Breast Cancer Index in Premenopausal Women

With Early-Stage Hormone Receptor–Positive Breast Cancer

Ruth M. O’Regan, MD; Yi Zhang, PhD; Gini F. Fleming, MD; Prudence A. Francis, MD; Roswitha Kammler, BA; Giuseppe Viale, MD; Patrizia Dell’Orto, MD;

Istvan Lang, MD, PhD; Meritxell Bellet, MD; Herve R. Bonnefoi, MD; Carlo Tondini, MD; Federica Villa, MD; Antonio Bernardo, MD;

Eva M. Ciruelos, MD, PhD; Patrick Neven, MD, PhD; Per Karlsson, MD; Bettina Müller, MD; Wolfram Jochum, MD, PhD; Khalil Zaman, MD, PhD;

Silvana Martino, DO; Charles E. Geyer Jr, MD; Katarzyna J. Jerzak, MD, MSc; Nancy E. Davidson, MD; Robert E. Coleman, MBBS, MD; James N. Ingle, MD;

Marion T. van Mackelenbergh, MD, PhD; Sherene Loi, MD, PhD; Marco Colleoni, MD; Catherine A. Schnabel, PhD;

Kai Treuner, PhD; Meredith M. Regan, ScD

IMPORTANCE Adjuvant ovarian function suppression (OFS) with oral endocrine therapy

improves outcomes for premenopausal patients with hormone receptor–positive (HR+

)

breast cancer but adds adverse effects. A genomic biomarker for selecting patients most

likely to benefit from OFS-based treatment is lacking.

OBJECTIVE To assess the predictive and prognostic performance of the Breast Cancer Index

(BCI) for OFS benefit in premenopausal women with HR+ breast cancer.

DESIGN, SETTING, AND PARTICIPANTS This prospective-retrospective translational study used

all available tumor tissue samples from female patients from the Suppression of Ovarian

Function Trial (SOFT). These individuals were randomized to receive 5 years of adjuvant

tamoxifen alone, tamoxifen plus OFS, or exemestane plus OFS. BCI testing was performed

blinded to clinical data and outcome. The a priori hypothesis was that BCI HOXB13/IL17BR

ratio (BCI[H/I])–high tumors would benefit more from OFS and high BCI portended poorer

prognosis in this population. Settings spanned multiple centers internationally. Participants

included premenopausal female patients with HR+ early breast cancer with specimens in the

International Breast Cancer Study Group tumor repository available for RNA extraction. Data

were collected from December 2003 to April 2021 and were analyzed from May 2022 to

October 2022.

MAIN OUTCOMES AND MEASURES Primary end points were breast cancer–free interval (BCFI)

for the predictive analysis and distant recurrence-free interval (DRFI) for the prognostic

analyses.

RESULTS Tumor specimens were available for 1718 of the 3047 female patients in the SOFT

intention-to-treat population. The 1687 patients (98.2%) who had specimens that yielded

sufficient RNA for BCI testing represented the parent trial population. The median (IQR)

follow-up time was 12 (10.5-13.4) years, and 512 patients (30.3%) were younger than 40

years. Tumors were BCI(H/I)-low for 972 patients (57.6%) and BCI(H/I)-high for 715 patients

(42.4%). Patients with tumors classified as BCI(H/I)-low exhibited a 12-year absolute benefit

in BCFI of 11.6% from exemestane plus OFS (hazard ratio [HR], 0.48 [95% CI, 0.33-0.71]) and

an absolute benefit of 7.3% from tamoxifen plus OFS (HR, 0.69 [95% CI, 0.48-0.97]) relative

to tamoxifen alone. In contrast, patients with BCI(H/I)-high tumors did not benefit from

either exemestane plus OFS (absolute benefit, −0.4%; HR, 1.03 [95% CI, 0.70-1.53]; P for

interaction = .006) or tamoxifen plus OFS (absolute benefit, −1.2%; HR, 1.05 [95% CI,

0.72-1.54]; P for interaction = .11) compared with tamoxifen alone. BCI continuous index was

significantly prognostic in the N0 subgroup for DRFI (n = 1110; P = .004), with 12-year DRFI of

95.9%, 90.8%, and 86.3% in BCI low-risk, intermediate-risk, and high-risk N0 cancers,

respectively.

CONCLUSIONS AND RELEVANCE In this prospective-retrospective translational study of

patients enrolled in SOFT, BCI was confirmed as prognostic in premenopausal women with

HR+ breast cancer. The benefit from OFS-containing adjuvant endocrine therapy was greater

for patients with BCI(H/I)-low tumors than BCI(H/I)-high tumors. BCI(H/I)-low status may

identify premenopausal patients who are likely to benefit from this more intensive endocrine

therapy.

JAMA Oncol. doi:10.1001/jamaoncol.2024.3044

Published online August 15, 2024.

Supplemental content

Author Affiliations: Author

affiliations are listed at the end of this

article.

Corresponding Author: Meredith M.

Regan, ScD, IBCSG Statistical Center,

Division of Biostatistics, Dana-Farber

Cancer Institute, 450 Brookline Ave,

Boston, MA 02215 (mregan@jimmy.

harvard.edu).

Research

JAMA Oncology | Original Investigation

(Reprinted) E1

© 2024 American Medical Association. All rights reserved.

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A djuvant tamoxifen therapy for 5 years in women

with hormone receptor–positive (HR+

) breast cancer

reduces recurrence by approximately 40% and breast

cancer mortality by approximately one-third throughout the

first 15 years.1 Postmenopausal women experience a 30%

reduction in recurrence from adjuvant aromatase inhibitors

(AIs) compared to tamoxifen.2 The treatment of premenopausal women with AIs requires ovarian function suppression (OFS) to overcome compensatory physiological

responses that induce ovarian estrogen production and similarly reduce recurrence compared with tamoxifen combined

with OFS.3,4

The Suppression of Ovarian Function Trial (SOFT)

demonstrated the addition of OFS to tamoxifen and in combination with exemestane improved invasive disease-free survival compared with tamoxifen alone in premenopausal

women with HR+ early-stage breast cancer. At 12 years, diseasefree survival was 71.9%, 76.1%, and 79.0% with tamoxifen

alone, tamoxifen plus OFS, and exemestane plus OFS, respectively. Absolute benefits were 4.2% for tamoxifen plus OFS and

7.1% for exemestane plus OFS compared to tamoxifen alone.5

Tamoxifen plus OFS and exemestane plus OFS also improved

overall survival, from 86.8% with tamoxifen alone to 89.0%

with tamoxifen plus OFS and 89.4% with exemestane plus

OFS.5 Adverse events of grade 3 or higher were more frequent

among patients receiving either exemestane plus OFS (32.3%)

or tamoxifen plus OFS (31.0%) than those treated with

tamoxifen alone (24.6%).6 Short-term adverse effects (eg, hot

flashes, musculoskeletal symptoms, vaginal dryness, depression) can negatively impact adherence to endocrine therapy.

