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Clinical Trial
. 2021 May;32(5):642-651.
doi: 10.1016/j.annonc.2021.02.011. Epub 2021 Feb 19.

Predicted sensitivity to endocrine therapy for stage II-III hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer before chemo-endocrine therapy

L Du  1 , C Yau  2 , L Brown-Swigart  3 , R Gould  1 , G Krings  3 , G L Hirst  2 , I Bedrosian  4 , R M Layman  5 , J M Carter  6 , M Klein  7 , S Venters  2 , S Shad  2 , M van der Noordaa  2 , A J Chien  8 , T Haddad  9 , C Isaacs  10 , L Pusztai  11 , K Albain  12 , R Nanda  13 , D Tripathy  5 , M C Liu  9 , J Boughey  14 , R Schwab  15 , N Hylton  16 , A DeMichele  17 , J Perlmutter  18 , D Yee  19 , D Berry  20 , L Van't Veer  3 , V Valero  5 , L J Esserman  2 , W F Symmans  21
Affiliations
Clinical Trial

Predicted sensitivity to endocrine therapy for stage II-III hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer before chemo-endocrine therapy

L Du et al. Ann Oncol. 2021 May.

Abstract

Background: We proposed that a test for sensitivity to the adjuvant endocrine therapy component of treatment for patients with stage II-III breast cancer (SET2,3) should measure transcription related to estrogen and progesterone receptors (SETER/PR index) adjusted for a baseline prognostic index (BPI) combining clinical tumor and nodal stage with molecular subtype by RNA4 (ESR1, PGR, ERBB2, and AURKA).

Patients and methods: Patients with clinically high-risk, hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-) breast cancer received neoadjuvant taxane-anthracycline chemotherapy, surgery with measurement of residual cancer burden (RCB), and then adjuvant endocrine therapy. SET2,3 was measured from pre-treatment tumor biopsies, evaluated first in an MD Anderson Cancer Center (MDACC) cohort (n = 307, 11 years' follow-up, U133A microarrays), cut point was determined, and then independent, blinded evaluation was carried out in the I-SPY2 trial (n = 268, high-risk MammaPrint result, 3.8 years' follow-up, Agilent-44K microarrays, NCI Clinical Trials ID: NCT01042379). Primary outcome measure was distant relapse-free survival. Multivariate Cox regression models tested prognostic independence of SET2,3 relative to RCB and other molecular prognostic signatures, and whether other prognostic signatures could substitute for SETER/PR or RNA4 components of SET2,3.

Results: SET2,3 added independent prognostic information to RCB in the MDACC cohort: SET2,3 [hazard ratio (HR) 0.23, P = 0.004] and RCB (HR 1.77, P < 0.001); and the I-SPY2 trial: SET2,3 (HR 0.27, P = 0.031) and RCB (HR 1.68, P = 0.008). SET2,3 provided similar prognostic information irrespective of whether RCB-II or RCB-III after chemotherapy, and in both luminal subtypes. Conversely, RCB was most strongly prognostic in cancers with low SET2,3 status (MDACC P < 0.001, I-SPY2 P < 0.001). Other molecular signatures were not independently prognostic; they could effectively substitute for RNA4 subtype within the BPI component of SET2,3, but they could not effectively substitute for SETER/PR index.

Conclusions: SET2,3 added independent prognostic information to chemotherapy response (RCB) and baseline prognostic score or subtype. Approximately 40% of patients with clinically high-risk HR+/HER2- disease had high SET2,3 and could be considered for clinical trials of neoadjuvant endocrine-based treatment.

Keywords: chemo-endocrine; hormonal; prediction; prognosis; response; treatments.

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Conflict of interest statement

Disclosure WFS is a co-inventor of a pending patent application for the sensitivity to endocrine therapy and co-founder with equity in Delphi Diagnostics that licensed the intellectual property. LP and WFS are co-inventors of an issued patent for the algorithm to calculate residual cancer burden that is freely available on the internet. LvV is a co-inventor of an issued patent for the MammaPrint test and holds equity in Agendia that licensed the intellectual property. The remaining authors have declared no conflicts of interest.

Figures

Figure 1.
Figure 1.. Description of SET2,3 algorithm.
Genes measured to calculate SET2,3 as a weighted sum of SETER/PR index of hormone receptor-related transcription not associated with proliferation and the baseline prognostic index (BPI) that combines clinical T stage (cT), clinical nodal stage (cN), and molecular risk subtype from four genes (RNA4).
Figure 2.
Figure 2.. Consort diagrams of samples used to evaluate the clinical cohorts.
(A) The MD Anderson Cancer Center (MDACC) cohort and (B) The I-SPY2 trial. cN, clinical nodal stage; cT, Clinical T stage; RCB, residual cancer burden.
Figure 3.
Figure 3.. Prognostic performance of SET2,3 relative to extent of residual cancer burden (RCB) and molecular subtype.
The distant relapse-free survival (DRFS) hazard function for SET2,3 in the patients with significant residual disease after neoadjuvant chemotherapy (RCB-II/III). Risk of DRFS event for each SET2,3 value relative to lowest SET2,3 value in each group, according to RCB-II or RCB-III in (A) the MD Anderson Cancer Center (MDACC) cohort and (B) the I-SPY2 trial; and, in the patients with RCB-II/III, according to genomic subtype defined by: (C) PAM50 classifier as luminal A or luminal B in the MDACC cohort and (D) MammaPrint test as high-risk (MP1) or ultra-high-risk (MP2) subtype in the I-SPY2 trial. Note: Dashed lines represent 95% confidence interval bounds. RCB-III includes progressive disease. The MP1 and MP2 groups are equivalent to luminal B and basal subtypes, respectively.
Figure 4.
Figure 4.. Prognosis of residual cancer burden (RCB) according to SET2,3 status.
RCB was evaluated within high and low SET2,3 classes, first as the hazard function for RCB values in the patients with residual disease (RD) by SET2,3 status (low SET2,3; high SET2,3), relative to all the patients with pathologic complete response (pCR) in (A) the MD Anderson Cancer Center (MDACC) cohort and (B) the I-SPY2 trial; and then as RCB classes (pCR or RCB-I, RCB-II, or RCB-III) in the MDACC cohort in cancers with low SET2,3 (C) or high SET2,3 (D), and in the I-SPY2 trial in cancers with low SET2,3 (E) or high SET2,3 (F). Note: Dashed lines represent 95% confidence interval bounds. In the MDACC cohort, there were 225 patients with RD and 36 with pCR (6 of 36 had high SET2,3). In the I-SPY2 trial, there were 215 patients with RD and 50 with pCR (8 of 50 had high SET2,3).
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References

    1. Sparano JA, Zhao F, Martino S, et al. Long-term follow-up of the E1199 phase III trial evaluating the role of taxane and schedule in operable breast cancer. J Clin Oncol. 2015;33(21):2353–2360. - PMC - PubMed
    1. Liu MC, Pitcher BN, Mardis ER, et al. PAM50 gene signatures and breast cancer prognosis with adjuvant anthracycline- and taxane-based chemotherapy: correlative analysis of C9741 (Alliance). NPJ Breast Cancer. 2016;2:15023. - PMC - PubMed
    1. Pan H, Gray R, Braybrooke J, et al. 20-Year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. N Engl J Med. 2017;377(19):1836–1846. - PMC - PubMed
    1. Albain KS, Barlow WE, Shak S, et al. Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet Oncol. 2010;11(1):55–65. - PMC - PubMed
    1. Symmans WF, Peintinger F, Hatzis C, et al. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol. 2007;25(28):4414–4422. - PubMed

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