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Combined Perioperative Lapatinib and Trastuzumab in Early HER2-Positive Breast Cancer Identifies Early Responders: Randomized UK EPHOS-B Trial Long-Term Results

Combined Perioperative Lapatinib and Trastuzumab in Early HER2-Positive Breast Cancer Identifies Early Responders: Randomized UK EPHOS-B Trial Long-Term Results
Combined Perioperative Lapatinib and Trastuzumab in Early HER2-Positive Breast Cancer Identifies Early Responders: Randomized UK EPHOS-B Trial Long-Term Results

Purpose: EPHOS-B aimed to determine whether perioperative anti-HER2 therapy inhibited proliferation and/or increased apoptosis in HER2-positive breast cancer. Patients and Methods: This randomized phase II, two-part, multicenter trial included newly diagnosed women with HER2-positive invasive breast cancer due to undergo surgery. Patients were randomized to: part 1 (1:2:2), no treatment (control), trastuzumab or lapatinib; part 2 (1:1:2) control, trastuzumab, or lapatinib and trastuzumab combination. Treatment was given for 11 days presurgery. Coprimary endpoints were change in Ki67 and apoptosis between baseline and surgery tumor samples (biologic response: ≥30% change). Central pathology review scored residual cancer burden (RCB). Relapse-free survival (RFS) explored long-term effects. Results: Between November 2010 and September 2015, 257 patients were randomized (part 1: control 22, trastuzumab 57, lapatinib 51; part 2: control 29, trastuzumab 32, combination 66). Ki67 response was evaluable for 223 patients: in part 1 Ki67 response occurred in 29/44 (66%) lapatinib versus 18/49 (37%) trastuzumab (P = 0.007) and 1/22 (5%) control (P < 0.0001); in part 2 in 36/49 (74%) combination versus 14/31 (45%) trastuzumab (P = 0.02) and 2/28 (7%) control (P < 0.0001). No significant increase in apoptosis after 11 days was seen in treatment groups. Six patients achieved complete pathologic response (pCR, RCB0) and 13 RCB1, all but two in the combination group. After 6 years median follow-up, 28 (11%) had recurrence and 19 (7%) died. No recurrences or deaths were observed among patients who achieved a pCR. Ki67% falls ≥50% associated with fewer recurrences (P = 0.002). Conclusions: Early response after short duration anti-HER2 dual therapy identifies cancers dependent on the HER2 pathway providing a strategy for exploring risk-adapted individualized treatment de-escalation.

1078-0432
1323-1334
Bundred, N
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Porta, N
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Murray Brunt, A
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Cramer, A
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Hanby, A
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Shaaban, A M
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Rakha, E A
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Armstrong, A
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Cutress, Ramsey
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Dodwell, D
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Emson, M A
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Evans, A
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Hartup, S M
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Horgan, K
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Miller, S E
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McIntosh, S A
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Morden, J P
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Naik, J
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Narayanan, S
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Ooi, J
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Skene, A I
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Cameron, D A
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Bliss, J M
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Bundred, N
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Porta, N
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Murray Brunt, A
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Cramer, A
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Hanby, A
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Shaaban, A M
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Rakha, E A
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Armstrong, A
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Cutress, Ramsey
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Dodwell, D
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Emson, M A
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Evans, A
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Hartup, S M
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Horgan, K
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Miller, S E
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McIntosh, S A
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Morden, J P
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Naik, J
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Narayanan, S
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Ooi, J
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Skene, A I
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Cameron, D A
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Bliss, J M
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Bundred, N, Porta, N, Murray Brunt, A, Cramer, A, Hanby, A, Shaaban, A M, Rakha, E A, Armstrong, A, Cutress, Ramsey, Dodwell, D, Emson, M A, Evans, A, Hartup, S M, Horgan, K, Miller, S E, McIntosh, S A, Morden, J P, Naik, J, Narayanan, S, Ooi, J, Skene, A I, Cameron, D A and Bliss, J M (2022) Combined Perioperative Lapatinib and Trastuzumab in Early HER2-Positive Breast Cancer Identifies Early Responders: Randomized UK EPHOS-B Trial Long-Term Results. Clinical Cancer Research, 28 (7), 1323-1334. (doi:10.1158/1078-0432.CCR-21-3177).

Record type: Article

Abstract

Purpose: EPHOS-B aimed to determine whether perioperative anti-HER2 therapy inhibited proliferation and/or increased apoptosis in HER2-positive breast cancer. Patients and Methods: This randomized phase II, two-part, multicenter trial included newly diagnosed women with HER2-positive invasive breast cancer due to undergo surgery. Patients were randomized to: part 1 (1:2:2), no treatment (control), trastuzumab or lapatinib; part 2 (1:1:2) control, trastuzumab, or lapatinib and trastuzumab combination. Treatment was given for 11 days presurgery. Coprimary endpoints were change in Ki67 and apoptosis between baseline and surgery tumor samples (biologic response: ≥30% change). Central pathology review scored residual cancer burden (RCB). Relapse-free survival (RFS) explored long-term effects. Results: Between November 2010 and September 2015, 257 patients were randomized (part 1: control 22, trastuzumab 57, lapatinib 51; part 2: control 29, trastuzumab 32, combination 66). Ki67 response was evaluable for 223 patients: in part 1 Ki67 response occurred in 29/44 (66%) lapatinib versus 18/49 (37%) trastuzumab (P = 0.007) and 1/22 (5%) control (P < 0.0001); in part 2 in 36/49 (74%) combination versus 14/31 (45%) trastuzumab (P = 0.02) and 2/28 (7%) control (P < 0.0001). No significant increase in apoptosis after 11 days was seen in treatment groups. Six patients achieved complete pathologic response (pCR, RCB0) and 13 RCB1, all but two in the combination group. After 6 years median follow-up, 28 (11%) had recurrence and 19 (7%) died. No recurrences or deaths were observed among patients who achieved a pCR. Ki67% falls ≥50% associated with fewer recurrences (P = 0.002). Conclusions: Early response after short duration anti-HER2 dual therapy identifies cancers dependent on the HER2 pathway providing a strategy for exploring risk-adapted individualized treatment de-escalation.

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Accepted/In Press date: 20 January 2022
Published date: 1 April 2022
Additional Information: We thank all participating patients and their families, involved staff at participating hospitals, and staff involved in the trial at The Institute of Cancer Research Clinical Trials & Statistics Unit (ICR-CTSU). The trial was funded by Cancer Research UK with approval of its design from their Clinical Trials Awards and Advisory Committee (CRUK/08/002). ICR-CTSU receives programme grant funding from Cancer Research UK (grant Nos. C1491/A9895, C1491/A15955, C1491/A25351). Lapatinib was provided to centers by Novartis (formerly GlaxoSmithKline), who also supplied an educational grant. None of the funders had a direct role in study design, data collection, data analysis, data interpretation, or writing of the report. The EPHOS-B trial represents independent research supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. We acknowledge support at participating sites by the NIHR Cancer Research Network (CRN)/NHS Research Scotland/Health and Care Research Wales.

Identifiers

Local EPrints ID: 455120
URI: http://eprints.soton.ac.uk/id/eprint/455120
ISSN: 1078-0432
PURE UUID: 51bb064b-22be-439a-a5ca-bde7c5e32a2c

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Date deposited: 10 Mar 2022 17:31
Last modified: 09 Jun 2022 17:05

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Contributors

Author: N Bundred
Author: N Porta
Author: A Murray Brunt
Author: A Cramer
Author: A Hanby
Author: A M Shaaban
Author: E A Rakha
Author: A Armstrong
Author: Ramsey Cutress
Author: D Dodwell
Author: M A Emson
Author: A Evans
Author: S M Hartup
Author: K Horgan
Author: S E Miller
Author: S A McIntosh
Author: J P Morden
Author: J Naik
Author: S Narayanan
Author: J Ooi
Author: A I Skene
Author: D A Cameron
Author: J M Bliss

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