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Abstract

Background

MammaPrint^® is a microarray-based gene expression test cleared by the US Food and Drug Administration to assess recurrence risk in early-stage breast cancer, aimed to guide physicians in making neoadjuvant and adjuvant treatment decisions. The increase in the incidence of invasive lobular carcinomas (ILCs) over the past decades and the modest representation of ILC in the MammaPrint development data set calls for a stratified survival analysis dedicated to this specific subgroup.

Study Aim

The current study aimed to validate the prognostic value of the MammaPrint test for breast cancer patients with early-stage ILCs.

Materials and Methods

Univariate and multivariate survival associations for overall survival (OS), distant metastasis-free interval (DMFI), and distant metastasis-free survival (DMFS) were studied in a study population of 217 early-stage ILC breast cancer patients from five different clinical studies.

Results and Discussion

A significant association between MammaPrint High Risk and poor clinical outcome was shown for OS, DMFI, and DMFS. A subanalysis was performed on the lymph node-negative study population. In the lymph node-negative study population, we report an up to 11 times higher change in the diagnosis of an event in the MammaPrint High Risk group. For DMFI, the reported hazard ratio is 11.1 (95% confidence interval = 2.3–53.0).

Conclusion

Study results validate MammaPrint as an independent factor for breast cancer patients with early-stage invasive lobular breast cancer. Hazard ratios up to 11 in multivariate analyses emphasize the independent value of MammaPrint, specifically in lymph node-negative ILC breast cancers.

Keywords

breast cancer invasive lobular carcinoma clinical prognostic value microarray diagnostic test MammaPrint

Introduction

Invasive lobular carcinoma (ILC) is the second most prevalent type of breast cancer based on histological criteria. Approximately 10%–15% of primary breast cancers fall into this category.^1,2 These carcinomas are in general more estrogen receptor (ER)-positive, more human epidermal growth factor receptor 2 (HER2)-negative, and of lower histological grade compared to the more common invasive ductal carcinomas (IDCs).^3,4 Pathological assessment of ILCs identified four different subtypes, illustrating heterogeneity in this group of tumors. There is a tendency to classify ILC as a type with low risk of relapse; however, available reports on survival data show heterogeneous outcome statistics.² As a result, in current clinical practice, it is unclear which ILC patients are at increased risk of tumor recurrence and whether there are patients who would benefit from specific treatment options. Treatment decisions for early-stage ILCs may benefit from clinical adoption of the MammaPrint^® test, in addition to evaluation of clinicopathological parameters, as is already common in clinical practice for IDCs, especially because systemic treatment options for both types of tumors are currently almost identical.⁴

The MammaPrint assay is a microarray-based test cleared by the US Food and Drug Administration, which uses the expression levels of the 70 MammaPrint genes to assess risk of recurrence in early-stage breast cancer.^5–7 The test aims to guide physicians in making neoadjuvant and adjuvant treatment decisions. This assay was developed and validated in cohorts of breast cancer patients, which consisted of approximately 85% of the more prevalent type of IDC. This dominance of IDC in the MammaPrint training and validation sets could potentially introduce a bias in the prognostic performance of the MammaPrint assay in favor of IDC, with the gene signature being more correctly prognostic in IDC than in ILC. However, a pathway analysis of the 70 signature genes of the MammaPrint assay demonstrated that the test measures a number of universal aspects of (breast) cancer biology, including proliferation, angiogenesis, invasion, and ER signaling, and it is likely that these processes are very similar in breast cancers of different origins.⁸ A recurrent clinical question about MammaPrint involves its prognostic value for specifically the ILC group of breast cancers. Some physicians feel that the smaller representation of invasive lobular cancers in the development data set calls for a survival analysis dedicated to this specific subgroup to determine the prognostic value of MammaPrint.

With the increase in the incidence of ILCs over the past decades,^9,10 there is a clear clinical need to better evaluate the prognostic value of the MammaPrint test for specifically invasive lobular breast carcinomas. Hence, we have sought to validate the prognostic capacity of MammaPrint in primary invasive lobular breast cancers. The results of this evaluation are presented here.

