Keywords
Oncotype DX - early breast cancer - recurrence - surgery
Multigene tumor assays (MGAs) have offered a greater insight into patient prognosis
in early, node negative, hormone receptor positive breast cancers. This further understanding
of tumor genetics has allowed oncologists and breast surgeons alike to tailor adjuvant
therapy more specifically to individual patients.
Despite the proven benefit of adjuvant chemotherapy (AC),[1]
[2]
[3] a large proportion of early breast cancer patients is exposed to its negative effects
unnecessarily.[4] In recent years, MGAs have guided the use of AC in this cohort resulting in a significant
reduction in the AC-related morbidity.[5] In addition, it provides objective, validated data[6] promoting a standardized approach to the management of these cancers across centers
globally with its utilization supported by the American Society of Clinical Oncology.[7]
Despite the evolution of systemic directed therapy, locoregional control through surgical
intervention and adjuvant radiotherapy remain the mainstay of treatment with proven
prognostic benefits.[8]
The specific MGA, Oncotype DX (ODX) 21-gene recurrence score, offers a widely accepted
tool to guide prognosis and predict chemotherapy efficacy in this group. Furthermore,
the ODX breast cancer assay for ductal carcinoma in situ[9] (DCIS) has emerged as a useful adjunct for predicting patients who stand to benefit
from post-breast conservation surgery radiotherapy.[10]
[11]
However, the routine utilization of MGAs to inform operative decision-making is yet
to be established with a paucity of published data. In this pilot study, we sought
to identify the relationship of the ODX score and mode of surgical intervention (breast
conserving and mastectomy) with a view to establishing the potential benefits of intervention
based on recurrence risk quantification. We hypothesize that ODX may predict the prognostic
advantages of various surgical interventions and hence inform initial operative decision-making.
Materials and Methods
Study Design and Participants
In this retrospective cohort study, all patients with stage T1 or T2, node negative,
estrogen receptor positive breast cancer undergoing ODX testing were included for
analysis. Consecutive ODX tests performed over a 9-year period from October 2007 to
May 2016 were evaluated. Study design was guided by the STROBE guidelines for reporting
observational trials[12] with full ethical approval granted by the Galway Clinical Research and Ethics Committee.
Pathological assessment of each tumor specimen was performed in the Department of
Pathology at University Hospital Galway. All cases were discussed in a multidisciplinary
(MDT) setting in the presence of at least one breast surgeon, radiologist, and pathologist.
Suitable cases, as described, were referred for ODX scoring with testing performed
by Genomic Health Laboratory, Redwood City, California using an established protocol.[2] Oncotype scores were classified as high (≥31), medium (18–30), or low risk (0–17)
as defined by Paik et al.[6] Adjuvant management was then determined following further MDT and patient consultation.
Outcomes
The primary outcome was breast cancer recurrence. Recurrence was confirmed locally
or distantly with either histological or radiological confirmation. Further subgroup
analysis assessed the recurrence effect of mode of surgical intervention for patient
groups as defined by the oncotype score. Secondary end points included tumor characterization,
adjuvant therapeutic stratification, and reintervention rates.
Data
Patient demographic, follow-up, recurrence, and adjuvant therapy data were extracted
from the regional Oncology Management System (Citrix Systems Inc. Santa Clara, CA).
Tumor detail was obtained from hospital pathology reports. Missing data were identified
from review of patient hospital notes. For comparative purposes, patients were cohorted
into low-, medium-, and high-risk oncotype score groups. Normally distributed data
were reported as mean (standard deviation), while outcome data were reported nominally
(percentage) and compared using the chi-squared test. All data were tabulated using
Microsoft Excel (Microsoft Corporation, Redmond, WA) and Statistical Package for the
Social Sciences (SPSS) software (SPSS Inc., Chicago, IL) was used for data analysis.
Results
Demographic Data
In total 361 patients underwent oncotype testing over the study period with outcome
data available for 353. The mean age was 55.25 years (±10.58). Mean follow-up was
38.59 months (±29.1). All tumors were both hormone receptor positive and HER2, node
negative. Mean tumor size was 21.64 mm (±9.05). Further tumor pathological characteristics
are summarized in [Table 1].
