identifier NCT01358877.",

keywords = "Adjuvant therapy, HER2-positive early breast cancer, Pertuzumab, STEPP (Subpopulation Treatment Effect Pattern Plot), SUBGROUP ANALYSES, SUBSETS, TILs (tumour infiltrating lymphocytes), TREATMENT-COVARIATE INTERACTIONS, Trastuzumab, WOMEN",

author = "Gelber, {Richard D} and Wang, {Xin V} and Cole, {Bernard F} and David Cameron and Fatima Cardoso and Vivianne Tjan-Heijnen and Ian Krop and Sherene Loi and Roberto Salgado and Astrid Kiermaier and Elizabeth Frank and Debora Fumagalli and Carmela Caballero and {de Azambuja}, Evandro and Marion Procter and Emma Clark and Eleonora Restuccia and Sarah Heeson and Jose Bines and Sibylle Loibl and Martine Piccart-Gebhart and {APHINITY Steering Committee and Investigators}",

year = "2022",

month = may,

doi = "10.1016/j.ejca.2022.01.031",

language = "English",

volume = "166",

pages = "219--228",

journal = "European Journal of Cancer",

issn = "0959-8049",

publisher = "ELSEVIER SCI LTD",

}

Gelber, RD, Wang, XV, Cole, BF, Cameron, D, Cardoso, F, Tjan-Heijnen, V, Krop, I, Loi, S, Salgado, R, Kiermaier, A, Frank, E, Fumagalli, D, Caballero, C, de Azambuja, E, Procter, M, Clark, E, Restuccia, E, Heeson, S, Bines, J, Loibl, S, Piccart-Gebhart, M & APHINITY Steering Committee and Investigators 2022, 'Six-year absolute invasive disease-free survival benefit of adding adjuvant pertuzumab to trastuzumab and chemotherapy for patients with early HER2-positive breast cancer: A Subpopulation Treatment Effect Pattern Plot (STEPP) analysis of the APHINITY (BIG 4-11) trial', European Journal of Cancer, vol. 166, pp. 219-228. https://doi.org/10.1016/j.ejca.2022.01.031

Six-year absolute invasive disease-free survival benefit of adding adjuvant pertuzumab to trastuzumab and chemotherapy for patients with early HER2-positive breast cancer: A Subpopulation Treatment Effect Pattern Plot (STEPP) analysis of the APHINITY (BIG 4-11) trial. / Gelber, Richard D; Wang, Xin V; Cole, Bernard F et al.
In: European Journal of Cancer, Vol. 166, 05.2022, p. 219-228.

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

TY - JOUR

T1 - Six-year absolute invasive disease-free survival benefit of adding adjuvant pertuzumab to trastuzumab and chemotherapy for patients with early HER2-positive breast cancer

T2 - A Subpopulation Treatment Effect Pattern Plot (STEPP) analysis of the APHINITY (BIG 4-11) trial