The long-term adverse effects of AI plus OFS may not yet be

fully appreciated. The impact of possible adverse effects must

be balanced against potential improvements in outcome in patients considering OFS.7-10

National Comprehensive Cancer Network guidelines

recommend a balanced discussion of the risks and benefits

associated with OFS. AI or tamoxifen for 5 years plus OFS

should be considered, based on the SOFT and Tamoxifen

and Exemestane Trial (TEXT) clinical trial outcomes for

premenopausal patients at higher risk of recurrence.11 Higher

risk has been defined as women at sufficient risk of recurrence to justify the use of chemotherapy, as well as women

younger than 35 years. A continuous, composite risk score using

patient and tumor characteristics can be used to aid with endocrine therapy decisions in premenopausal patients with

HR+

/ERBB2-negative breast cancer.12 Unlike adjuvant chemotherapy indication in HR+ breast cancer, currently there are no

genomic biomarkers to predict which premenopausal patients have the greatest potential to benefit from the combination of OFS and oral endocrine therapy with either

tamoxifen or AI.

The Breast Cancer Index (BCI) is a gene expression–based

signature composed of 2 functional biomarker panels.13,14BCI

(H/I) is a ratio of the HOXB13 and IL17BR genes and measures

estrogen signaling. The 5-gene Molecular Grade Index assesses tumor proliferation. Integration of the Molecular Grade

Index and H/I provides a single prognostic score that quantifies the risk of both late (5 to 10 years) and overall (0 to 10 years)

distant recurrence.14,15 For patients with 1 to 3 positive lymph

nodes, the BCIN+ prognostic model integrates the BCI score

with tumor size and grade.16 In addition, BCI(H/I) has been validated to predict benefit from extended endocrine therapy in

several prospective-retrospective studies that included predominantly postmenopausal patients with HR+ cancers without regard to ERBB2 expression. In these studies, patients with

BCI(H/I)-high tumors benefitted significantly from extended

endocrine therapy, whereas those with BCI(H/I)-low tumors

did not.17-20

The primary objective of this study was to assess the

predictive performance of BCI(H/I) in premenopausal women

with HR+ disease randomized in SOFT. Our a priori hypothesis was that BCI(H/I)-high tumors would have greater benefit from the use of 5 years adjuvant OFS adjuvant therapy than

BCI(H/I)-low tumors. The prognostic performance of BCI and

BCIN+ in this population was also assessed.

Methods

Study Design and Participants

SOFT is a prospective clinical trial that randomized 3066

premenopausal women with HR+ early-stage breast cancer to

receive 5 years of tamoxifen alone, tamoxifen plus OFS, or exemestane plus OFS.21 SOFT assessed the clinical value of adding OFS to tamoxifen and of using an AI plus OFS as adjuvant

endocrine therapy. Randomization was stratified by previous receipt of chemotherapy and lymph node status. Patients

had documented premenopausal status; those who had received chemotherapy were eligible for randomization if a premenopausal level of circulating estradiol was confirmed by

laboratory results within 8 months following completion of

chemotherapy.8 OFS was achieved by choice of triptorelin by

intramuscular injection every 28 days, bilateral oophorectomy, or ovarian irradiation. Patients initiating OFS with triptorelin could subsequently undergo oophorectomy or irradiation at any time.

Key Points

Question Can the Breast Cancer Index (BCI) prognosticate and

predict benefit of ovarian function suppression–based adjuvant

endocrine therapy in premenopausal women with hormone

receptor–positive breast cancer?

Findings In this prospective-retrospective translational study of

1687 patients enrolled in SOFT (Suppression of Ovarian Function

Trial), individuals with BCI HOXB13/IL17BR ratio (BCI[H/I])–low

tumors had greater benefit from ovarian function

suppression–based adjuvant endocrine therapy than patients with

BCI(H/I)-high tumors. A higher BCI continuous index was

confirmed to be associated with poorer prognosis in this

population.

Meaning If validated in additional studies, BCI may aid

decision-making about adjuvant endocrine therapy for

premenopausal patients with hormone receptor–positive breast

cancer.

Research Original Investigation Breast Cancer Index in Premenopausal Women With Early-Stage Hormone Receptor–Positive Breast Cancer

E2 JAMA Oncology Published online August 15, 2024 (Reprinted) jamaoncology.com

© 2024 American Medical Association. All rights reserved.

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Our prospective-retrospective translational study of

patients enrolled in SOFT aimed to evaluate the predictive

performance of BCI(H/I) status (high vs low), and the

prognostic performance of BCI in the context of adjuvant OFS

plus oral endocrine therapy after 12 years ofmedian follow-up.5

All patients enrolled in SOFT with available formalin-fixed paraffin-embedded (FFPE) tumor samples forRNA extractionwere

included. This study was approved by the IBCSG Translational Research Working Group. Patients provided written informed consent for the use of biological samples for future research. This study followed theREMARK reporting guideline.

Data were collected from December 2003 to April 2021.

BCI Assay

BCI gene expression analysis by reverse transcription

polymerase chain reaction was performed using RNA samples

extracted by the IBCSG Central Pathology Office, blinded to

clinical and outcome data. RNA was isolated from FFPE

primary tumor specimens.14Macrodissectionwas performed on

FFPE sections to enrich tumor content before RNA extraction.

For BCI testing, total RNA was reverse transcribed, and the resulting cDNA was preamplified by PCR using the PreAmp

Master Mix Kit (Thermo Fisher Scientific) before TaqMan PCR

analysis as reported previously.14BCI, BCIN+

, and BCI(H/I) were

calculated and BCI, BCIN+ risk groups, and BCI(H/I) categories

were determined using the prespecified cut points as described previously.14,16

Statistical Analysis

Analyses were prespecified prior to unblinding assay results.

The end points were breast cancer–free interval (BCFI), defined as the time from randomization to first invasive local,

regional, or distant recurrence, or contralateral breast tumor;

and distant recurrence-free interval (DRFI), defined as the time

from randomization to distant recurrence. In the absence of

an end point–defining event, the end point was censored at the

date of the last disease assessment.

The primary objective assessed the predictive performance of BCI(H/I) status (high vs low) for benefit from exemestane plus OFS compared to tamoxifen alone, and secondarily for

benefit of adding OFS to tamoxifen. The analysis used a Cox proportional hazards model for BCFI that included treatment assignment (3 treatment groups),BCI(H/I) status (low vs high), and

the interaction terms, stratified by prior chemotherapy and

lymph node status. Hypothesis testing for treatment-by-BCI

(H/I) status interaction used stratified log-rank tests. The hazard ratios (HRs) and associated 95%Wald CIs for comparing exemestane plus OFS vs tamoxifen alone and tamoxifen plus OFS

vs tamoxifen alone in each of the BCI(H/I) groups were estimated from themodel.Results from themodel that adjusted for

age, tumor size and grade, and ERBB2 status gave consistent results. The absolute benefit of each treatment compared to tamoxifen alone was estimated as the difference of the KaplanMeier estimates of 12-year BCFI between treatment groups.

A secondary objective evaluated the prognostic performance of continuous BCI and BCIN+

. Stratified Cox models for

DRFI were used to assess the prognostic performance

of BCI (for N0 cancers) and of BCIN+ (for N1 cancers) risk groups.

