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BREAST CANCER
original reports
Response to Induction Neoadjuvant Hormonal
Therapy Using Upfront 21-Gene Breast
Recurrence Score Assay—Results From the
SAFIA Phase III Trial
Khalid AlSaleh, MD, MSc
1
; Heba Al Zahwahry, MD
2
; Adda Bounedjar, MD
3
; Mohammed Oukkal, MD
4
; Ahmed Saadeddine, MD
5
;
Hassen Mahfouf, MD
6
; Kamel Bouzid, MD
7
; Assia Bensalem, MD
8
; Taha Filali, MD
9
; Hikmat Abdel-Razeq, MD
10
; Blaha Larbaoui, MD
11
;
Alaa Kandil, MD
12
; Omalkhair Abulkhair, MD
13
; Meteb Al Foheidi, MD
14
; Hassan Errihani, MD
15
; Marwan Ghosn, MD
16
;
Nashwa Abdel-Aziz, MD
17
; Maria Arafah, MD
18
; Hamouda Boussen, MD
19
; Farida Dabouz, PhD
20
; Haleem Rasool, MD
21
;
Mohun Bahadoor, MD
20
; Jihen Ayari, MD
22
; Sharif Kullab, MD
17
; and Jean-Marc Nabholtz, MD, PhD
17
; on behalf of King Saud University
and the International Cancer Research Group (ICRG)
abstract
PURPOSE Luminal, human epidermal growth factor receptor 2–negative breast cancer represents the most
common subtype of breast malignancies. Neoadjuvant strategies of operable breast cancer are mostly based on
chemotherapy, whereas it is not completely understood which patients might benefit from neoadjuvant hormone
therapy (NAHT).
MATERIALS AND METHODS The SAFIA trial is a prospective multicenter, international, double-blind, neoadjuvant
phase III trial, using upfront 21-gene Oncotype DX Breast Recurrence Score assay (recurrence score [RS] ,31)
to select operable luminal human epidermal growth factor receptor 2–negative patients, for induction hormonal
therapy HT (fulvestrant 500 mg with or without goserelin) before randomly assigning responding patients to
fulvestrant 500 mg (with or without goserelin) plus either palbociclib (cyclin-dependent kinase 4/6 inhibitor) or
placebo. The objectives of this interim analysis were to assess the feasibility of upfront RS determination on core
biopsies in the Middle-East and North Africa region and evaluate the efficacy of induction NAHT in patients with
an RS ,31.
RESULTS At the time of this interim analysis, 258 patients with relative risk were accrued, including 202 patients
(RS ,31% to 78.3%) treated with induction NAHT and 182 patients evaluable so far for response. The
feasibility of performing the Oncotype DX assays on core biopsy specimens was optimal in 96.4% of cases.
Overall, 93.4% of patients showed hormone sensitivity and no difference in NAHT efficacy was noticed between
RS 0-10, 11-25, and 26-30. Interestingly, patients with high RS (26-30) showed a trend toward a higher major
response rate (P= .05).
CONCLUSION The upfront 21-gene assay performed on biopsies is feasible in our population and has allowed us
to select patients with high hormone sensitivity (RS ,31). This approach could be an alternative to upfront
surgery without significant risk of progression, particularly during pandemic times.
JCO Global Oncol 7:811-819. © 2021 by American Society of Clinical Oncology
Creative Commons Attribution Non-Commercial No Derivatives 4.0 License
INTRODUCTION
Breast cancer (BC) is the leading cause of death in
women according to the WHO, responsible for an
estimated 626,679 deaths worldwide in 2018.
1,2
The
heterogenous nature of BC leads to differential prog-
nosis, treatment choices, and outcomes. Tumors with
estrogen receptor (ER)-positive and human epidermal
growth factor receptor 2 (HER2)-negative (luminal A
and B) are the most common, comprising 65%-75%
of all invasive BCs at time of diagnosis.
3,4
Multiple
mechanisms can target ER signaling; either by inhib-
iting or downregulating the receptor or by modulating
the downstream effectors, and the dual inhibition of
cyclin-dependent kinase (CDK) 4/6 and ER signaling
possess a highly synergistic anticancer and anti-
proliferative potential.
5,6
Fulvestrant, a 17 β-estradiol analog, is an ER down-
regulator, was shown to be one of the most potent
endocrine therapies for advanced breast when used
at high dose (500 mg), and thus deserves to be
evaluated in early BC management.
7,8
Palbociclib (PD
0332991), first-in-class CDK4/6 inhibitor, has signifi-
cantly improved patients’outcome when combined
with endocrine therapy in the metastatic setting.
9,10
ASSOCIATED
CONTENT
Protocol
Author affiliations
and support
information (if
applicable) appear at
the end of this
article.
Accepted on April 19,
2021 and published at
ascopubs.org/journal/
go on June 4, 2021:
DOI https://doi.org/10.