AU - Gelber, Richard D

AU - Wang, Xin V

AU - Cole, Bernard F

AU - Cameron, David

AU - Cardoso, Fatima

AU - Tjan-Heijnen, Vivianne

AU - Krop, Ian

AU - Loi, Sherene

AU - Salgado, Roberto

AU - Kiermaier, Astrid

AU - Frank, Elizabeth

AU - Fumagalli, Debora

AU - Caballero, Carmela

AU - de Azambuja, Evandro

AU - Procter, Marion

AU - Clark, Emma

AU - Restuccia, Eleonora

AU - Heeson, Sarah

AU - Bines, Jose

AU - Loibl, Sibylle

AU - Piccart-Gebhart, Martine

AU - APHINITY Steering Committee and Investigators

PY - 2022/5

Y1 - 2022/5

N2 - AIM: The APHINITY trial showed that adding adjuvant pertuzumab (P) to trastuzumab and chemotherapy, compared with adding placebo (Pla), significantly improved invasive disease-free survival (IDFS) for patients with HER2+ early breast cancer both overall and for the node-positive (N+) cohort. We explored whether adding P could benefit some N- subpopulations and whether to consider de-escalation for some N+ subpopulations.METHODS: Subpopulation Treatment Effect Pattern Plot (STEPP) is an exploratory, graphical method that plots estimates of treatment effect for overlapping patient subpopulations defined by a covariate of interest. We used STEPP to estimate Kaplan-Meier differences in 6-year IDFS percentages (P minus Pla: Δ ± standard error [SE]), both overall and by nodal status, for overlapping subpopulations defined by (1) a clinical composite risk score, (2) tumour infiltrating lymphocytes (TILs) percentage, and (3) human epidermal growth factor receptor 2 (HER2) FISH copy number. Because of multiplicity, a Δ of at least three SE is required to warrant attention.RESULTS: The average absolute gains in 6-year IDFS percentages were 2.8 ± 0.9 overall; 4.5 ± 1.2 for N+ and 0.1 ± 1.1 for N-. Largest gains were for patients with intermediate clinical composite risk (5.3 ± 1.9 overall; 6.9 ± 2.3 N+; 4.0 ± 3.0 N-), highest TILs percentage (6.3 ± 1.7 overall; 7.4 ± 2.4 N+; 3.2 ± 1.7 N-), and intermediate HER2 copy number (2.8 ± 1.9 overall; 7.4 ± 2.5 N+; -1.3 ± 1.9 N-), but clear evidence indicating a pattern of differential subpopulation treatment effects was lacking.CONCLUSIONS: STEPP plots for N- did not identify subpopulations clearly benefiting from adding P, and those for N+ did not identify subpopulations warranting de-escalation. TILs percentage appeared to be more predictive of P treatment effect than clinical composite risk score.TRIAL REGISTRATION: clinicaltrials.gov Identifier NCT01358877.

AB - AIM: The APHINITY trial showed that adding adjuvant pertuzumab (P) to trastuzumab and chemotherapy, compared with adding placebo (Pla), significantly improved invasive disease-free survival (IDFS) for patients with HER2+ early breast cancer both overall and for the node-positive (N+) cohort. We explored whether adding P could benefit some N- subpopulations and whether to consider de-escalation for some N+ subpopulations.METHODS: Subpopulation Treatment Effect Pattern Plot (STEPP) is an exploratory, graphical method that plots estimates of treatment effect for overlapping patient subpopulations defined by a covariate of interest. We used STEPP to estimate Kaplan-Meier differences in 6-year IDFS percentages (P minus Pla: Δ ± standard error [SE]), both overall and by nodal status, for overlapping subpopulations defined by (1) a clinical composite risk score, (2) tumour infiltrating lymphocytes (TILs) percentage, and (3) human epidermal growth factor receptor 2 (HER2) FISH copy number. Because of multiplicity, a Δ of at least three SE is required to warrant attention.RESULTS: The average absolute gains in 6-year IDFS percentages were 2.8 ± 0.9 overall; 4.5 ± 1.2 for N+ and 0.1 ± 1.1 for N-. Largest gains were for patients with intermediate clinical composite risk (5.3 ± 1.9 overall; 6.9 ± 2.3 N+; 4.0 ± 3.0 N-), highest TILs percentage (6.3 ± 1.7 overall; 7.4 ± 2.4 N+; 3.2 ± 1.7 N-), and intermediate HER2 copy number (2.8 ± 1.9 overall; 7.4 ± 2.5 N+; -1.3 ± 1.9 N-), but clear evidence indicating a pattern of differential subpopulation treatment effects was lacking.CONCLUSIONS: STEPP plots for N- did not identify subpopulations clearly benefiting from adding P, and those for N+ did not identify subpopulations warranting de-escalation. TILs percentage appeared to be more predictive of P treatment effect than clinical composite risk score.TRIAL REGISTRATION: clinicaltrials.gov Identifier NCT01358877.

KW - Adjuvant therapy

KW - HER2-positive early breast cancer

KW - Pertuzumab

KW - STEPP (Subpopulation Treatment Effect Pattern Plot)

KW - SUBGROUP ANALYSES

KW - SUBSETS

KW - TILs (tumour infiltrating lymphocytes)

KW - TREATMENT-COVARIATE INTERACTIONS

KW - Trastuzumab

KW - WOMEN

U2 - 10.1016/j.ejca.2022.01.031

DO - 10.1016/j.ejca.2022.01.031

M3 - Article

C2 - 35313167

SN - 0959-8049

VL - 166

SP - 219

EP - 228

JO - European Journal of Cancer

JF - European Journal of Cancer

ER -

Gelber RD, Wang XV, Cole BF, Cameron D, Cardoso F, Tjan-Heijnen V et al. Six-year absolute invasive disease-free survival benefit of adding adjuvant pertuzumab to trastuzumab and chemotherapy for patients with early HER2-positive breast cancer: A Subpopulation Treatment Effect Pattern Plot (STEPP) analysis of the APHINITY (BIG 4-11) trial. European Journal of Cancer. 2022 May;166:219-228. Epub 2022 Mar 18. doi: 10.1016/j.ejca.2022.01.031