The models were stratified by prior chemotherapy and treatment assignment to estimate the HRs for high-risk and intermediate-risk vs low-risk groups. Additionally, Cox models for

DRFI that fit the continuous BCI or BCIN+ score as a linear functionwere used to estimate 12-year probabilities of freedom from

distant recurrence (reported as 12-year risk by subtracting from

1). The hypothesis testing used stratified tests. Statistical significance was defined as P < .05. SAS statistical software, version 9.4 (SAS Institute), was used for the statistical analysis.

Data were analyzed from May 2022 to October 2022.

Results

Tumor specimens were available for 1718 of 3047 patients in the

SOFT intention-to-treat population. The 1687 patients (98.2%)

whose specimens yielded sufficient RNA for BCI testing represented the parent trial population (eFigure 1 in Supplement 1;

Table). In the BCI cohort, 900 patients (53.3%) were premenoTable. Clinicopathologic Characteristics of Patients in SOFT

Characteristic

No. (%)

BCI cohort ITT population

Patients randomized 1687 (100) 3047 (100)

Treatment assignment

Tamoxifen 573 (34.0) 1018 (33.4)

Tamoxifen plus OFS 551 (32.7) 1015 (33.3)

Exemestane plus OFS 563 (33.4) 1014 (33.3)

Chemotherapy

No 787 (46.7) 1419 (46.6)

Yes 900 (53.3) 1628 (53.4)

Lymph node status

N0 1110 (65.8) 1995 (65.5)

N+ 577 (34.2) 1052 (34.5)

1-3 Nodes 426 (25.3) 754 (24.7)

≥4 Nodes 151 (9.0) 298 (9.8)

Age at randomization, y

<35 190 (11.3) 350 (11.5)

35-39 322 (19.1) 583 (19.1)

40-44 498 (29.5) 907 (29.8)

45-49 499 (29.6) 910 (29.9)

≥50 178 (10.6) 297 (9.7)

Tumor size, cm

≤2 1082 (64.1) 2013 (66.1)

>2 580 (34.4) 964 (31.6)

Unknown 25 (1.5) 70 (2.3)

Tumor gradea

1 428 (25.4) 789 (25.9)

2 846 (50.1) 1555 (51.0)

3 387 (22.9) 642 (21.1)

Unknown 26 (1.5) 61 (2.0)

ERBB2 statusa

Negative 1442 (85.5) 2586 (84.9)

Positive 198 (11.7) 367 (12.0)

Unknown 47 (2.8) 94 (3.1)

Abbreviations: BCI, Breast Cancer Index; ITT, intention to treat; OFS, ovarian

function suppression.

a Tumor grade and ERBB2 status were determined locally.

Breast Cancer Index in Premenopausal Women With Early-Stage Hormone Receptor–Positive Breast Cancer Original Investigation Research

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pausal after receiving chemotherapy before randomization,

1110 patients (65.8%) had N0 disease, and 198 (11.7%) had

ERBB2-positive cancers. In the BCI cohort, the absolute benefit

value at 12 years in BCFI was 6.6% from exemestane plus OFS

(HR, 0.69 [95% CI, 0.52-0.90]) and 3.7% from tamoxifen plus

OFS (HR, 0.83 [95% CI, 0.64-1.08]) vs tamoxifen alone (eTable 1

in Supplement 1).

Predictive Performance of BCI(H/I)

BCI(H/I) assessment stratified 972 patients (57.6%) with BCI

(H/I)-low tumors and 715 patients (42.4%) with BCI(H/I)-

high tumors (eTable 2 in Supplement 1). Patients with

tumors classified as BCI(H/I)-low exhibited a 12-year absolute benefit in BCFI of 11.6% from exemestane plus OFS (HR,

0.48 [95% CI, 0.33-0.71]) and an absolute benefit of 7.3%

from tamoxifen plus OFS (HR, 0.69 [95% CI, 0.48-0.97]),

relative to tamoxifen alone (Figure 1; eTable 3 in Supplement 1). In contrast, patients with BCI(H/I)-high tumors did

not derive the same benefit from either exemestane plus

OFS (absolute benefit, −0.4%; HR, 1.03 [95% CI, 0.70-1.53];

P for interaction = .006) or tamoxifen plus OFS (absolute

benefit, −1.2%; HR, 1.05 [95% CI, 0.72-1.54]; P for interaction = .11) compared with tamoxifen alone.

Similar results were observed in the predominant

subgroup of patients with ERBB2-negative cancers. Patients

with BCI(H/I)-low tumors experienced 12-year absolute benefit of 13.2% in BCFI from exemestane plus OFS (HR, 0.39 [95%

CI, 0.25-0.60]) and 7.4% from tamoxifen plus OFS (HR, 0.64

[95% CI, 0.44-0.93]) compared to tamoxifen alone (Figure 1).

Similar to the overall BCI cohort, patients with ERBB2-

negative cancers classified as BCI(H/I)-high showed no such

benefit from exemestane plus OFS (absolute benefit, −0.2%;

HR, 1.03 [95% CI, 0.64-1.68]) or tamoxifen plus OFS (absolute

benefit, −6.8%; HR, 1.37 [95% CI, 0.89-2.13]), relative to taFigure 1. Predictive Performance of Breast Cancer Index HOXB13/IL17BR Ratio (BCI[H/I]) Overall and in the ERBB2-Negative Subset of SOFT

A BCI(H/I)-low tumors

0

No. at risk

0 4 6 8 10 12

100

80 Breast cancer–free interval, %

Time since randomization, y

60

40

20

2

Tamoxifen

Tamoxifen plus OFS

Exemestane plus OFS

B BCI(H/I)-high tumors

0

No. at risk

0 4 6 8 10 12

100

80 Breast cancer–free interval, %

Time since randomization, y

60

40

20

2

Tamoxifen

Tamoxifen plus OFS

Exemestane plus OFS

314 258 231 206 101 280 182 259 217 205 181 88 236 147

321 278 261 244 135 302 214 230 189 176 166 79 209 149

337 295 274 255 125 310 218 226 181 166 154 77 199 132

C ERBB2-negative BCI(H/I)-low tumors

0

No. at risk

0 4 6 8 10 12

100

80 Breast cancer–free interval, %

Time since randomization, y

60

40

20

2

Tamoxifen

Tamoxifen plus OFS

Exemestane plus OFS

D ERBB2-negative BCI(H/I)-high tumors

0

No. at risk

0 4 6 8 10 12

100

80 Breast cancer–free interval, %

Time since randomization, y

60

40

20

2

Tamoxifen

Tamoxifen plus OFS

Exemestane plus OFS

283 233 207 185 90 255 163 210 178 173 152 73 193 124

290 251 236 219 124 272 194 186 153 142 132 57 166 120

301 269 251 235 112 280 201 172 143 132 123 59 158 105

Tamoxifen

Tamoxifen plus OFS

Exemestane plus OFS

Treatment

Absolute

benefit, %

E+OFS vs T

T+OFS vs T

HR

(95% CI)

0.48 (0.33-0.71)

0.69 (0.48-0.97)

11.6

7.3

Treatment

Absolute

benefit, %

E+OFS vs T

T+OFS vs T

HR

(95% CI)

1.03 (0.70-1.53)

1.05 (0.72-1.54)

–0.4

–1.2

Treatment

Absolute

benefit, %

E+OFS vs T

T+OFS vs T

HR

(95% CI)

0.39 (0.25-0.60)

0.64 (0.44-0.93)

13.2

7.4

Treatment

Absolute

benefit, %

E+OFS vs T

T+OFS vs T

HR

(95% CI)

1.03 (0.64-1.68)

1.37 (0.89-2.13)

–0.2

–6.8

Kaplan-Meier estimates of breast cancer–free interval (BCFI) for patients

assigned exemestane (E) plus ovarian function suppression (OFS), tamoxifen

(T) plus OFS, or tamoxifen alone according to BCI(H/I)-low and BCI(H/I)-high

groups in the overall cohort (N = 1687) and ERBB2-negative subset (n = 1442).