1200/GO.20.00575
811
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The role of the combination of palbociclib and hormone
therapy (HT) is presently investigated in early BC in either
the adjuvant or neoadjuvant settings.
11,12
In contrast to neoadjuvant chemotherapy (NACT), neo-
adjuvant endocrine therapy in luminal BC is not commonly
used as standard of care in current practice. This situation
arose mostly from the historical approach, basing thera-
peutic strategies upon a prognostic rather than a predictive
approach. The problem resides in the assessment of
chemosensitivity versus hormonal sensitivity, weighing the
potential benefit of either intervention for early luminal BC.
A significant fraction of those with luminal B, HER2–tumors
and a limited number of those with luminal A tumors will
benefit from NACT.
The 21-gene expression–based Oncotype DX Breast Re-
currence Score test has been shown to be both prognostic in
ER+ disease if treated with tamoxifen alone and predictive of
benefit from adding chemotherapy (CT), particularly for
those with Recurrence Score (RS) results .30.
13,14
These
conclusions came from retrospective analyses of pro-
spective trials in which patients with high RS appeared to
benefitsignificantly from the addition of standard CT to
tamoxifen, whereas those with low RS results did not.
14-17
The results from the large-scale prospective trial TAILORx
showed that patients with an RS ,11, treated with ad-
juvant HT alone, had at 5 years a very low rate of freedom
from recurrence of BC at distant site (99.3%; 95% CI, 98.7
to 99.6), eliminating any role for CT in this context.
18,19
Patients with RS results between 11 and 25 (n = 6,711)
HT alone had a similar efficacy compared with HT + CT
with comparable disease-free survival at 9 years (risk ratio:
1.08; 95% CI, 0.94 to 1.24; P= .26). Freedom from
distant recurrence was 94.5% and 95%, respectively.
18
A
retrospective exploratory subgroup analysis suggested
that some benefit from adding CT to HT could be seen in
some young women (,50 years) with the RS results
between 16 and 25. Finally, for the group of patients with
the RS results from 26 to 100, the estimated rate of
freedom from recurrence at a distant site was 93% at 5
years, suggesting a better outcome than expected with HT
alone. Overall, no benefit for CT was reported in the low-
RS group (,18), whereas the benefit was debatable for
the intermediate-RS group of 18-30.
20
In terms of feasi-
bility, the 21-gene assay can be confidently performed on
core biopsies to support clinical treatment planning in
ER+, HER2–invasive BCs, and the results can efficiently
guide decisions about appropriate neoadjuvant therapy,
including HT context.
21,22
The SAFIA trial is a multicenter, neoadjuvant phase III
study, performed in six countries of the Middle-East and
North Africa (MENA) region, comparing in a double-blind
manner HT plus placebo with HT plus palbociclib in pa-
tients with operable luminal BC, responding to induction
HT. We report the first interim analysis of the feasibility of
the upfront prospective use of the 21-gene assay to select
patients for induction neoadjuvant HT (NAHT) and the
related efficacy of HT before random assignment.
MATERIALS AND METHODS
SAFIA Study Design and Treatment Regimens
SAFIA trial is the first BC neoadjuvant phase III trial
designed and performed in the MENA region (Clinical-
Trials.gov identifier: NCT03447132).
23
This is a prospective
multicenter, international, double-blind, randomized con-
trolled, third-generation neoadjuvant phase III trial com-
paring fulvestrant 500 mg (with or without goserelin) plus
palbociclib (CDK 4/6 inhibitor) with fulvestrant 500 mg
(with or without goserelin) plus placebo in patients with
CONTEXT
Key Objective
The SAFIA trial is a first prospective phase III, multicenter, double-blind, third-generation neoadjuvant trial designed in the
Middle-East and North Africa region and run in six countries using upfront 21-gene assay (Recurrence Score [RS] ,31) to
select operable luminal human epidermal growth factor receptor 2–negative patients for induction hormone therapy
(fulvestrant with or without goserelin) before randomly assigning responding patients to hormone therapy with or without
palbociclib.
Knowledge Generated
This interim analysis reports on the feasibility of the 21-gene assay performed on core biopsies in our population and evaluates
the efficacy of induction neoadjuvant hormone therapy (NAHT) in patients with an RS ,31 including the three groups RS
0-10, 11-25, and 26-30. We found that the use of upfront 21-gene assay on biopsies is feasible and has allowed us to select
patients for NAHT without affecting their outcome.
Relevance
Our data support NAHT for patients with operable luminal estrogen receptor–positive, human epidermal growth factor re-
ceptor 2–negative breast cancer and an RS ,31 as an alternative to upfront surgery without significant loss of chance, in
particular, during pandemic times.
AlSaleh et al
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operable luminal BC responding to fulvestrant 500 mg (with
or without goserelin).