Table 1
Tumor pathological characteristics
|
Tumor subtype (n [%])
|
Lobular
|
57 (16)
|
|
Ductal
|
289 (80)
|
|
Mixed
|
2 (0.5)
|
|
Tubular
|
3 (0.8)
|
|
Colloid
|
6 (1.6)
|
|
Other
|
4 (1.1)
|
|
Grade (n* [%])
|
1
|
40 (11)
|
|
2
|
231 (64)
|
|
3
|
90 (25)
|
Surgical and Adjuvant Intervention
The majority of patients underwent a breast conserving wide local excision (WLE) (n = 313, [86.7%]) of the tumor. A further 32 (8.9%) and 16 (4.4%) patients had either
a mastectomy or WLE with completion mastectomy, respectively. Of note, 52 (14.4%)
patients required reintervention for either a re-excision of margins (n = 36) or completion mastectomy (n = 16).
With regard to overall adjuvant therapy, 148 patients (40.9%) received chemotherapy
with 333 (92.2%) undergoing radiotherapy. Three-hundred and fifteen patients (87.2%)
undertook regular systemic hormonal therapy. Adjuvant treatment according to oncotype
risk group is outlined further in [Table 2].
Table 2
Patient, tumor, and treatment characteristics as defined by oncotype risk score
|
Oncotype risk group
|
Low
|
Medium
|
High
|
|
Patient number
|
181
|
142
|
30
|
|
Age
|
55.1
|
55.3
|
55.9
|
|
Tumor size (mm)
|
22.2
|
20.6
|
23.25
|
|
Grade
|
|
1
|
29
|
10
|
0
|
|
2
|
122
|
95
|
8
|
|
3
|
30
|
37
|
22
|
|
Follow-up (months)
|
37.1
|
41.4
|
37.5
|
|
Mode of surgery (n [%])
|
|
Wide local excision
|
154 (85)
|
125 (88)
|
28 (93.3)
|
|
Mastectomy
|
19 (10.5)
|
10 (7)
|
1 (3.3)
|
|
Wide local excision with completion mastectomy
|
8 (4.5)
|
7 (5)
|
1 (3.3)
|
|
Surgical reintervention (%)
|
15.4
|
12.6
|
16.6
|
|
Adjuvant therapy (n [%])
|
|
Chemotherapy
|
21 (11.6)
|
99 (69.7)
|
28 (93.3)
|
|
Radiotherapy
|
159 (87.8)
|
125 (88.65)
|
30 (100)
|
|
Hormonal therapy
|
160 (88.3)
|
128 (90.1)
|
27 (93.1)
|
Note: All figures are means unless otherwise stated. n, number, mm, millimeters.
Oncotype Score
Three-hundred and fifty-three patients had a documented oncotype score over the study
period. When stratified according to recurrence risk, the majority of patients had
a “low risk” score (n = 181, [51.3%]). A further 40.2% (n = 142) patients were deemed to be of intermediate risk with a minority [n = 30, (8.5%)] having a high-risk score. Risk groups as defined by oncotype score
are further described in [Table 2].
Disease Recurrence
In total five patients (1.38%) had disease recurrence at a mean of 43.4 months (range:
19–82 months). One patient experienced local recurrence with four further patients
developing distant recurrence. Three further patients were diagnosed with DCIS of
the contralateral breast during follow-up surveillance.
Subgroup analysis assessing the recurrence effect of mode of surgical intervention
for patient groups as defined by the oncotype score is summarized in [Table 3]. Disease recurrence was 6.66% (2/30) in the high-risk oncotype group with 0.7 (1/142)
and 1.1% (2/181) rates of recurrence in the medium- and low-risk oncotype groups,
respectively. Two patients undergoing WLE in both the high- and low-risk groups experienced
recurrence with one further recurrence identified in the intermediate group following
mastectomy. Comparative analysis of operative groups in each oncotype cohort revealed
no difference in disease recurrence in the low- (p = 0.84) and high-risk groups (p = 0.92) with a statistically higher rate of recurrence identified in the intermediate-risk
mastectomy group (p = 0.002).
Table 3
A comparison of disease recurrence among operative groups as defined by oncotype score
|
Oncotype score
|
Mode of surgery
|
Follow-up
|
Recurrence (n/total)
|
Subgroup analysis (p-Value)
|
|
<18
|
WLE
|
37.4
|
2/154
|
|
|
Mastectomy
|
35.2
|
0/9
|
|
|
WLE with completion mastectomy
|
36.9
|
0/8
|
0.84
|
|
18–31
|
WLE
|
41.5
|
0/125
|
|
|
Mastectomy
|
36.7
|
1/10
|
|
|
WLE with completion mastectomy
|
47.1
|
0/7
|
0.002
|
|
>31
|
WLE
|
37.0
|
2/28
|
|
|
Mastectomy
|
59.0
|
0/1
|
|
|
WLE with completion mastectomy
|
30.0
|
0/1
|
0.92
|
Abbreviations: n, number; WLE, wide local excision.
Note: p-Value represents the comparative analysis of the recurrence effect of mode of surgical
intervention for patient groups as defined the oncotype score.
Discussion
This study examines the influence of various surgical interventions, based on oncotype
risk group, on breast cancer recurrence. Additionally, it further defines the early
breast cancer cohort in the genetically diverse West of Ireland. Over the past decade,
ODX has emerged as a reliable, externally validated[6]
[13] tool in the management of this patient group allowing effective individualization
of therapy. This study aimed to clarify the potential role for ODX in guiding surgical
approach.
The majority of early breast cancers consisted of Grade 2 invasive ductal carcinomas
with a low overall recurrence rate (1.38%). Adjuvant therapy in the form of radiotherapy
and systemic hormone therapy remained consistent across all risk groups. However,
the use of AC varied from 11.6% in the low-risk group to 93.3% in the high-risk oncotype
group. These figures are in keeping with previous evidence from the region.[14] A majority of patients in all groups underwent WLE with minorities undergoing mastectomy
or WLE with completion. As such, this study remains inadequately powered to definitively
identify a role for ODX in determining the surgical approach to these early breast
cancers.
The study itself is subject to certain limitations. It is single-centered and retrospective
and thus subject to the inherent limitations associated with such studies. While a
relatively large sample of 353 patients underwent oncotype testing, recurrence was
infrequent and as such standard statistical methods including cox hazard ratios were
not incorporated. Furthermore, a majority of recurrences occur after 5 years of endocrine
treatment.[15]
[16] In keeping with international figures, recurrence rates in the study cohort were
less than 3% exposing the study to potentially being underpowered. It is, however,
unique in its analysis of ODX testing to evaluate the merits of each surgical mode
and the authors would expect larger multicenter studies to add to this knowledge as
the role of MGAs develops.
While the management of early breast cancer continues to evolve, local disease control
in the form of surgery and radiotherapy remains the cornerstone of therapy. Meta-analysis
data has suggested that mode of locoregional control directly influences disease recurrence
based on luminal classification.[17]
[18] As such tumor subtypes with increased metastatic potential should invariably be
approached with more aggressive local intervention. ODX offers an effective tool in
further characterizing node negative, hormone receptor positive breast cancers. It
has been widely effective in tailoring both chemotherapy and radiotherapy prescription
thus limiting disease recurrence in high-risk patients and the debilitating side effects
of adjuvant therapy in the lower-risk cohort.[5]
[10]
[11] The use of MGAs has significant potential to guide mode of surgical intervention;
however, to date its merits are yet to be established in the absence of larger multicenter
trials.
Conclusion
While MGA, an effective, accessible tool, has offered treating physicians a greater
understanding of breast cancer genetics, it may well remain underutilized. In this
pilot study, we sought to identify the relationship of the ODX score and mode of surgical
intervention with a view to establishing the potential benefits of intervention based
on recurrence risk. To date we have been unable to definitively identify a role for
ODX in guiding surgical approach. There is, however, a need for larger multicenter
studies examining this hypothesis.