Absolute benefits are differences in 12-year BCFI vs tamoxifen alone; hazard

ratios (HRs) and 95% CIs were estimated from stratified Cox models. SOFT

indicates the Suppression of Ovarian Function Trial.

Research Original Investigation Breast Cancer Index in Premenopausal Women With Early-Stage Hormone Receptor–Positive Breast Cancer

E4 JAMA Oncology Published online August 15, 2024 (Reprinted) jamaoncology.com

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moxifen alone. The ERBB2-positive subset (n = 198) was too

small to analyze.

Predictive Performance of BCI(H/I) in Other Clinical Subsets

The patterns were very consistent across other clinically

notable subgroups. Among patients who received prior

chemotherapy, those with tumors classified as BCI(H/I)-low exhibited a 12-year BCFI absolute benefit of 15.8% from exemestane plus OFS (HR, 0.48 [95% CI, 0.30-0.77]) and 10.8% from

tamoxifen plus OFS (HR, 0.69 [95% CI, 0.45-1.06) in comparison with tamoxifen alone, not observed for those with BCI(H/

I)-high tumors (Figure 2). Among patients who chose with their

physicians not to receive chemotherapy before trial enrollment, those with tumors classified as BCI(H/I)-low derived a

larger benefit than those classified as BCI(H/I)-high from exemestane plus OFS (absolute benefit, 8.8%; HR, 0.48 [95% CI,

0.25-0.94] vs 6.6%; HR, 0.55 [95% CI, 0.23-1.29]) and from tamoxifen plus OFS compared to tamoxifen alone (absolute

benefit, 5.5%; HR, 0.67 [95% CI, 0.36-1.24] vs 2.1%; HR, 0.72

[95% CI, 0.33-1.57]).

Among 1110 patients (65.8%)with N0 disease, thosewith tumors classified as BCI(H/I)-low derived an absolute benefit of

14.5% from exemestane plus OFS (HR, 0.33 [95% CI, 0.19-

0.57]) and9.6% from tamoxifenplusOFS (HR,0.57 [95%CI,0.36-

0.91]) compared with tamoxifen alone, not observed for BCI(H/

I)-high tumors (Figure 3). In thesmallersubgroupofpatientswith

node-positive (N+

) disease, a similar but attenuated pattern was

observed (Figure 3). BCI(H/I) also consistently predicted

benefit in BCFI for younger (<40 years) and older (≥40 years)

premenopausal patients with BCI(H/I)-low tumors. This benefitwas not observed for thosewith BCI(H/I)-high tumors (eFigure 2 in Supplement 1).

Figure 2. Predictive Performance of Breast Cancer Index HOXB13/IL17BR Ratio (BCI[H/I]) in Patients

With Prior Chemotherapy or No Chemotherapy in SOFT

A BCI(H/I)-low tumors in those who received prior chemotherapy

0

No. at risk

0 4 6 8 10 12

100

80 Breast cancer–free interval, %

Time since randomization, y

60

40

20

2

Tamoxifen

Tamoxifen plus OFS

Exemestane plus OFS

B BCI(H/I)-high tumors in those who received prior chemotherapy

0

No. at risk

0 4 6 8 10 12

100

80 Breast cancer–free interval, %

Time since randomization, y

60

40

20

2

Tamoxifen

Tamoxifen plus OFS

Exemestane plus OFS

145 108 93 84 41 122 71 161 125 117 110 58 142 92

161 137 125 119 69 150 103 137 107 96 90 45 123 78

161 142 128 119 60 151 102 135 102 93 84 39 116 72

C BCI(H/I)-low tumors in those who did not receive chemotherapy

0

No. at risk

0 4 6 8 10 12

100

80 Breast cancer–free interval, %

Time since randomization, y

60

40

20

2

Tamoxifen

Tamoxifen plus OFS

Exemestane plus OFS

D BCI(H/I)-high tumors in those who did not receive chemotherapy

0

No. at risk

0 4 6 8 10 12

100

80 Breast cancer–free interval, %

Time since randomization, y

60

40

20

2

Tamoxifen

Tamoxifen plus OFS

Exemestane plus OFS

169 150 138 122 60 158 111 98 92 88 71 31 94 55

160 141 136 125 66 152 111 93 82 80 76 34 86 71

176 153 146 136 64 159 116 91 79 73 70 38 83 60

Tamoxifen

Tamoxifen plus OFS

Exemestane plus OFS

Treatment

Absolute

benefit, %

E+OFS vs T

T+OFS vs T

HR

(95% CI)

0.48 (0.30-0.77)

0.69 (0.45-1.06)

15.8

10.8

Treatment

Absolute

benefit, %

E+OFS vs T

T+OFS vs T

HR

(95% CI)

1.24 (0.79-1.95)

1.18 (0.76-1.84)

–5.3

–3.8

Treatment

Absolute

benefit, %

E+OFS vs T

T+OFS vs T

HR

(95% CI)

0.48 (0.25-0.94)

0.67 (0.36-1.24)

8.8

5.5

Treatment

Absolute

benefit, %

E+OFS vs T

T+OFS vs T

HR

(95% CI)

0.55 (0.23-1.29)

0.72 (0.33-1.57)

6.6

2.1

Kaplan-Meier estimates of breast cancer–free interval (BCFI) for patients

assigned exemestane (E) plus ovarian function suppression (OFS), tamoxifen

(T) plus OFS, or tamoxifen alone according to BCI(H/I)-low and BCI(H/I)-high

groups in those who received prior chemotherapy (n = 900) and those who did

not receive chemotherapy (n = 787). Absolute benefits are differences in

12-year BCFI vs tamoxifen alone; hazard ratios (HRs) and 95% CIs were

estimated from stratified Cox models. SOFT indicates the Suppression of

Ovarian Function Trial.