23
In terms of design (Fig 1), after signing the consent form,
patients underwent upfront screening by the 21-gene as-
say, performed centrally on core biopsies, to select can-
didates for NAHT (RS ,31). Patients with an RS ,31 were
treated with induction neoadjuvant fulvestrant (500 mg
intramuscular at days 1, 14, and 28 and then every 4 weeks
for 4 months) plus goserelin (3.6 mg subcutaneous every
4 weeks), for pre- and perimenopausal patients for
5 months, initiated 1 month before fulvestrant.
This treatment was followed by clinical and radiologic re-
sponse assessment at both primary breast tumor and nodal
disease, using mammography plus breast ultrasound and,
when indicated, magnetic resonance imaging.
24,25
Radio-
logic responses were defined as per RECIST 1.1 criteria.
26
Additionally, to precisely assess the real response to HT and
thus the hormone sensitivity, we divided stable disease in
minor response (MR): 0%-50% reduction in cross-product
and minor progression (MP): 1%-25% increase in cross-
product or any new lesion.
Responding patients (complete response [CR], partial re-
sponse [PR], and MR) to induction HT were then randomly
assigned, in a double-blind manner, to fulvestrant 500 mg
(with or without goserelin) with either palbociclib 125 mg
orally once daily or placebo (3 weeks on/1 week off) every
4 weeks for 4 months.
Patient Population
The study population consisted of postmenopausal or pre-
or perimenopausal patients with operable stage II and IIIA
luminal BC (ER+, HER2–). Inclusion and exclusion criteria
are tabulated in Table 1. This trial was performed in 24
centers and six countries of the MENA region (Saudi
Arabia, Egypt, Jordan, Lebanon, Algeria, and Tunisia), after
appropriate institutional approval through respective in-
stitutional review boards.
Objectives
The objectives of this interim analysis are (1) to report the
response rates of induction NAHT with fulvestrant with or
without goserelin given for 4-5 months in a patient pop-
ulation selected upfront by the 21-gene assay, (2) to assess
the prediction of objective hormone sensitivity according to
the levels of upfront RS levels, and (3) to analyze the
feasibility of the 21-gene test performed on core biopsies in
our Middle-East and Maghreb patient population.
Processing of the 21-Gene Assay
After obtaining the signature on the consent form and
before initiating any neoadjuvant therapy, biopsy samples
of eligible patients were immediately sent for upfront 21-
gene assay at Genomic Health Inc (Redwood City, CA),
following the established Standard Operating Procedures.
Excluded from the trial were patients with insufficient tumor
material in blocks or slides and unconfirmed diagnosis by
Genomic Health pathologists.
Statistical Considerations
Sample size calculation. The sample size calculation of
SAFIA trial was based on the assumption that the patho-
logical complete response (pCR) rate will increase from 5%
for fulvestrant (with or without goserelin) to 15% for the
combination of fulvestrant–palbociclib. With an αvalue set
at 5%, using one-sided significance tests and a βvalue at
20%, the sample size was conservatively set in 260
patients.
Considering that around 20% of patients will show de novo
resistance to induction fulvestrant before random assign-
ment, 60 additional patients were needed to identify 260
patients sensitive to induction therapy, bringing the sample
size to 320.
Finally, assuming that around 20% of na¨
ıve patients with
luminal tumors will be classified of high risk (RS ≥31), an
additional 80 screened patients were considered necessary
to identify the 320 patients with a score ,31. Therefore,
the total sample size of the trial was estimated to be 400
patients (Fig 1).
Statistical methodology. The current analysis includes a
description of the enrolled population with known RS re-
sults: patients with an RS ,31 (treated by NAHT) and an
RS ≥31. Descriptive statistics (median and minimum-
maximum) were used for continuous variables, and fre-
quency or percentage for categorical variables. Correlations
between the RS result and responses to NAHT were
assessed by χ
2
or Fisher’s exact tests. Data presented for
this interim analysis were collected via an electronic ob-
servation booklet (eCRF) developed on a web-based
MARVIN electronic system (XClinical, Munich, Germany),
validated according to US Food and Drug Administration
Fulvestrant 4 months
Response No response
Randomly assign
(n = 260) CT or surgery
Surgery
Oncotype DX
(n = 400)
BC patients
(n = 320; score < 30)
Fulvestrant 4 months
plus palbociclib
Fulvestrant 4 months
plus placebo
FIG 1. SAFIA trial design flow sheet. BC, breast cancer; CT,
chemotherapy.
Response to Induction Neoadjuvant Hormonal Therapy
JCO Global Oncology 813
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regulations (21CFR Part 11). The analyses were conducted
on data extracted from the ongoing SAFIA database and
were performed using the validated SAS 9.4, software.
RESULTS
Patient Disposition
At the time of this interim analysis of SAFIA trial (May 2020),
a total of 331 patients were accrued in 24 centers and six
countries of the MENA region (Saudi Arabia, Egypt, Jordan,
Lebanon, Algeria, and Tunisia) (Fig 2). Owing to admin-
istrative barriers at the governmental level barring pathology
samples to be shipped overseas, 53 patients from Egypt did
not benefit from the determination of 21-gene test; four
patients dropped out before sending the pathology material
for testing; and one patient was deemed noneligible. Two
hundred seventy-three 21-gene assays were performed: 10
patients had insufficient carcinoma material for RS result
determination, and five patients dropped out after the re-
sults of the RS test and before NAHT. Among the remaining
258 patients, 202 patients with an RS of 0-30 (78.3%) were
treated with induction NAHT.
Description of Patient Population With Known RS Results
(n = 258)
Patient characteristics with known RS results are as follows:
median age: 49 years (25-84); pre- or perimenopausal: 151
(58.5%) or postmenopausal: 107 (41.5%); invasive ductal
carcinoma: 205 (79.5%), invasive lobular carcinoma: 30
(11.6%) and other carcinomas: 23 (8.9%); grade I: 27
(10.8%), grade II: 196 (78.7%), and grade III: 26 (10.5%);
Ki-67 ≤14%: 98 (38%) and Ki-67 .14%: 160 (62%); and
clinical stage: IIA: 117 (45.3%), IIB: 103 (39.9%), and IIIA:
34 (13.2%) and missing: 4 (1.6%); Differential charac-
teristics according to RS ,31 and ≥31 are shown in
Table 2.
TABLE 1. Patient Selection Criteria for SAFIA Trial
Inclusion Criteria Exclusion Criteria
1. Written informed consent before beginning specific protocol procedures,
including expected cooperation of the patients for the treatment and
follow-up, must be obtained and documented according to the local
regulatory requirements
2. Age .18
3. Postmenopausal women or premenopausal
4. Performance status ,2 (according to WHO criteria)
5. Histologically confirmed, nonmetastatic BC (luminal A or B)
•HR+ (estrogen or progesterone) .1%
•HER2–(score 0 or 1 by immunochemistry)
•FISH-negative (if the IHC score is 2)
6. Clinical stages II and IIIA
7. No previous BC surgery, radiotherapy, HT, or CT
8. Measurable disease
9. Hematology
•Neutrophil count ≥1.5 ×10
9
/L
•Platelet count ≥100 ×10
9
/L
•Leukocyte count .3,000/mm
•Hb .9 g/dL
10. Hepatic function
•Total bilirubin ≤1.5 ×UNL
•ASAT ≤2.5 ×UNL
•ALAT ≤2.5 ×UNL
•Alkaline phosphatase ≤2.5 ×UNL
11. Renal function
•Creatinine clearance ≥40 mL/min in the case of MRI
•Serum creatinine ≤1.5 ×UNL (and if serum creatinine .1.5 ×UNL
and creatinine clearance ≥50 mL/min)
12. Metabolic function
•Serum calcium ≥lower limit of normal
•Serum magnesium ≥lower limit of normal
13. No anthracycline contraindication and no progressive heart disease
and (normal LFEV per institution guidelines)
14. Negative pregnancy test (urine or serum) within 7 days before registration
for all women of childbearing age. Patients of childbearing potential must
implement adequate nonhormonal contraceptive measures during study
treatment
1. Male patients
2. HER2+ tumors or unknown HR-HER2 status
3. Pregnant or breastfeeding, or plan to become pregnant within 6 months
post-treatment
4. Pre- or perimenopausal women not willing to use highly effective methods
of contraception (per institutional standard) during treatment and for 6
months post-treatment
5. Any form of BC other than the inclusion criteria, particularly inflammatory
and/or overlooked forms (stage IIIb or IV)
6. Nonmeasurable tumor
7. Bilateral BC
8. Previous treatment for BC including surgery for their disease or have had
primary axillary dissection, radiotherapy, and systemic therapy
9. Patients with a history of other cancer, except in situ cervical cancer or
basocellular skin cancer, considered cured
10. Patients have another disease, which is deemed incompatible with the
inclusion in the protocol
11. Heart, kidney, medullary, respiratory, or liver failure
•Clinically significant cardiovascular disease (including myocardial
infarction, unstable angina, symptomatic congestive heart failure, and
serious uncontrolled cardiac arrhythmia) ,1 year before enrollment in
the study
•History of interstitial lung disease, eg, pneumonitis or pulmonary fibrosis
or evidence of interstitial lung disease at baseline
•Acute urinary infection and ongoing hemorrhagic cystitis
12. Uncontrolled diabetes
13. A symptomatic or progressive disorder of the CNS or peripheral
neuropathy .grade II
14. Significant psychiatric abnormalities
15. History of hypersensitivity to studied treatment or excipients
16. Known previous or ongoing abuse narcotic drug, other medication, or
alcohol
17. Any investigational agent within 30 days before initiation of study
treatment
18. Major surgical procedure within 28 days of initiation of treatment
19. Subject unwilling or unable to comply with study requirement
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CT, chemotherapy; ET, endocrine therapy; HR+, hormone positive; HT,
hormonal therapy; LVEF, left ventricular ejection fraction.