Materials and Methods

Patient samples

MammaPrint results,⁶ clinicopathological data, and survival data were collected for all early breast cancers of the invasive lobular type from Agendia's clinical series database. The study population consisted of 217 unique cases that were derived from five clinical series, including the RAtional THerapy for breast cancER (RATHER) ILC series,¹¹ and the microarRAy-prognoSTics-in-breast-cancER (RASTER) series¹² (refer Supplementary File 1 for detailed information).^11–14 Clinicopathological data included age at surgery, differentiation grade, lymph node (LN) involvement, surgery type, and administration of adjuvant chemotherapy and hormone therapy. Additionally, information on ER status and HER2 status, as assessed by the TargetPrint assay,¹⁵ was available for analyses. TargetPrint readout was as described previously by Roepman et al.¹⁵ The mean follow-up time for this study cohort was 85 months (range: four months–22 years).

Research was performed according to the principles of the Declaration of Helsinki. All patient samples and data were anonymously coded in accordance with national ethical guidelines (“Code for Proper Secondary Use of Human Tissues”, Dutch Federation of Medical Scientific Societies), and the study samples had institutional review board approvals for the anonymized use of archival tissues.^11–14 This study was performed based on the guidance of the REporting recommendations for tumor MARKer prognostic studies (REMARK) (National Cancer Institute-European Organisation for Research and Treatment of Cancer [NCI-EORTC]).¹⁶

Data analysis

Statistical analyses, survival analyses, and visualization of data were performed using the statistical package SPSS 22.0 for Windows (SPSS Inc, Chicago, IL, USA).

The relationship between MammaPrint results (MammaPrint index values dichotomized to Low Risk and High Risk) and known clinicopathological parameters was investigated using the Pearson chi-squared test or Fisher's exact test.

MammaPrint results were used in survival analyses. The Cox proportional-hazards model was used to analyze the association between MammaPrint results for survival at 10 years after surgery. Overall survival (OS) was defined as the time from surgery until death by any cause.¹⁷ Distant metastasis-free interval (DMFI) was defined as the time from surgery until the diagnosis of a distant recurrence. Distant metastasis-free survival (DMFS) was defined as the time from surgery until the diagnosis of a distant metastasis or death by any cause.¹⁷ Differences in survival between patient groups are presented as hazard ratios (HRs). The MammaPrint Low Risk group was used as the reference group for all survival analyses. Kaplan-Meier curves were used to visualize the univariate survival associations. Multivariate survival analyses were performed to account for the effects of other variables or confounders on survival and to account for potential differences in distribution of clinicopathological factors between Mamma Print Low Risk and High Risk groups. Multivariate models included the following predetermined clinically important covariates: age at surgery, LN involvement, differentiation grade, adjuvant chemotherapy, ER status, and HER2 status, irrespective of statistical significance. Age at surgery and differentiation grade were entered as continuous variables into the multivariate models. All tests were two-tailed types, and P-values < 0.05 were considered statistically significant.

Results

Patient characteristics

Clinicopathological and survival data were available for n = 217 invasive lobular cases. These cases originate from multiple clinical study series, as described in the “Materials and Methods” section. The association of MammaPrint verdict results (Low Risk and High Risk for MammaPrint) with clinicopathological parameters is described in Table 1. Analyses were performed for the entire study cohort (n = 217), as well as for the group of LN-negative cases (n = 144). MammaPrint verdict results of the entire study cohort correlated with the established prognostic parameter of LN involvement, with the MammaPrint Low Risk group containing slightly more LN-negative tumors. Most patients had ER-positive and HER2-negative disease. The mean patient age at surgery was 58 years (range: 29–93 years). As expected, a higher percentage of breast-conserving therapy was the choice of surgery for MammaPrint Low Risk patients, and less patients in the MammaPrint Low Risk group received adjuvant chemotherapy. Interestingly, we observed more patients older than 55 years in the MammaPrint High Risk group compared to those in the Low Risk group.

Table 1.

Associations of the study cohort with clinicopathological parameters.