Breast Cancer Index in Premenopausal Women With Early-Stage Hormone Receptor–Positive Breast Cancer Original Investigation Research

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Prognostic Performance of BCI and BCIN+ for DRFI

BCI and BCIN+ were significantly prognostic as continuous indices in the N0 subgroup (n = 1110; P = .004) and the N1 subgroup (n = 409; P = .01) (Figure 4). BCI stratified 677 patients

(61.0%) with N0 disease into BCI low-risk, 240 (21.6%) into BCI

intermediate-risk (intermediate-risk vs low-risk: HR, 1.76 [95%

CI, 0.98-3.17]), and 193 (17.4%) into BCI high-risk (high-risk vs

low-risk: HR, 1.98 [95% CI, 1.10-3.56]) groups with 12-year DRFI

of 95.9% (low risk), 90.8% (intermediate risk), and 86.3% (high

risk) (Figure 4). BCIN+ stratified 90 patients (21.1%) with N1 disease into low risk and 319 patients (74.9%) into high risk (highrisk vs low-risk: HR, 1.97 [95% CI, 0.90-4.31]) with 12-year DRFI

of 92.2% (low risk) and 78.0% (high risk); 17 patients (4.0%)were

unclassified. However, BCIN+ classifications of low risk vs high

risk were almost completely concordant with histologic grade 1

vs grade 2 or 3 tumors, respectively, with only 3 patients being

different in this cohort (eTable 4 in Supplement 1).

Discussion

In this prospective-retrospective translational study of

patients enrolled in SOFT, we demonstrated that OFS with

either tamoxifen or exemestane improved outcomes in

premenopausal women with HR+ early breast cancer, and also

that tamoxifen alone remains a suitable treatment option

for many premenopausal women with lower-risk disease.6

The Addition of Ovarian Suppression to Tamoxifen in

Young Women With Hormone-Sensitive Breast Cancer Who

Remain Premenopausal or Regain Vaginal Bleeding After

Figure 3. Predictive Performance of Breast Cancer Index HOXB13/IL17BR Ratio (BCI[H/I]) in Patients

With Node-Negative or Node-Positive Breast Cancer in SOFT

A BCI(H/I)-low tumors in those with N0 disease

0

No. at risk

0 4 6 8 10 12

100

80 Breast cancer–free interval, %

Time since randomization, y

60

40

20

2

Tamoxifen

Tamoxifen plus OFS

Exemestane plus OFS

B BCI(H/I)-high tumors in those with N0 disease

0

No. at risk

0 4 6 8 10 12

100

80 Breast cancer–free interval, %

Time since randomization, y

60

40

20

2

Tamoxifen

Tamoxifen plus OFS

Exemestane plus OFS

222 189 171 151 77 204 135 161 147 140 119 55 154 92

221 199 188 176 100 212 156 132 116 109 105 47 122 98

232 207 195 186 93 216 155 142 124 115 110 56 131 93

C BCI(H/I)-low tumors in those with N+ disease

0

No. at risk

0 4 6 8 10 12

100

80 Breast cancer–free interval, %

Time since randomization, y

60

40

20

2

Tamoxifen

Tamoxifen plus OFS

Exemestane plus OFS

D BCI(H/I)-high tumors in those with N+ disease

0

No. at risk

0 4 6 8 10 12

100

80 Breast cancer–free interval, %

Time since randomization, y

60

40

20

2

Tamoxifen

Tamoxifen plus OFS

Exemestane plus OFS

92 69 60 55 24 76 47 98 70 65 62 33 82 55

100 79 73 68 35 90 58 98 73 67 61 33 87 51

105 88 79 69 31 94 63 84 57 51 44 21 68 39

Tamoxifen

Tamoxifen plus OFS

Exemestane plus OFS

Treatment

Absolute

benefit, %

E+OFS vs T

T+OFS vs T

HR

(95% CI)

0.33 (0.19-0.57)

0.57 (0.36-0.91)

14.5

9.6

Treatment

Absolute

benefit, %

E+OFS vs T

T+OFS vs T

HR

(95% CI)

0.83 (0.44-1.56)

1.10 (0.61-1.99)

0.6

–3.3

Treatment

Absolute

benefit, %

E+OFS vs T

T+OFS vs T

HR

(95% CI)

0.74 (0.42-1.30)

0.90 (0.52-1.54)

6.2

2.7

Treatment

Absolute

benefit, %

E+OFS vs T

T+OFS vs T

HR

(95% CI)

1.20 (0.72-1.99)

1.03 (0.62-1.70)

–2.5

3.6

Kaplan-Meier estimates of breast cancer–free interval (BCFI) for patients

assigned exemestane (E) plus ovarian function suppression (OFS), tamoxifen

(T) plus OFS, or tamoxifen alone according to BCI(H/I)-low and BCI(H/I)-high

groups in the N0 (n = 1110) and N+ (n = 577) subsets. Absolute benefits are

differences in 12-year BCFI vs tamoxifen alone; hazard ratios (HRs) and 95% CIs

were estimated from stratified Cox models. SOFT indicates the Suppression of

Ovarian Function Trial.

Research Original Investigation Breast Cancer Index in Premenopausal Women With Early-Stage Hormone Receptor–Positive Breast Cancer

E6 JAMA Oncology Published online August 15, 2024 (Reprinted) jamaoncology.com

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Chemotherapy (ASTRRA) trial confirmed the value of adding

OFS to tamoxifen for younger patients who remained premenopausal after chemotherapy.22,23The increased treatmentrelated adverse effects from OFS may reduce adherence to

therapy and poor adherence has been associated with poorer

outcomes.24,25 The long-term adverse effects of OFS have yet

to be fully characterized in women diagnosed with breast cancer although concerns have been raised in reports of patients

without breast cancer who have premature menopause.26-28

The decision to recommend OFS in premenopausal women has

been largely based on age and receipt of chemotherapy, which

is informed by classical pathological risk features.29 The use

of genomic assays can guide the omission of chemotherapy in

postmenopausal patients with early-stage HR+ breast

cancer.30-32Currently no genomic assay is predictive of which

premenopausal patients are most likely to benefit from OFS

with an AI in this setting.

In SOFT, BCI(H/I) predicted differential benefit from either

tamoxifen plus OFS or exemestane plus OFS compared to tamoxifen alone, in terms of freedom from breast cancer recurrence. The benefits were almost exclusively limited to the BCI

(H/I)-low group and not the BCI(H/I)-high group. This

investigation suggests a potential clinical use of BCI(H/I)

results, adding to theiruse to identify patientsmost likely to benefit from extended endocrine therapy, as proven in multiple

studies,17,18,20 although in the extended endocrine validation

studies, it was the BCI(H/I)-high group that derived the greatest benefit.