AlSaleh et al
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Distribution of RS Scores (n = 263)
Overall, the RS result determination showed a median of 18
(0-75) with 56 patients with an RS ≥31 (21.3%) and 207
with an RS ,31 (78.7%) distributed as follows: RS results
0-10: 35 (13.3%), 11-18: 88 (33.5%), 19-25: 59 (22.4%),
and 26-30: 25 (9.5%).
Response to Induction Fulvestrant 500 mg (With or
Without Goserelin)
At the time of this interim analysis, 182 patients were
evaluable for response. Responses, according to the RS
results, are displayed in Table 3 and Figure 3. Overall, the
nonprogression (NP) rate (CR + PR + MR) was 93.4% with
CR: 4.9% and PR: 67% for a major response rate (CR + PR)
of 71.9% and a MR rate of 26.4%. Alternatively, six patients
(3.3%) had a progression disease (PD), and six additional
patients (3.3%) a MP (between 1% and 25%) for a total
overall progression (PD + MP) of 6.6%.
Correlations Between Radiologic Response and RS Result
When considering NP rates between the RS groups 0-10,
11-25, and 26-30, no significant differences were observed
with NP rates of 97%, 93%, and 95%, respectively, sug-
gesting that all tumors in these subgroups are expressing a
high hormone sensitivity. Interestingly, major response
rates (CR + PR) were comparable for the two groups RS 0-
10 (70%) and 11-25 (64%) but higher for the RS 26-30
group at 86% at the limit of the statistical significance
(P= .05).
Feasibility of the 21-Gene Assay on Core Biopsies
At the time of the analysis, 273 core biopsies were sent and
the RS results were available in a median time of 8 days.
Two hundred sixty-three patients had a positive determi-
nation of RS results (96.3%), whereas 10 patients (3.7%)
had insufficient carcinoma on the provided specimens.
DISCUSSION
Neoadjuvant therapy was initially used to treat inoperable
inflammatory and locally advanced breast carcinoma.
27
First-generation neoadjuvant trials for operable disease
showed that NACT was similar to adjuvant CT in terms of
disease-free survival and overall survival, while increasing
the rates of conservative surgery and pCR, which was shown
to be correlated with improved survival. Second-generation
Enrollment (n = 331)
Core-biopsy samples sent for
RS determination (n = 273)
Excluded from NAHT
Insufficient carcinoma
Dropout after RS testing
before NAHT
RS ≥ 31
(n = 71)
(n = 10)
(n = 5)
(n = 56)
Randomly assigned
(n = 211)
With an RS < 31
(n = 176)
Egypt (n = 35)
Radiologic response for patients with
RS < 31
After 4-5 months of NAHT (n = 182)
No 21-gene testing
Dropout
Noneligibility
Egypt
(n = 58)
(n = 4)
(n = 1)
(n = 53)
Included in NAHT
(n = 255)
With RS < 31 (n = 202)
Egypt (n = 53)
FIG 2. Patient disposition. NAHT, neoadjuvant hormone therapy;
RS, recurrence score.
Response to Induction Neoadjuvant Hormonal Therapy
JCO Global Oncology 815
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neoadjuvant trials aimed at optimizing the pCR rates using
various CT therapeutic strategies.
28
A meta-analysis of the
three prospective studies that compared endocrine therapy
(ET) with CT in the neoadjuvant setting of ER + BC showed
that CT was comparable with ET.
29
Third-generation neoadjuvant trials allow the prospective
selection of in vivo patient subpopulations with secondary
therapeutic adaptation on the basis of the individual patient
sensitivity to induction therapy, representing a potential
model for individual biologic developments.
30
In our third-generation neoadjuvant trial, we used upfront
21-gene assay to select patients with a higher probability of
hormone sensitivity (RS ,31) to prospectively assess
in vivo the efficacy of induction fulvestrant 500 mg (with or
without goserelin) before randomly assigning hormone-
sensitive patients to fulvestrant 500 mg (with or without
goserelin) plus palbociclib vs fulvestrant 500 mg (with or
without goserelin) plus placebo. The characteristics of our
cohort are in line with the literature on the BC population
from the MENA region with a majority of pre- or peri-
menopausal patients (58.5%) with relatively aggressive
clinical-pathologic luminal characteristics such as Ki-
67 ≥14% in 62% of cases.
31
Of note, the majority of
patients presented with stage II (89.6%) tumors.