		ALL CASES							LN-NEGATIVE CASES
		LR		HR		P-VALUE	TOTAL		LR		HR		P-VALUE	TOTAL
		n = 165	76%	n = 52	24%		n = 217	100%	n = 118	82%	n = 26	18%		n = 144	100%
		n	%	n	%		n	%	n	%	n	%		n	%
Age at Surgery	<55	76	46.1	17	32.7	0.089	93	42.9	61	51.7	7	26.9	0.022	68	47.2
Age at Surgery	≥55	89	53.9	35	67.3	0.089	124	57.1	57	48.3	19	73.1	0.022	76	52.8
ER status^a,b	neg	7	4.2	7	13.5	0.018	14	6.5	6	5.1	4	15.4	0.082	10	6.9
ER status^a,b	pos	158	95.8	45	86.5	0.018	203	93.5	112	94.9	22	84.6	0.082	134	93.1
HER2 status^a,b	neg	154	93.3	45	86.5	0.121	199	91.7	110	93.2	24	92.3	1.000	134	93.1
HER2 status^a,b	pos	11	6.7	7	13.5	0.121	18	8.3	8	6.8	2	7.7	1.000	10	6.9
LN involvement	0	118	71.5	26	50.0	0.013	144	66.4	118	100.0	26	100.0	NA	144	100.0
	1–3	33	20.0	20	38.5		53	24.4	0	0.0	0	0.0		0	0.0
	>3	14	8.5	6	11.5		20	9.2	0	0.0	0	0.0		0	0.0
Differentiation Grade	well	29	17.6	5	9.6	0.009	34	15.7	23	19.5	1	3.8	0.080	24	16.6
	Moderate	131	79.4	40	76.9		171	78.8	92	78.0	23	88.5		115	79.9
	Poor	5	3.0	7	13.5		12	5.5	3	2.5	2	7.7		5	3.5
Surgery Type^a	Ablatio	13	8.0	3	5.8	0.022	16	7.4	13	11.2	3	11.5	0.036	16	11.3
	BCT	76	46.6	14	26.9		90	41.9	66	56.9	8	30.8		74	52.1
	Mastectomy	74	45.4	35	67.3		109	50.7	37	31.9	15	57.7		52	36.6
Chemotherapy^b	no	134	81.2	35	67.3	0.035	169	77.9	106	89.8	21	80.8	0.193	127	88.2
Chemotherapy^b	Yes	31	18.8	17	32.7	0.035	48	22.1	12	10.2	5	19.2	0.193	17	11.8
Hormone Therapy	No	70	42.4	20	38.5	0.613	90	41.5	60	50.8	11	42.3	0.430	71	49.3
Hormone Therapy	Yes	95	57.6	32	61.5	0.613	127	58.5	58	49.2	15	57.7	0.430	73	50.7

Notes: This table shows the relationship of MammaPrint dichotomized verdict results with clinicopathological parameters.

ER status and HER2 status were assessed by TargetPrint¹⁵.

A Fisher's exact test was used in the analyses for the LN-negative cases. ^cTwo missing values for specification surgery.

Abbreviations: BCT, breast-conserving therapy; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; HR, High Risk for MammaPrint; LN, lymph node; LR, Low Risk for MammaPrint; n, number of patients; NA, not applicable.

Prognostic value of MammaPrint in the ILC subgroup

Results of univariate survival analyses are shown in Table 2, and visualized in Kaplan–Meier curves (Fig. 1). A significant association between MammaPrint High Risk and poor clinical outcome was shown in univariate analyses for OS, DMFI, and DMFS. Based on the univariate analyses, patients with tumors classified as High Risk showed a 3.6 times higher chance to develop a distant metastasis within 10 years after surgery (DMFI HR: 3.6; 95% confidence interval [CI]: 1.6–7.8) or to die within 10 years after surgery (OS HR: 3.6; 95% CI: 1.8–7.0), and a 3.3 times higher chance to present with either event (DMFS HR: 3.3; 95% CI: 1.8–6.1).

Table 2.

Univariate survival associations for invasive lobular breast cancer.