The results were consistent regardless of chemotherapy

receipt or age, and in the predominant subgroup, patients

with ERBB2-negative disease. Premenopausal women younger

than 40 years with HR+ breast cancer are at greater risk of

recurrence.25,33 Yet BCI(H/I)-low status was similarly observed

for 54% of thosewomen younger than 40 years and 59% of those

40 years and older, and the benefit from exemestane plus OFS

vs tamoxifen alone was very similar for both younger and older

premenopausal women who had BCI(H/I)-low tumors. Notably, patients who did not receive chemotherapy and had BCI(H/

I)-low tumors exhibited clinically significant absolute BCFI

benefits from exemestane plus OFS and tamoxifen plus OFS as

Figure 4. Prognostic Performance of Breast Cancer Index (BCI) and the Node-Positive BCI Model (BCIN+

) in SOFT

A 12-y Risk of distant recurrence by continuous BCI score for N0 disease

0

0 4 6 8 10

0.5

0.4 12-y Proportion with distant recurrence

BCI score

0.3

0.2

0.1

2

B 12-y Risk of distant recurrence by continuous BCIN+ score for N1 disease

0

0 4 6 8 10

0.5

0.4 12-y Proportion with distant recurrence

BCIN+ score

0.3

0.2

0.1

2

C BCI score risk groups for N0 disease

0

No. at risk

0 4 6 8 10 12

100

80 Distant recurrence-free interval, %

Time since randomization, y

60

40

20

2

Low risk

Intermediate risk

High risk

D BCIN+ score risk groups for N1 disease

0

No. at risk

0 4 6 8 10 12

100

80 Distant recurrence-free interval, %

Time since randomization, y

60

40

20

2

Low risk

High risk

677 617 589 555 304 641 495 90 77 73 69 32 82 58

240 218 203 187 90 228 319 256 236 220 112 157 287 194

193 175 165 151 74 182 122

Low risk

Intermediate risk

High risk

Low risk

High risk

The 12-year risk of distant recurrence as a function of BCI and BCIN+ as a

continuous risk index; and Kaplan-Meier estimates of BCI and BCIN+ risk groups

in patients with N0 (n = 1110) and N1 (n = 409 of 426 able to be scored) breast

cancer, respectively. The BCIN+ prognostic model integrates the BCI score with

tumor size and grade; thus, scores are unavailable when tumor size and/or

grade are unknown. SOFT indicates the Suppression of Ovarian Function Trial.

Breast Cancer Index in Premenopausal Women With Early-Stage Hormone Receptor–Positive Breast Cancer Original Investigation Research

jamaoncology.com (Reprinted) JAMA Oncology Published online August 15, 2024 E7

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compared with tamoxifen alone (8.8% and 5.5% at 12 years,

respectively). Traditional clinical pathologic features have not

been useful for estimating the differential magnitude of

benefit of OFS for this patient group,who on average have lowerrisk features.12,34Thus, in contrast to prognostic clinical pathologic features, for which the relative benefits of OFS are similar

leading to greater absolute benefits of OFS for thosewith higherrisk features,3,5-8BCI(H/I) estimated differential relative and absolute treatment benefits, adding to previously demonstrated

predictive performance.14,17-20,35

BCI(H/I) is an endocrine response biomarker assessing

estrogen signaling and BCI(H/I)-high tumors have shown

consistent benefit from extended endocrine therapy in several

randomized clinical trials of patientswho had completed 5 years

of adjuvant endocrine therapy.14,17,20,35,36 Our a priori hypothesiswas that BCI(H/I)-high tumorswould benefitmore from the

use of 5 years OFS with oral endocrine therapy than BCI(H/I)-

low tumors. Contrary to this hypothesis, the BCI(H/I)-low group

consistently obtained benefits from OFS in combinationwith endocrine therapy,whereas theBCI(H/I)-high group did not. These

results point to potential differences in premenopausal breast

tumor biological characteristics and hormonal regulation underlying the response to OFS,wherebyBCI(H/I)-low tumors benefit more from the maximal suppression of circulating estrogenswith thecombination of OFS plus AI. Incontrast, the benefit

of endocrine therapy in BCI(H/I)-high tumors may be adequately provided by tamoxifen alone. Based on prior results,

theBCI(H/I)-high tumorsbenefittedwhen endocrine therapywas

given for an extended duration.14,16-20Overall, the prediction of

OFS benefit in premenopausal patients is a very different clinical question than the prediction of extended endocrine therapy

benefit in who were disease-free after 5 years and each question informs a different decision time point. On further validation, BCI(H/I)may help inform decisions for the optimal type of

endocrine therapy. Potentially clinicians could recommend that

those with BCI(H/I)-low cancers undergo 5 years ofmore intensive endocrine therapy with OFS with an AI, while those with

BCI(H/I)-high cancers might avoid OFS but benefit from extension of endocrine therapy beyond 5 years.

The expression of HOXB13 and IL17BR in breast cancer

is regulated by estrogen signaling whereby, in response to

estradiol, HOXB13 expression is suppressed and IL17BR

expression is increased and this regulation is abrogated by

tamoxifen.37 Conversely, HOXB13 has been shown to confer

tamoxifen resistance by directly downregulating estrogen receptor (ER)–α transcription and protein expression.38 Additional confirmation and results demonstrated that transient

HOXB13 overexpression in breast cancer cells rapidly reprograms and expands the binding pattern (cistrome) of ER to genomic regions that were previously inaccessible and inactive.39

These results support a model of HOXB13-mediated reprogramming of the ER cistrome in breast cancer, similar to what

has been described for HOXB13 in prostate tumorigenesis.40

Accordingly, expression ofHOXB13might drive distinct ER signaling patterns in premenopausal and postmenopausalwomen

by interactingwith other transcription factors. Further, it is possible that OFS blocks ER-independent pathways breast tumors rely on for progression, such as signaling through growth

factors. For example, luteinizing hormone has been shown to

increase the expression of vascular endothelial growth factor, which can facilitate tumor growth andmetastasis in breast

cancer.41,42 The biological mechanisms of estrogen sensitivity or dependence and their relation to BCI(H/I) before and during treatment remain to be fully elucidated and are the subject of ongoing research.

BCI was significantly prognostic for DRFI in patients with

N0 disease, with a higher 12-year risk of distant recurrence in

patients with higher BCI scores. However, in assessing BCIN+

,

which incorporates BCI with tumor size and grade, BCIN+ low

vs high recapitulated tumor grade 1 vs grade 2 or 3 in the SOFT

N1 subgroup and thus did not provide clinically useful information beyond grade. BCI and BCIN+ have previously been

shown to be prognostic in postmenopausal patients with N0

and N1 HR+ cancers, and these new findings extend BCI prognostic value to premenopausal patients with N0 breast cancer who received endocrine therapy.16,43

Limitations

Although the BCI cohort was similar to the parent trial on average, the patient numbers especially for clinical subgroups

may be too small to definitively confirm the predictive value

of BCI(H/I) in determining which premenopausal patients are

most likely to benefit from a regimen containing OFS. The

analyses of the clinical subgroups defined according to

chemotherapy use, nodal status, or age were exploratory. We

plan to further validate these findings in other patient cohorts. Another limitation of this study was its retrospective nature, although the statistical analysis plan was prospectively

defined and BCI testing was conducted blinded to clinical outcome and used previously established calculations and risk

groups.

Conclusions

The potential adverse effects of OFS make it critical to

determine which premenopausal patients derive the greatest benefit from OFS-containing adjuvant endocrine

therapy. To our knowledge, this prospective-retrospective

translational study of patients enrolled in SOFT was the first

study in which a genomic assay was able to predict which

premenopausal patients were most likely to benefit from

OFS. Although these results revealed intriguing novel

possible predictive capabilities of BCI(H/I), further validation is needed before expanding the use of BCI to aid with

OFS decision-making.

ARTICLE INFORMATION

Accepted for Publication: April 16, 2024.

Published Online: August 15, 2024.

doi:10.1001/jamaoncol.2024.3044

Author Affiliations: University of Rochester

Department of Medicine, Rochester, New York

(O’Regan); Biotheranostics, A Hologic Company,

San Diego, California (Zhang, Schnabel, Treuner);

The University of Chicago Medical Center, Chicago,

Illinois (Fleming); The Sir Peter MacCallum

Research Original Investigation Breast Cancer Index in Premenopausal Women With Early-Stage Hormone Receptor–Positive Breast Cancer

E8 JAMA Oncology Published online August 15, 2024 (Reprinted) jamaoncology.com

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Department of Medical Oncology, The University of

Melbourne, Parkville, Australia (Francis, Loi);

Department of Medical Oncology, Peter MacCallum

Cancer Center, Melbourne, Australia (Francis);

St Vincent’s Hospital, Melbourne, Australia

(Francis); Breast Cancer Trials Australia & New

Zealand, Newcastle, Australia (Francis); University

of Newcastle, Callaghan, Newcastle, Australia

(Francis); International Breast Cancer Study Group,

ETOP IBCSG Partners Foundation, Bern,

Switzerland (Kammler, Loi, Colleoni); International

Breast Cancer Study Group Central Pathology

Office, European Institute of Oncology IRCCS,

Milan, Italy (Viale); Department of Pathology and

Laboratory Medicine, European Institute of

Oncology IRCCS, Milan, Italy (Viale, Dell’Orto);

Clinexpert-Research, Budapest, Hungary (Lang);

Vall d’Hebron Institute of Oncology (VHIO) and Vall

d’Hebron University Hospital, Barcelona, Spain

(Bellet); SOLTI Breast Cancer Research Cooperative

Group, Barcelona, Spain (Bellet, Ciruelos); Institut

Bergonie Comprehensive Cancer Center, Universite

de Bordeaux, INSERM U1312, Bordeaux, France

(Bonnefoi); European Organization for Research

and Treatment of Cancer (EORTC), Brussels,

Belgium (Bonnefoi, Neven); Ospedale Papa

Giovanni XXIII, Bergamo, Italy (Tondini); Oncology

Unit, Department of Oncology, Alessandro Manzoni

Hospital, ASST Lecco, Lecco, Italy (Villa); Operative

Unit of Medical Oncology, IRCCS ICS Maugeri, Pavia,

Italy (Bernardo); Medical Oncology Department,

University Hospital 12 de Octubre, Madrid, Spain

(Ciruelos); Gynecologic Oncology and

Multidisciplinary Breast Center, University Hospitals

UZ Leuven, KU Leuven, Leuven, Belgium (Neven);

Department of Oncology, Institute of Clinical

Sciences, Sahlgrenska Academy, University of

Gothenburg, Gothenburg, Sweden (Karlsson);

Chilean Cooperative Group for Oncologic Research

(GOCCHI), Santiago, Chile (Müller); Institute of

Pathology, Cantonal Hospital St. Gallen, St. Gallen,

Switzerland (Jochum); Swiss Group for Clinical

Cancer Research (SAKK), Bern, Switzerland

(Jochum, Zaman); Breast Center, Lausanne

University Hospital CHUV, Lausanne, Switzerland

(Zaman); The Angeles Clinic and Research Institute,

Santa Monica, California (Martino); SWOG Cancer

Research Network, San Antonio, Texas (Martino);

University of Pittsburgh Medical Center Hillman

Cancer Center Pittsburgh, Pennsylvania (Geyer);

NSABP Foundation/NRG Oncology, Pittsburgh,

Pennsylvania (Geyer); Division of Medical Oncology,

Sunnybrook Odette Cancer Centre, University of

Toronto, Toronto, ON, Canada (Jerzak); Fred

Hutchinson Cancer Center, University of

Washington Seattle, Washington (Davidson);

ECOG-ACRIN Cancer Research Group, Philadelphia,

Pennsylvania (Davidson); Weston Park Hospital,

Sheffield, United Kingdom (Coleman); National

Cancer Research Institute, Breast Cancer Clinical

Studies Group (NCRI-BCSG), London, United

Kingdom (Coleman); The Institute for Cancer

Research, The Clinical Trials and Statistics Unit

(ICR-CTSU), London, United Kingdom (Coleman);

Mayo Clinic and Alliance for Clinical Trials in

Oncology, Rochester, Minnesota (Ingle); German

Breast Group, Neu Isenburg, Germany (van

Mackelenbergh); University Hospital of

Schleswig-Holstein, Campus Kiel, Germany (van

Mackelenbergh); Division of Cancer Research, Peter

MacCallum Cancer Center, Melbourne Australia

(Loi); Division of Medical Senology, IEO, European

Institute of Oncology IRCCS, Milan, Italy (Colleoni);

IBCSG Statistical Center, Dana-Farber Cancer

Institute and Harvard Medical School, Boston,

Massachusetts (Regan).

Author Contributions: Prof Regan had full access

to all of the data in the study and takes

responsibility for the integrity of the data and the

accuracy of the data analysis.

Concept and design: O’Regan, Zhang, Francis,

Bellet, Bernardo, Ciruelos, Martino, Loi, Schnabel,

Treuner, Regan.

Acquisition, analysis, or interpretation of data:

Zhang, Fleming, Francis, Kammler, Viale, Dell’Orto,

Lang, Bellet, Bonnefoi, Tondini, Villa, Neven,

Karlsson, Müller, Jochum, Zaman, Martino, Geyer,

Jerzak, Davidson, Coleman, Ingle, van

Mackelenbergh, Loi, Colleoni, Schnabel,

Treuner, Regan.

Drafting of the manuscript: O’Regan, Zhang, Bellet,

Treuner, Regan.

Critical review of the manuscript for important

intellectual content: All authors.

Statistical analysis: Zhang, Regan.

Obtained funding: Schnabel, Regan.

Administrative, technical, or material support:

Kammler, Viale, Dell’Orto, Bonnefoi, Karlsson,

Jochum, Zaman, Martino, Jerzak, Treuner.

Supervision: O’Regan, Zhang, Lang, Bellet, Tondini,

Villa, Neven, Müller, van Mackelenbergh, Loi,

Schnabel, Treuner.

Conflict of Interest Disclosures: Dr O’Regan

reported personal fees from Pfizer Advisos and

Gilead DSMB, grants from the Puma Clinical trial,

and nonfinancial support from the Novartis Clinical

trial. Dr Zhang reported a pending patent for BCI,

an issued patent for BCI from Biotheranostics,

A Hologic Company, and employment at

Biotheranostics. Dr Fleming reported institutional

principal investigator (PI) roles for trials sponsored

by Iovance, Sermonix, AbbVie, Celldex, Corcept,

AstraZeneca, Molecular Templates, CytomX,

Astellas, K group beta, Pfizer, Artios, and Blueprint,

and grants from Caris for a continuing medical

education conference. Dr Francis reported personal

fees from Eli Lilly for lectures. Prof Viale reported

personal fees from Roche, AstraZeneca, Daiichi

Sankyo, Pfizer, Agilent, Eli Lilly, and Gilead. Dr Bellet

reported participation in Novartis, Pfizer, and Lilly

advisory boards. Prof Bonnefoi reported consulting

fees from AZ-Daiichi Sankyo and Pfizer, and travel

grants from Pfizer. Dr Ciruelos reported grants from

Roche and Daichi Sankyo, personal fees from

AstraZeneca, Pfizer, Gilead, Novartis, Lilly, and

Reveal Genomics. Dr Karlsson reported personal

fees from AstraZeneca, Seagen, and Novartis, and

issued patents for Exact Sciences and Preludex DX.