Our feasibility in performing the 21-gene assays on core
biopsy specimens was optimal in 96.4% in our MENA
population with insufficient carcinoma material in only
3.6% of cases. These results compare favorably with re-
ports from the literature with failure rates ranging from 4.8%
to 10.2%, further validating the feasibility of the 21-gene
assay in a neoadjuvant setting.
32
In terms of RS result distribution, Iwata et al
33
reported in
the TransNEOS study on 275 patients with known RS:
RS ,18: 53.2%, RS 18-30: 28.5%, and RS ≥31: 18.3%.
Our results are comparable with 263 patients from the
MENA region: RS ,18: 46.8%, RS 18-30: 31.9%, and
RS ≥31: 21.3%.
Our responses to induction NAHT with fulvestrant with or
without goserelin for patients with an RS ,31 confirm a
high hormone sensitivity with a NP rate (CR + PR + MR) of
93.4%. We chose to divide stable disease into MR (re-
sponse from 0% to 25%) and MP (from 1% to 25%), to
assess more precisely the potential hormone sensitivity, in
particular, for tumors with a low proliferative index such as
the majority of luminal A subtypes. Alternatively, we con-
sider that tumors with MP express an intrinsic hormone
resistance. This approach was aimed at maximizing pa-
tients with in vivo hormone sensitivity before exposure to
palbociclib versus placebo in the postrandomization stage.
The low rate of progression (6.6%), combining MP (3.3%)
and the classical PD (3.3%), suggests that the upfront
determination of 21-gene assay RS ,31 has allowed us to
TABLE 2. Patient Characteristics (RS ,31 and RS ≥31)
RS <31 (n = 202),
No. (%)
RS ‡31 (n = 56),
No. (%)
Histologic type
Ductal 154 (77) 51 (91)
Lobular 29 (14) 1 (2)
Mixed 2 (1) 1 (2)
Others 16 (8) 3 (5)
Histologic grade SBR
I 27 (13.4) 0 (0)
II 155 (76.7) 41 (73.2)
III 13 (6.4) 13 (23.2)
NA 7 (3.6) 2 (3.6)
Ki67 value, %
≤14 95 (47) 3 (5)
.14 107 (53) 53 (95)
Clinical stage
IIA 99 (49) 18 (32.1)
IIB 79 (39.1) 24 (42.9)
IIIA 21 (10.3) 13 (23.2)
NA 3 (1.6) 1 (1.8)
Luminal subtype by
IHC
A 111 (55) 9 (16)
B 90 (44.6) 47 (84)
NA 11 (5.4) 0 (0)
Abbreviations: IHC, immunohistochemistry; NA, not available; RS, recurrence
score; SBR, Scarff Bloom Richardson.
TABLE 3. Radiologic Response for Patients With an RS ,31
RS or Response 0-10, No. (%) 11-25, No. (%) 26-30, No. (%) Total, No. (%) P
CR 2 (6) 6 (5) 1 (5) 9 (5) NS
PR 19 (64) 77 (59) 17 (81) 113 (62) .05
CR + PR 21 (70) 83 (64) 18 (86) 122 (67) .05
SD 29 (97) 121 (93) 20 (95) 170 (93.4) NS
PD 1 (3) 10 (7) 1 (5) 12 (3.3) NS
Total 30 (100) 131 (100) 21 (100) 182 (100) NS
Abbreviations: CR, complete response; NS, nonsignificant; PD, progressive disease (.25%); PR, partial response (response .50%); RS, recurrence
score; SD, stable disease.
AlSaleh et al
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eliminate the majority of potential de novo hormone-
resistant tumors. Consequently, using induction fulves-
trant 500 mg (with or without goserelin) in the RS ,31
group is not bearing a significant risk of progression for
these patients. Of note is the fact that when evaluating the
NP rates (CR + PR + MR) according to the RS (0-10, 11-25,
and 26-30), we noticed that there was no significant dif-
ference in terms of hormone sensitivity between the three
groups (NP rates 97%, 93%, and 95%, respectively). In-
terestingly, the major response rate (CR + PR) was superior
in the RS 26-30 group compared with the RS 0-10 and 11-
25 groups (respectively, 86% v70%, 64%) at the limit of
the statistical significance (P= .05). Alternatively, MR rates
were lower in the RS 26-30 group compared with the RS 0-
10 and 11-25 groups (respectively, 9% v27%, 29%).
These observations suggest that the tumor proliferation rate
may play an important role in the kinetics of response to
fulvestrant 500 mg (with or without goserelin) and thus
could plead for a longer exposure to NAHT before drawing
conclusions in terms of efficacy. This might be particularly
true for tumors with low proliferation rates such as luminal A
and low RS result tumors. These results, obtained by post
hoc, exploratory analyses, are hypothesis-generating and
deserve confirmation.