		OVERALL SURVIVAL (AT 10 YEARS)			DISTANT METASTASIS FREE INTERVAL (AT 10 YEARS)			DISTANT METASTASIS FREE SURVIVAL (AT 10 YEARS)
		HR	95% CI	P-VALUE	HR	95% CI	P-VALUE	HR	95%CI	P-VALUE
All cases
MammaPrint	HR/LR	3.577	1.842–6.948	<0.001	3.556	1.621–7.799	0.002	3.308	1.789–6.116	<0.001
LN-negative cases
MammaPrint	HR/LR	7.465	2.582–21.583	<0.001	10.535	2.496–44.465	0.001	7.806	2.892–21.068	<0.001

Notes: Shown are data from univariate survival analyses of MammaPrint for the invasive lobular breast cancer study cohort at 10 years after surgery.

HR >1 indicates that the HR group has a worse clinical outcome compared to the LR group. The reference group for each covariate in the multivariate model is underlined in column 2. For significant associations, P-values are indicated in bold.

Abbreviations: CI, confidence interval; HR, hazard ratio; HR, High Risk for MammaPrint; LR, Low Risk for MammaPrint.

Figure 1.

Univariate survival curves for invasive lobular breast cancer stratified by MammaPrint.

Results of multivariate survival analyses are shown in Table 3. In multivariate analyses, MammaPrint was validated as an independent factor for DMFI and DMFS. MammaPrint High Risk status was associated with worse clinical outcome in invasive lobular breast cancer. In these analyses, accounting for the effect of confounders or differences in distribution of clinicopathological factors between analyses groups, patients with a tumor classified as MammaPrint High Risk showed a 2.4 times higher chance to develop a distant metastasis within 10 years after surgery (DMFI HR: 2.4; 95% CI: 1.0–5.6). The chance to develop a distant metastasis or die within 10 years after surgery was 2.1 times higher in the MammaPrint High Risk group (DMFS HR: 2.1; 95% CI: 1.0–4.1). Multivariate survival analyses were further performed by including only those clinicopathological parameters that showed a significant association with MammaPrint outcome (Supplementary File 2). These analyses confirm MammaPrint as independent factor for OS, DMFI, and DMFS.

Table 3.

Multivariate survival associations for invasive lobular breast cancer.

		OVERALL SURVIVAL (AT 10 YEARS)			DISTANT METASTASIS FREE INTERVAL (AT 10 YEARS)			DISTANT METASTASIS FREE SURVIVAL (AT 10 YEARS)
		HR	95% CI	P-VALUE	HR	95% CI	P-VALUE	HR	95%CI	P-VALUE
All cases
MammaPrint	HR/LR	2.015	0.944–4.299	0.070	2.362	1.004–5.556	0.049	2.078	1.045–4.135	0.037
Age^a	continuous	1.693	1.228–2.336	0.001	1.209	0.817–1.789	0.341	1.444	1.069–1.949	0.016
LN group	pos/neg	2.150	1.024–4.514	0.043	2.999	1.180–7.620	0.021	2.335	1.168–4.665	0.016
Differentiation grade	continuous 1 to 3	2.123	0.805–5.605	0.128	1.719	0.673–4.388	0.257	1.432	0.653–3.142	0.370
Chemotherapy	yes/no	1.015	0.347–2.967	0.979	1.285	0.428–3.861	0.655	0.989	0.379–2.577	0.981
ER status^b	pos/neg	0.290	0.103–0.819	0.019	0.443	0.105–1.859	0.266	0.280	0.103–0.760	0.012
HER2 status^b	pos/neg	0.202	0.043–0.963	0.045	0.436	0.104–1.833	0.257	0.312	0.088–1.110	0.072
LN-negative cases
MammaPrint	HR/LR	5.102	1.516–17.174	0.008	11.12	2.332–53.020	0.003	6.399	2.136–19.171	0.001
Age^a	continuous	1.429	0.877–2.331	0.152	1.099	0.529–2.286	0.800	1.361	0.855–2.169	0.194
Differentiation grade	continuous 1 to 3	1.312	0.250–6.889	0.748	0.892	0.121–6.556	0.911	1.023	0.245–4.273	0.975
Chemotherapy	yes/no	0.606	0.062–5.884	0.666	0.720	0.065–7.991	0.789	0.418	0.047–3.714	0.434
ER status^b	pos/neg	0.220	0.049–0.985	0.048	0.522	0.050–5.405	0.585	0.272	0.068–1.088	0.066
HER2 status^b	pos/neg	0.576	0.062–5.329	0.627	0.662	0.051–8.515	0.752	1.002	0.179–5.615	0.998

