NEOCENT: a Randomised Feasibility and Translational Study Comparing Neoadjuvant Endocrine

NEOCENT: A randomised feasibility and translational Study Comparing Neoadjuvant Endocrine Therapy with Chemotherapyin ER rich Postmenopausal Primary Breast Cancer

Supplementary Data Legends

Table S1: TaqMan Low-Density Array (TLDA v2.0) card data showing significant miRs identified between baseline and control plasma by P value (Dunn’s multiple comparison test) and fold change.

Table S2: Baseline characteristics by treatment group

Table S3: Pathological tumour characteristics by treatment group

Table S4: Maximum graded toxicity over all treatment visits by treatment group

Table S5: miRNA univariate analysis by treatment group.

Figure S5: Median (IQR) TOI score by treatment group

Figure S6: Median (IQR) FACT-B score by treatment group

Figure S7: Median (IQR) FACT-An score by treatment group

Supplementary Table S1:

miR / P value / Fold change
hsa-miR-98 / 0.003 / 10.1536
hsa-let-7a / 0.010 / 9.32615
hsa-miR-194 / 0.019 / 8.1176
hsa-let-7f / 0.018 / 6.63355
hsa-miR-22 / 0.043 / 6.4025
hsa-miR-15b / 0.038 / 4.90855
hsa-miR-23b / 0.030 / 4.87115
hsa-miR-21 / 0.024 / 4.5918
hsa-miR-141 / 0.039 / 4.5505
hsa-miR-26a / 0.020 / 3.98115

Supplementary Table S2:

Chemotherapy (N=22) / Letrozole
(N=22) / Total
(N=44)
n / % / n / % / n / %
Age group (years)
50-54 / 7 / 31.8 / 4 / 18.2 / 11 / 25.0
55-59 / 4 / 18.2 / 8 / 36.4 / 12 / 27.3
60-64 / 6 / 27.3 / 3 / 13.6 / 9 / 20.5
65-69 / 5 / 22.7 / 7 / 31.8 / 12 / 27.3
Previous HRT use
Yes / 6 / 27.3 / 7 / 31.8 / 13 / 29.6
No / 16 / 72.7 / 15 / 68.2 / 31 / 70.5
Pre-treatment operability
Mastectomy / 10 / 45.5 / 11 / 50.0 / 21 / 47.7
Wide Local Excision / 12 / 54.6 / 11 / 50.0 / 23 / 52.3
WHO performance status
0 / 8 / 36.4 / 9 / 40.9 / 17 / 38.6
1 / 13 / 59.1 / 13 / 59.1 / 26 / 59.1
Missing / 1 / 4.6 / 0 / 0.0 / 1 / 2.3
Ethnicity
Asian (Asian British) / 1 / 4.6 / 0 / 0.0 / 1 / 2.3
Black (Black British) / 1 / 4.6 / 0 / 0.0 / 1 / 2.3
South Korean / 13 / 59.1 / 14 / 63.6 / 27 / 61.4
White / 6 / 27.3 / 8 / 36.4 / 14 / 31.8
Not stated / 1 / 4.6 / 0 / 0.0 / 1 / 2.3
Postmenopausal status
>12 months since last period / 14 / 63.6 / 22 / 100.0 / 36 / 81.8
>12 months since last period & gonadotrophin level above local criteria / 1 / 4.6 / 0 / 0.0 / 1 / 2.3
Gonadotrophin level above local criteria & oestrogen level below local criteria / 5 / 22.7 / 0 / 0.0 / 5 / 11.4
Oestrogen level below local criteria / 1 / 4.6 / 0 / 0.0 / 1 / 2.3
Missing / 1 / 4.6 / 0 / 0.0 / 1 / 2.3
Side of tumour
Left / 10 / 45.5 / 13 / 59.1 / 23 / 52.3
Right / 11 / 50.0 / 9 / 40.9 / 20 / 45.5
Missing / 1 / 4.6 / 0 / 0.0 / 1 / 2.3
Location of tumour
Central/Periareolar / 3 / 13.6 / 2 / 9.1 / 5 / 11.4
Central inner / 0 / 0.0 / 1 / 4.6 / 1 / 2.3
Lower inner / 2 / 9.1 / 3 / 13.6 / 5 / 11.4
Lower outer / 1 / 4.6 / 1 / 4.6 / 2 / 4.6
Upper central / 2 / 9.1 / 1 / 4.6 / 3 / 6.8
Upper inner / 2 / 9.1 / 3 / 13.6 / 5 / 11.4
Upper outer / 9 / 40.9 / 10 / 45.5 / 19 / 43.2
Missing / 3 / 13.6 / 1 / 4.6 / 4 / 9.1
Hormone receptor status
ER+/PgR+ / 16 / 72.7 / 14 / 63.6 / 30 / 68.2
ER+/PgR- / 5 / 22.7 / 7 / 31.8 / 12 / 27.3
ER+/PgR unknown / 1 / 4.6 / 1 / 4.6 / 2 / 4.6
HER2 status
Positive / 2 / 9.1 / 2 / 9.1 / 4 / 9.1
Negative / 18 / 81.8 / 20 / 90.9 / 38 / 86.4
Unknown/missing / 1 / 9.1 / 0 / 0.0 / 2 / 4.6
Histological type
Ductal / 20 / 90.9 / 17 / 77.3 / 37 / 84.1
Lobular / 0 / 0.0 / 3 / 13.6 / 3 / 6.8
Mucinous / 0 / 0.0 / 1 / 4.6 / 1 / 2.3
Other / 1 / 4.6 / 1 / 4.6 / 2 / 4.6
Missing / 1 / 4.6 / 0 / 0.0 / 1 / 2.3
DCIS present?
Yes / 3 / 13.6 / 2 / 9.1 / 5 / 11.4
No / 18 / 81.8 / 20 / 90.9 / 38 / 86.4
Missing / 1 / 4.6 / 0 / 0.0 / 1 / 2.3
Tumour grade
Well differentiated / 0 / 0.0 / 1 / 4.6 / 1 / 2.3
Moderately differentiated / 15 / 68.2 / 14 / 63.6 / 29 / 65.9
Poorly differentiated / 4 / 18.2 / 4 / 18.2 / 8 / 18.2
Unknown / 2 / 9.1 / 3 / 13.6 / 5 / 11.4
Missing / 1 / 4.6 / 0 / 0.0 / 1 / 2.3
Clinical tumour size (cm)
<2 / 0 / 0.0 / 0 / 0.0 / 0 / 0.0
2-5 / 15 / 68.2 / 17 / 77.3 / 32 / 72.7
>5 / 5 / 22.7 / 5 / 22.7 / 10 / 22.7
Missing / 2 / 9.1 / 0 / 0.0 / 2 / 4.6
Surgery received
Wide local excision / 12 / 54.6 / 15 / 68.2 / 27 / 61.4
Mastectomy / 8 / 36.4 / 7 / 31.8 / 15 / 34.1
Unknown / 2 / 9.1 / 0 / 0.0 / 2 / 4.6