Our observations in selecting patients with potential hor-
mone sensitivity with upfront 21-gene assay might be of
value, especially during the COVID-19 outbreak during
which many centers had to delay planned elective sur-
geries. Consequently, fulvestrant 500 mg (with or without
goserelin) in patients with luminal ER+, HER2–, and an
RS ,31 could be an alternative to upfront surgery without
significant loss of chance in pandemic times. The COVID-
19 Pandemic Breast Cancer Consortium has formulated
preliminary guidelines regarding patients with ER+,
HER2–tumors, that is, deferring surgery and receiving
neoadjuvant endocrine therapy for 6-12 months without
clinical compromise.
34
In conclusion, the use of upfront 21-gene assay on biopsies
is feasible and has allowed us to select in SAFIA neo-
adjuvant phase III study a large population of patients
(78.7%) with an RS ,31 expressing a high hormone
sensitivity. With an overall NP rate of 93.4%, no significant
difference in fulvestrant (with or without goserelin) efficacy
was noticed between RS results 0-10, 11-25, and 26-30.
Interestingly, in exploratory analyses, patients with high RS
results (26-30) showed a trend toward a higher major re-
sponse rate, probably related to a higher tumor proliferation
(Ki-67 .14% in 95% of cases). Neoadjuvant fulvestrant
with or without goserelin in patients with luminal ER+,
HER2–, and an RS ,31 could be an alternative to upfront
surgery without significant risk of progression, particularly
in pandemic times.
AFFILIATIONS
1
Department of Medicine, College of Medicine, King Saud University,
Riyadh, Saudi Arabia
2
National Cancer Institute (NCI), Cairo University, Cairo, Egypt
3
Anti Cancer Center, Blida, Algeria
4
Medical Oncology Department, Beni-Messous University Hospital,
Algiers, Algeria
5
Oncology Center, King Abdulaziz Medical City (KAMC), Riyadh, Saudi
Arabia
6
Medical Oncology EPH, Rouiba, Algeria
7
Oncology Center of Pierre et Marie Curie, Algiers, Algeria
8
Oncology Department, Dr Benbadis University Hospital, Constantine,
Algeria
9
Oncology Department, Constantine University Hospital, Constantine,
Algeria
10
King Hussein Cancer Center (KHCC), Amman, Jordan
11
Oncology Center of Emir Abdelkader, Oran, Algeria
12
Alexandria University, Alexandria, Egypt
13
Specialized Medical Center (SMC), Riyadh, Saudi Arabia
14
Oncology Center of Princess Noorah, King Abdulaziz Medical City
(KAMC), Jeddah, Saudi Arabia
15
Medical Oncology, National Institute of Oncology, Mohammed V
University, Rabat, Morocco
655
64
59
81
27 29
9
3
75
0
10
20
30
40
50
60
70
80
90
0-10 11-25 26-30
Percentage Response
RS
CR PR MR PD
FIG 3. Bar chart depicting response rates
(%) to induction fulvestrant with or without
goserelin according to RS. CR, complete
response; MR, minor response; PD, pro-
gressive disease; PR, partial response;
RS, recurrence score.
Response to Induction Neoadjuvant Hormonal Therapy
JCO Global Oncology 817
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16
Hematology-Oncology Department, Hotel Dieu de France, University
Saint Joseph, Beirut, Lebanon
17
Oncology Center, King Saud University Medical City (KSUMC), Riyadh,
Saudi Arabia
18
Department of Pathology, King Saud University Medical City (KSUMC),
Riyadh, Saudi Arabia
19
Faculty of Medicine Tunis, University Tunis El Manar, Abderrahmen
Mami Hospital, Ariana, Tunisia
20
International Cancer Research Group (ICRG), Sharjah, United Arab
Emirates
21
King Faisal Specialist Hospital and Research Center (KFSHRC),
Jeddah, Saudi Arabia
22
Faculty of Medicine Tunis, Oncology Department, University Tunis El
Manar, Military Hospital of Tunis, Tunis, Tunisia
CORRESPONDING AUTHOR
Khalid AlSaleh, MBBS, MSc, Oncology Center, King Khalid University
Hospital, King Saud University, PO Box 80101, Riyadh 16911,
Saudi Arabia; e-mail: Khaalsaleh@ksu.edu.sa.
PRIOR PRESENTATION
Presented at 2020 ASCO Virtual Scientific Program 2020, May 29-June 2.
SUPPORT
Supported by Pfizer, AstraZeneca, and Genomic Health on the basis of
investigator-initiated trial. Supplemental fund received from Deanship of
Scientific Research, King Saud University, Researcher Supporting
Project Number RSP-2019/88 for Dr K.A.
CLINICAL TRIAL INFORMATION
NCT03447132 (SAFIA)
DATA SHARING STATEMENT
Data are private as the study is still ongoing.