Notes: Shown are data from multivariate survival analyses of MammaPrint for the invasive lobular breast cancer study cohort at 10 years after surgery. HR >1 indicates that the HR group has a worse clinical outcome compared to the LR group. The reference group for each covariate in the multivariate model is underlined in column 2. For significant associations, P-values are indicated in bold. The covariates “age at surgery” and “differentiation grade” were entered as continuous variables into the multivariate model.

For age at surgery, the HR is given per unit increase, with one unit representing 10-year increase in age.

ER status and HER2 status were assessed by TargetPrint.¹⁵

Abbreviations: CI, confidence interval; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; HR, High Risk for MammaPrint; LN, lymph node; LR, Low Risk for MammaPrint.

Prognostic value of MammaPrint in ILC without LN involvement

In the patient group without LN involvement (n = 144), MammaPrint was validated for OS, DMFI, and DMFS in univariate (Table 2) and multivariate (Table 3) survival analyses. Additionally, Kaplan-Meier curves were plotted to visualize the univariate survival associations (Fig. 2). The lower number of cases in the LN-negative subgroup as compared to the whole study cohort inherently resulted in wider CIs. Based on univariate analyses, patients with tumors classified as High Risk showed a 7.5–10.5 times higher chance for an OS-related event (OS HR: 7.5; 95% CI: 2.6–21.6), DMFI (DMFI HR: 10.5; 95% CI: 2.5–44.5) or DMFS-related event (DMFS HR: 7.8; 95% CI: 2.9–21.1). Based on multivariate analyses, the MammaPrint High Risk group showed, for DMFS, a 6.4 times higher chance for an event within 10 years after surgery (DMFS HR: 6.4; 95% CI: 2.1–19.2). Patients with tumor classified as MammaPrint High Risk showed an 11.1 times higher chance to develop a distant metastasis within 10 years after surgery (DMFI HR: 11.1; 95% CI: 2.3–53.0), or a 5.1 times higher chance to die within 10 years after surgery (OS HR: 5.1; 95% CI: 1.5–17.2). Additionally, multivariate survival analyses were performed (Supplementary File 2) by including only those clinicopathological parameters with a significant association with MammaPrint outcome as shown in Table 1. These analyses confirm MammaPrint as an independent factor for OS, DMFI, and DMFS in the patient group with LN-negative cases. Patient numbers were too low to report any results for the LN-positive subanalysis.

Figure 2.

Univariate survival curves for invasive lobular breast cancer without lymph node involvement stratified by MammaPrint.

Discussion

The results of this study validate MammaPrint as an independent factor for early-stage invasive lobular breast cancer. The significantly high HRs (up to 11 for DMFI) in multivariate analyses emphasize the independent value of MammaPrint, specifically in LN-negative invasive lobular breast cancers.

The study data set is comparable to ILC cohorts described previously.² The current study showed a distribution of differentiation grade, ER status, and HER2 status that is comparable to the overall characteristics reported in a review on ILC by Guiu et al.² Additionally, the percentage of MammaPrint Low Risk versus High Risk tumors, as well as the percentage of ILC patients, is comparable to that in the studies reviewed by Guiu et al.² The authors of the review supported the need for personalized treatment by using gene expression assays, such as MammaPrint, for patients with lobular tumors. Because the patient numbers were low in the reported studies, we combined the results of multiple studies. In the current study, follow-up data of 217 ILC patients have been combined, and the results show a significant difference between Low Risk and High Risk of recurrence.

The study cohort comprises patients from five different clinical studies, and therefore systemic therapy decisions and adherence to treatment might not be fully comparable. This could have effect on the long-term outcome.

Demonstrating the usefulness of a test in clinical practice – or clinical utility – may be the most significant hurdle for clinical adoption of diagnostic tests. Recently, the results of the large Microarray In Node-negative and 1 to 3 positive lymph node Disease may Avoid ChemoTherapy (MIND-ACT) trial have been reported,¹⁸ demonstrating the clinical utility of MammaPrint in early-stage breast cancer with Level 1a evidence.¹⁸ This prospectively randomized study enrolled 6693 patients, of whom 500 were classified as having ILC. A separate analysis of the five-year outcome data of this ILC group will be part of further subanalyses of the MINDACT clinical trial data and will provide a larger number of patients for whom comprehensive data are available at the level of both clinical risk and genomic risk. The current study was planned to validate the prognostic value of the MammaPrint test for ILC breast cancer patients, thereby supporting the clinical adoption of MammaPrint prior to the comprehensive MINDACT analysis. The clear difference in 10-year outcome between MammaPrint Low Risk and High Risk patients indicates the utility of MammaPrint as an aid in systemic treatment decision for patients with early-stage ILCs, especially in the LN-negative group. Although IDC and ILC are recognized as different subgroups of the same disease with distinct clinical features,³ MammaPrint has demonstrated prognostic values in the combined subgroups. The current study emphasizes the prognostic power of MammaPrint, specifically in primary invasive lobular breast cancers.

The ongoing research on breast cancer is currently focusing on further stratification and substratification of IDC and ILC. For both breast cancer subgroups, the future lies in creating focused treatment options based on insights in patient-specific variation¹⁹ and the combination of clinicopathological parameters and multiple genetic classifiers that reflect tumor biology for individual tumors. Clinicopathological parameters and established genetic classifiers, such as MammaPrint and BluePrint,²⁰ can be combined with new genetic markers to even further identify patient subgroups with distinct relapse risks or benefit from specific treatment options. A specific example for the ILC subgroup is the identification of an immune-responsive subpopulation¹¹ that can be distinguished using gene expression classification.

The independent value of MammaPrint in LN-negative early-stage invasive lobular breast cancer indicates the beneficial effect of risk of recurrence determination by MammaPrint and subsequent adjuvant chemotherapy decision.

Author Contributions

Conceived and designed the experiments: IJB, LJvtV, RB, AMG. Data acquisition: IJB, AW, S-FC, S-JS, MS, CC, SL. Analysis: IJB, AW, CD. Interpretation of the data for the work: IJB, MP, CD, S-FC, S-JS. Wrote the first draft of the manuscript: IJB, MP. Contributed to the writing of the manuscript: IJB, MP, AW, CD, S-FC, S-JS, MS. Agree with manuscript results and conclusions: IJB, MP, AW, CD, S-FC, S-JS, MS, CC, SL, LJvtV, RB, AMG. Jointly developed the structure and arguments for the paper: IJB, RB, LJvtV, AMG. Made critical revisions and approved final version: CC, SL. All authors reviewed and approved of the final manuscript.

Footnotes

Supplementary Material

References

Desmedt

, Zoppoli

, Gundem

Genomic characterization of primary invasive lobular breast cancer. J Clin Oncol. 2016; 34: 1872–81.

Guiu

, Wolfer

, Jacot

Invasive lobular breast cancer and its variants: how special are they for systemic therapy decisions?

Crit Rev Oncol Hematol. 2014; 92: 235–57.

Pestalozzi

B.C.

, Zahrieh

, Mallon

; International Breast Cancer Study Group. Distinct clinical and prognostic features of infiltrating lobular carcinoma of the breast: combined results of 15 International Breast Cancer Study Group clinical trials. J Clin Oncol. 2008; 26: 3006–14.

Wang

, Mittendorf

E.A.

, Sahin

A.A.

Outcomes of sentinel lymph node dissection alone vs. axillary lymph node dissection in early stage invasive lobular carcinoma: a retrospective study of the surveillance, epidemiology and end results (SEER) database. PLoS One. 2014; 9: e89778.

van ‘t Veer

L.J.

, Dai

, van de Vijver

M.J.

, He

Y.D.

, Hart

A.A.M.

, Friend

S.H.

Expression profiling predicts outcome in breast cancer. Breast Cancer Res. 2002; 5: 57–8.

Glas

A.M.

, Floore

, Delahaye

L.J.

Converting a breast cancer microarray signature into a high-throughput diagnostic test. BMC Genomics. 2006; 7: 278.

Delahaye

L.J.

, Wehkamp

, Floore

A.N.

, Bernards

, van ‘t Veer

L.J.

, Glas

A.M.

Performance characteristics of the MammaPrint(R) breast cancer diagnostic gene signature. Per Med. 2013; 10: 801–11.

Tian

, Roepman

, Veer

L.J.V.

, Bernards

, de Snoo

, Glas

A.M.

Biological functions of the genes in the mammaprint breast cancer profile reflect the hallmarks of cancer. Biomark Insights. 2010; 5: 129–38.

Talman

M-LM

, Jensen

M-B

, Rank

Invasive lobular breast cancer. Prognostic significance of histological malignancy grading. Acta Oncol. 2007; 46: 803–9.

10.

C.I.

, Weiss

N.S.

, Stanford

J.L.

, Daling

J.R.

Hormone replacement therapy in relation to risk of lobular and ductal breast carcinoma in middle-aged women. Cancer. 2000; 88: 2570–7.

11.

Michaut

, Chin

S.F.

, Majewski

Integration of genomic, transcriptomic and proteomic data identifies two biologically distinct subtypes of invasive lobular breast cancer. Sci Rep. 2016; 6: 18517.

12.

Bueno-de-Mesquita

J.M.

, van Harten

W.H.

, Retel

V.P.

Use of 70-gene signature to predict prognosis of patients with node-negative breast cancer: a prospective community-based feasibility study (RASTER). Lancet Oncol. 2007; 8: 1079–87.

13.

Kok

, Koornstra

R.H.

, Mook

Additional value of the 70-gene signature and levels of ER and PR for the prediction of outcome in tamoxifen-treated ERpositive breast cancer. Breast. 2012; 21: 769–78.

14.

van de Vijver

M.J.

, He

Y.D.

, Veer

L.J.V.

A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002; 347: 1999–2009.

15.

Roepman

, Horlings

H.M.

, Krijgsman

Microarray-based determination of estrogen receptor, progesterone receptor, and HER2 receptor status in breast cancer. Clin Cancer Res. 2009; 15: 7003–11.

16.

McShane

L.M.

, Altman

D.G.

, Sauerbrei

, Taube

S.E.

, Gion

, Clark

G.M.

REporting recommendations for tumour MARKer prognostic studies (REMARK). Br J Cancer. 2005; 93: 387–91.

17.

Hudis

C.A.

, Barlow

W.E.

, Costantino

J.P.

Proposal for standardized definitions for efficacy end points in adjuvant breast cancer trials: the STEEP system. J Clin Oncol. 2007; 25: 2127–32.

18.

Cardoso

, van't Veer

L.J.

, Bogaerts

; MINDACT Investigators. 70-Gene signature as an aid to treatment decisions in early-stage breast cancer. N Engl J Med. 2016; 375: 717–29.

19.

Nagarajan

, Upreti

An approach for deciphering patient-specific variations with application to breast cancer molecular expression profiles. J Biomed Inform. 2016; 63: 120–30.

20.

Krijgsman

, Roepman

, Zwart

A diagnostic gene profile for molecular subtyping of breast cancer associated with treatment response. Breast Cancer Res Treat. 2011; 133: 37–47.

Prognostic Value of MammaPrint ® in Invasive Lobular Breast Cancer

Abstract

Background

Study Aim

Materials and Methods

Results and Discussion

Conclusion

Keywords

Introduction

Materials and Methods

Patient samples

Data analysis

Results

Patient characteristics

Prognostic value of MammaPrint in the ILC subgroup

Prognostic value of MammaPrint in ILC without LN involvement

Discussion

Author Contributions

Footnotes

Supplementary Material

References