Dr Zaman reported support from Seattle Genetics,

advisory roles, and travel support from Daiichi,

AstraZeneca, Gilead, Seagen, Roche, and Pierre

Fabre. Dr Martino reported grants from SWOG

during the study. Dr Geyer reported support from

the National Cancer Institute, grants from

Genentech/Roche, Daiichi Sankyo, AstraZeneca,

and Exact Sciences, and nonfinancial support from

Genentech/Roche, Daiichi Sankyo, AstraZeneca,

and Exact Sciences. Dr Jerzak reported personal

fees from Amgen, AstraZeneca, ApoBiologix, Eli

Lilly, Esai, Exact Sciences, Gilead Sciences, Knight

Therapeutics, Merck, Myriad Genetics, Pfizer,

Roche, Seagen, Organon, and Daiichi Sankyo, and

grants from AstraZeneca, Eli Lilly, and Seagen. Prof

Coleman reported personal fees from Amgen and

Beigene. Dr Ingle reported grants from the National

Cancer Institute. Dr van Mackelenbergh reported

personal fees from Amgen, AstraZeneca, Daiichi

Sankyo, Gilead, GSK, Lilly, Molecular Health, Mylan,

MSD, Novartis, Pfizer, Pierre Fabre, Roche, Seagen,

and Jenapharm, and nonfinancial support from

Daiichi Sankyo, Gilead, Lilly, and Novartis. Prof Loi

reported research funding from Novartis, Bristol

Myers Squibb, Puma Biotechnology, AstraZeneca/

Daiichi Sankyo, Roche-Genentech, and Seattle

Genetics, and consultancy roles with

Roche-Genentech, MSD, Gilead Sciences,

AstraZeneca/Daiichi Sankyo, Bristol Myers Squibb,

Novartis, Amaroq Therapeutics, Mersana

Therapeutics, and Domain Therapeutics.

Dr Colleoni reported grants from Roche.

Dr Schnabel reported former employment with

Biotheranostics/Hologic and pending and issued

patents for Breast Cancer Index. Dr Treuner

reported a pending patent for BCI and employment

at Biotheranostics,

A Hologic Company. Prof Regan reported support

from Biotheranostics, DebioPharm, Ipsen, TerSera

Therapeutics, AstraZeneca, and Pfizer during the

study, and personal fees from Tolmar and TerSera,

and advisory roles with Ipsen and DebioPharm,

grants from Bayer, BMS, Novartis, Pfizer, and

Roche, personal fees from AstraZeneca and BMS,

and additional support from Biotheranostics

outside the submitted work. No other disclosures

were reported.

Funding/Support: The Suppression of Ovarian

Function Trial (SOFT) was coordinated and

sponsored by the International Breast Cancer Study

Group (IBCSG), part of the ETOP IBCSG Partners

Foundation, in collaboration with the Breast

International Group (BIG) and US NCI National

Clinical Trials Network cooperative groups. This

translational research study was supported by

Biotheranostics. The SOFT clinical trial received

financial support for trial conduct and long-term

follow-up from Pfizer, IBCSG, the Breast Cancer

Research Foundation (grants 16-185, 17-187, 18-003,

19-011, 20-011, 21-011 to MMR), Ipsen, DebioPharm,

TerSera, AstraZeneca, and private donors. Pfizer

and Ipsen provided drug supply. Support for central

pathology included the Susan G. Komen for the

Cure Promise Grant (KG080081 to GV, MMR) and

the Breast Cancer Research Foundation. Additional

support for the IBCSG came from Frontier Science

Foundation, Swiss Group for Clinical Cancer

Research (SAKK), Oncosuisse, Cancer League

Switzerland, Foundation for Clinical Cancer

Research of Eastern Switzerland (OSKK), and the

US National Cancer Institute (US NIH grant

CA075362). Cooperative group support included

Breast Cancer Trials Australia & New Zealand

(NHMRC grants 351161, 510788, 1105058; Breast

Cancer Research Foundation supports Bio-Bank),

the Institute of Cancer Research Clinical Trials and

Statistics Unit (ICR-CTSU) on behalf of the National

Cancer Research Institute Breast Clinical Studies

Group United Kingdom (NCRI-BCSG–ICR-CTSU

Partnership, Cancer Research UK grants CRUKE/03/

022, CRUKE/03/023, A15955), the National

Institute for Health Research Royal Marsden/

Institute of Cancer Research Biomedical Research

Centre, and the National Institute for Health

Research/Cambridge Biomedical Research Centre.

SOFT conduct in the US and Canada was supported

by the US National Cancer Institute of the National

Institutes of Health via the Alliance for Clinical Trials

in Oncology (US NIH grant U10CA180821), SWOG

(US NIH grants U10CA180888, UG1CA233160,

UG1CA233329), ECOG-ACRIN Cancer Research

Breast Cancer Index in Premenopausal Women With Early-Stage Hormone Receptor–Positive Breast Cancer Original Investigation Research

jamaoncology.com (Reprinted) JAMA Oncology Published online August 15, 2024 E9

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Group (US NIH grants U10CA180820,

U10CA180794), NRG Oncology (US NIH grants

U10CA180868, U10CA180822, UG1CA189867),

Canadian Cancer Trials Group (US NIH grant

U10CA180863), and the Canadian Cancer Society

(grant 707213).

Role of the Funder/Sponsor: The SOFT trial

sponsor, ETOP IBCSG Partners (formerly,

International Breast Cancer Study Group), and

Biotheranostics collaborated on this translational

research study and are responsible for the design

and conduct of the study; collection, management,

analysis, and interpretation of the data;

preparation, review, or approval of the manuscript;

and decision to submit the manuscript for

publication. Other funders had no role in the design

and conduct of the study; collection, management,

analysis, and interpretation of the data;

preparation, review, or approval of the manuscript;

and decision to submit the manuscript for

publication.

Disclaimer: The content is solely the responsibility

of the authors and does not necessarily represent

the official views of the US National Institutes

of Health.

Meeting Presentation: This research study was

presented at the 2022 San Antonio Breast Cancer

Symposium; December 6, 2022;

San Antonio, Texas.

Data Sharing Statement: See Supplement 2.

Additional Contributions: We thank the women,

clinicians, pathologists, and study teams who

participated in the SOFT clinical trial and submitted

tumor tissue blocks for research purposes. We also

thank the IBCSG Central Pathology Office for tissue

block collection and processing.

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