AUTHOR CONTRIBUTIONS
Conception and design: Khalid AlSaleh, Adda Bounedjar, Ahmed
Saadeddine, Hassen Mahfouf, Hikmat Abdel-Razeq, Blaha Larbaoui,
Alaa Kandil, Omalkhair Abulkhair, Meteb Al Foheidi, Hassan Errihani,
Marwan Ghosn, Nashwa Abdel-Aziz, Farida Dabouz, Sharif Kullab,
Jean-Marc Nabholtz
Financial support: Alaa Kandil
Administrative support: Nashwa Abdel-Aziz, Sharif Kullab, Jean-Marc
Nabholtz
Provision of study materials or patients: Heba Al Zahwahry, Adda
Bounedjar, Mohammed Oukkal, Ahmed Saadeddine, Hassen Mahfouf,
Kamel Bouzid, Taha Filali, Omalkhair Abulkhair, Marwan Ghosn,
Hamouda Boussen, Jihen Ayari
Collection and assembly of data: Heba Al Zahwahry, Adda Bounedjar,
Mohammed Oukkal, Hassen Mahfouf, Kamel Bouzid, Assia Bensalem,
Taha Filali, Hikmat Abdel-Razeq, Blaha Larbaoui, Alaa Kandil,
Omalkhair Abulkhair, Meteb Al Foheidi, Hassan Errihani, Marwan Ghosn,
Nashwa Abdel-Aziz, Hamouda Boussen, Farida Dabouz, Haleem Rasool,
Mohun Bahadoor, Jihen Ayari, Sharif Kullab, Jean-Marc Nabholtz
Data analysis and interpretation: Adda Bounedjar, Hikmat Abdel-Razeq,
Blaha Larbaoui, Alaa Kandil, Meteb Al Foheidi, Hassan Errihani, Marwan
Ghosn, Maria Arafah, Hamouda Boussen, Farida Dabouz, Mohun
Bahadoor, Jihen Ayari, Sharif Kullab, Jean-Marc Nabholtz
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
AUTHORS’DISCLOSURES OF POTENTIAL CONFLICTS OF
INTEREST
The following represents disclosure information provided by the authors
of this manuscript. All relationships are considered compensated unless
otherwise noted. Relationships are self-held unless noted. I = Immediate
Family Member, Inst = My Institution. Relationships may not relate to the
subject matter of this manuscript. For more information about ASCO’s
conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.
org/go/authors/author-center.
Open Payments is a public database containing information reported by
companies about payments made to US-licensed physicians (Open
Payments).
Khalid AlSaleh
Honoraria: Amgen, AstraZeneca, Novartis, Pfizer, Roche
Research Funding: Pfizer, AstraZeneca
Mohammed Oukkal
Consulting or Advisory Role: Amgen, Roche, Novartis, Pfizer
Speakers’Bureau: Bayer, Ipsen
Ahmed Saadeddin
Consulting or Advisory Role: Novartis
Travel, Accommodations, Expenses: Novartis, Roche, MSD, Sanofi
Kamel Bouzid
Consulting or Advisory Role: Roche, Pfizer, MSD Oncology, Merck, SANFI,
Mylan
Omalkhair Abulkhair
Travel, Accommodations, Expenses: MSD, Roche
Meteb Al-Foheidi
Honoraria: Pfizer, Lilly, Roche, Novartis
Consulting or Advisory Role: Novartis
Speakers’Bureau: Pfizer, Roche, AstraZeneca, Novartis, Lilly
Travel, Accommodations, Expenses: Pfizer, Roche, Novartis, AstraZeneca
Hassan Errihani
Consulting or Advisory Role: Pfizer, Roche, MSD, Merck, Janssen
Oncology, AstraZeneca
Speakers’Bureau: Novartis, Amgen, Astellas Pharma, Servier
Research Funding: Roche
Travel, Accommodations, Expenses: Pierre Fabre, Merck
Marwan Ghosn
Consulting or Advisory Role: Bayer, MSD Oncology, Bristol Myers Squibb,
Pfizer, Novartis, Sanofi, Lilly, Astellas Pharma
Research Funding: Pfizer, Novartis, Sanofi
Travel, Accommodations, Expenses: Astellas Pharma, Bristol Myers
Squibb, Celgene
Haleem Rasool
Travel, Accommodations, Expenses: Bayer
Mohun Bahadoor
Travel, Accommodations, Expenses: Pfizer
Sharif Kullab
Travel, Accommodations, Expenses: Pfizer
Jean-Marc Nabholtz
Consulting or Advisory Roles: Pfizer, AstraZeneca, Genomic Health, MSD,
Roche
Honoraria: Pfizer, AstraZeneca, AMGEN, Novartis, Roche
Research Funding: Pfizer, AstraZeneca, Genomic Health
Travel, Accommodations, Expenses: Pfizer, AstraZeneca, Roche, Novartis
No other potential conflicts of interest were reported.
AlSaleh et al
818 © 2021 by American Society of Clinical Oncology
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JCO Global Oncology 819
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