Supplementary Table S3:

Chemotherapy
(N = 22) / Letrozole (N = 22) / Total
(N = 44)
n / % / n / % / n / %
Pathological tumour size
<2cm / 6 / 27.3 / 2 / 9.1 / 8 / 18.2
2-5cm / 10 / 45.5 / 19 / 86.4 / 29 / 65.9
>5cm / 3 / 13.6 / 1 / 4.6 / 4 / 9.1
Unknown / 3 / 13.6 / 0 / 0.0 / 3 / 6.8
Histological type
Ductal / 18 / 81.8 / 17 / 77.3 / 35 / 79.6
Lobular / 1 / 4.6 / 4 / 18.2 / 5 / 11.4
Other / 0 / 0.0 / 1 / 4.6 / 1 / 2.3
Unknown / 3 / 13.6 / 0 / 0.0 / 3 / 6.8
Tumour grade
G1 / 1 / 4.6 / 2 / 9.1 / 3 / 6.8
G2 / 14 / 63.6 / 15 / 68.2 / 29 / 65.9
G3 / 2 / 9.1 / 5 / 22.7 / 7 / 15.9
Unknown / 5 / 22.7 / 0 / 0.0 / 5 / 11.4
DCIS associated with tumour?
Yes / 6 / 27.3 / 5 / 22.7 / 11 / 25.0
No / 13 / 59.1 / 17 / 77.3 / 30 / 68.2
Unknown / 3 / 13.6 / 0 / 0.0 / 3 / 6.8
ER+ status confirmed?
Yes / 16 / 72.7 / 17 / 77.3 / 33 / 75.0
Test not repeated / 4 / 18.2 / 5 / 22.7 / 9 / 20.5
Unknown / 2 / 9.1 / 0 / 0.0 / 2 / 4.6
PgR Status
Positive / 13 / 59.1 / 11 / 50.0 / 17 / 38.6
Negative / 6 / 27.3 / 8 / 36.4 / 21 / 47.7
Unknown / 3 / 13.6 / 3 / 13.6 / 6 / 13.6
HER2 status
Positive / 4 / 18.2 / 4 / 18.2 / 8 / 18.2
Negative / 15 / 68.2 / 16 / 72.7 / 31 / 70.5
Unknown / 3 / 13.6 / 2 / 9.1 / 5 / 11.4
Vascular Invasion
Yes / 13 / 59.1 / 9 / 40.9 / 22 / 50.0
No / 4 / 18.2 / 10 / 45.5 / 14 / 31.8
Not reported/Unknown / 5 / 22.7 / 3 / 13.6 / 8 / 18.2

Supplementary Table S4:

CTC grade / Chemotherapy (N = 20) / Letrozole (N = 22) / P-value
0 / 1 / 2 / 3 / 4 / 5 / NA / 0 / 1 / 2 / 3 / 4 / 5 / NA
Pre-specified toxicities
Hot flushes / 18 / 1 / 1 / 0 / 0 / 0 / 0 / 13 / 6 / 3 / 0 / 0 / 0 / 0 / 0.04
Sweating / 19 / 0 / 1 / 0 / 0 / 0 / 0 / 15 / 6 / 1 / 0 / 0 / 0 / 0 / 0.05
Fatigue / 13 / 3 / 4 / 0 / 0 / 0 / 0 / 12 / 8 / 2 / 0 / 0 / 0 / 0 / 0.54
Arthralgia / 16 / 4 / 0 / 0 / 0 / 0 / 0 / 13 / 8 / 1 / 0 / 0 / 0 / 0 / 0.19
Arthritis / 19 / 1 / 0 / 0 / 0 / 0 / 0 / 18 / 4 / 0 / 0 / 0 / 0 / 0 / 0.35
Myalgia / 12 / 6 / 1 / 1 / 0 / 0 / 0 / 18 / 3 / 1 / 0 / 0 / 0 / 0 / 0.18
Headaches / 17 / 2 / 1 / 0 / 0 / 0 / 0 / 15 / 7 / 0 / 0 / 0 / 0 / 0 / 0.28
Dizziness / 17 / 3 / 0 / 0 / 0 / 0 / 0 / 17 / 5 / 0 / 0 / 0 / 0 / 0 / 0.70
Neuropathy / 17 / 1 / 2 / 0 / 0 / 0 / 0 / 21 / 1 / 0 / 0 / 0 / 0 / 0 / 0.33
Alopecia / 0 / 13 / 7 / 0 / 0 / 0 / 0 / 21 / 1 / 0 / 0 / 0 / 0 / 0 / <0.001
Nausea / 4 / 11 / 5 / 0 / 0 / 0 / 0 / 20 / 2 / 0 / 0 / 0 / 0 / 0 / <0.001
Vomiting / 12 / 2 / 6 / 0 / 0 / 0 / 0 / 22 / 0 / 0 / 0 / 0 / 0 / 0 / 0.001
Diarrhoea / 13 / 3 / 1 / 3 / 0 / 0 / 0 / 20 / 2 / 0 / 0 / 0 / 0 / 0 / 0.06
Neutropenia / 12 / 2 / 1 / 2 / 3 / 0 / 0 / 14 / 2 / 0 / 0 / 0 / 0 / 6 / 0.03
Constipation / 15 / 3 / 2 / 0 / 0 / 0 / 0 / 20 / 2 / 0 / 0 / 0 / 0 / 0 / 0.23
Stomatitis / 8 / 7 / 5 / 0 / 0 / 0 / 0 / 22 / 0 / 0 / 0 / 0 / 0 / 0 / <0.001
Mucositis / 15 / 0 / 5 / 0 / 0 / 0 / 0 / 22 / 0 / 0 / 0 / 0 / 0 / 0 / 0.02
Anaemia / 11 / 5 / 4 / 0 / 0 / 0 / 0 / 14 / 0 / 0 / 0 / 0 / 0 / 8 / <0.001
Thrombocytopenia / 19 / 0 / 1 / 0 / 0 / 0 / 0 / 14 / 0 / 0 / 0 / 0 / 0 / 8 / 0.48
Infection / 16 / 1 / 2 / 1 / 0 / 0 / 0 / 21 / 0 / 1 / 0 / 0 / 0 / 0 / 0.17
Transaminitis / 19 / 0 / 1 / 0 / 0 / 0 / 0 / 14 / 1 / 0 / 0 / 0 / 0 / 7 / 1.00
Other toxicities
Decreased appetite / 17 / 0 / 3 / 0 / 0 / 0 / 0 / 22 / 0 / 0 / 0 / 0 / 0 / 0 / 0.10
Febrile neutropenia / 18 / 0 / 0 / 2 / 0 / 0 / 0 / 22 / 0 / 0 / 0 / 0 / 0 / 0 / 0.22
PPE / 17 / 0 / 2 / 1 / 0 / 0 / 0 / 22 / 0 / 0 / 0 / 0 / 0 / 0 / 0.10

NA = Not assessed

The p-values are calculated using Fisher’s exact test and compare any graded toxicity versus no toxicity for the two treatment groups. Missing data are assumed to be grade zero.

Supplementary Table S5:

Variable / Chemotherapy Arm / Endocrine therapy Arm
Mann-Whitney Test / Mann-Whitney Test
P / Q-value (within the treatment arm) / P / Q-value (with the treatment arm)
let_7a / 0.008 / 0.08 / 0.046 / 0.23
let_7f / 0.456 / 0.57 / 0.115 / 0.29
miR_15b / 0.272 / 0.45 / 0.699 / 1
miR_21 / 0.224 / 0.45 / 0.351 / 0.702
miR_22 / 0.272 / 0.45 / 0.037 / 0.23
miR_23b / 0.328 / 0.47 / 1 / 1
miR_26a / 0.181 / 0.45 / 0.877 / 1
miR_98 / 0.066 / 0.33 / 0.115 / 0.29
miR_141 / 0.689 / 0.77 / 1 / 1
miR_194 / 0.776 / 0.78 / 0.485 / 0.81

Supplementary Figure S5:

Supplementary Figure S6:

Supplementary Figure S7: