A. Kuijer

Using a gene expression signature when controversy exists regarding the indication for adjuvant systemic treatment reduces the proportion of patients receiving adjuvant chemotherapy: a nationwide study

Purpose:The Dutch national guideline advises use of gene-expression signatures, such as the 70-gene signature (70-GS), in case of ambivalence regarding the benefit of adjuvant chemotherapy (CT). In this nationwide study, the impact of 70-GS use on the administration of CT in early breast cancer patients with a dubious indication for CT is assessed.Methods:Patients within a national guideline directed indication area for 70-GS use who were surgically treated between November 2011 and April 2013 were selected from the Netherlands Cancer Registry database. The effect of 70-GS use on the administration of CT was evaluated in guideline- and age-delineated subgroups addressing potential effect of bias by linear mixed-effect modeling and instrumental variable (IV) analyses.Results:A total of 2,043 patients within the indicated area for 70-GS use were included, of whom 298 received a 70-GS. Without use of the 70-GS, 45% of patients received CT. The 70-GS use was associated with a 9.5% decrease in CT administration (95% confidence interval (CI): −15.7 to −3.3%) in linear mixed-effect model analyses and IV analyses showed similar results (−9.9%; 95% CI: −19.3 to −0.4).Conclusion:In patients in whom the Dutch national guidelines suggest the use of a gene-expression profile, 70-GS use is associated with a 10% decrease in the administration of adjuvant CT.Genet Med 18 7, 720–726.Genetics in Medicine (2016); 18 7, 720–726. doi:10.1038/gim.2015.152

Impact of 70-Gene Signature Use on Adjuvant Chemotherapy Decisions in Patients With Estrogen Receptor–Positive Early Breast Cancer: Results of a Prospective Cohort Study

Purpose Gene-expression profiles increasingly are used in addition to conventional prognostic factors to guide adjuvant chemotherapy (CT) decisions. The Dutch guideline suggests use of validated gene-expression profiles in patients with estrogen receptor (ER) -positive, early-stage breast cancer without overt lymph node metastases. We aimed to assess the impact of a 70-gene signature (70-GS) test on CT decisions in patients with ER-positive, early-stage breast cancer. Patients and Methods In a prospective, observational, multicenter study in patients younger than 70 years old who had undergone surgery for ER-positive, early-stage breast cancer, physicians were asked whether they intended to administer adjuvant CT before deployment of the 70-GS test and after the test result was available. Results Between October 1, 2013, and December 31, 2015, 660 patients, treated in 33 hospitals, were enrolled. Fifty-one percent of patients had pT1cN0, BRII, HER2-Neu-negative breast cancer. On the basis of conventional clinicopathological characteristics, physicians recommended CT in 270 (41%) of the 660 patients and recommended withholding CT in 107 (16%) of the 660 patients. For the remaining 43% of patients, the physicians were unsure and unable to give advice before 70-GS testing. In patients for whom CT was initially recommended or not recommended, 56% and 59%, respectively, were assigned to a low-risk profile by the 70-GS (κ, 0.02; 95% CI, -0.08 to 0.11). After disclosure of the 70-GS test result, the preliminary advice was changed in 51% of patients who received a recommendation before testing; the definitive CT recommendation of the physician was in line with the 70-GS result in 96% of patients. Conclusion In this prospective, multicenter study in a selection of patients with ER-positive, early-stage breast cancer, 70-GS use changed the physician-intended recommendation to administer CT in half of the patients.

Changes over time in the impact of gene-expression profiles on the administration of adjuvant chemotherapy in estrogen receptor positive early stage breast cancer patients : A nationwide study

Ten years ago gene‐expression profiles were introduced to aid adjuvant chemotherapy decision making in breast cancer. Since then subsequent national guidelines gradually expanded the indication area for adjuvant chemotherapy. In this nation‐wide study the evolution of the proportion of patients with estrogen‐receptor positive (ER+) tumors receiving adjuvant chemotherapy in relation to gene‐expression profile use in patient groups that became newly eligible for chemotherapy according to national guideline changes over time is assessed. Data on all surgically treated early breast cancer patients diagnosed between 2004–2006 and 2012–2014 were obtained from the Netherlands Cancer Registry. ER+/Her2− patients with tumor‐characteristics making them eligible for gene‐expression testing in both cohorts and a discordant chemotherapy recommendation over time (2004 guideline not recommending and 2012 guideline recommending chemotherapy) were identified. We identified 3,864 patients eligible for gene‐expression profile use during both periods. Gene‐expression profiles were deployed in 5% and 35% of the patients in the respective periods. In both periods the majority of patients was assigned to a low genomic risk‐profile (67% and 69%, respectively) and high adherence rates to the test result were observed (86% and 91%, respectively). Without deploying a gene‐expression profile 8% and 52% (p <0.001) of the respective cohorts received chemotherapy while 21% and 28% of these patients received chemotherapy when a gene‐expression profile was used (p 0.191). In conclusion, in ER+/Her2− early stage breast cancer patients gene‐expression profile use was associated with a consistent proportion of patients receiving chemotherapy despite an adjusted guideline‐based recommendation to administer chemotherapy.

Trends on Axillary Surgery in Nondistant Metastatic Breast Cancer Patients Treated Between 2011 and 2015: A Dutch Population-based Study in the Acosog-z0011 and Amaros Era

Objectives: To evaluate patterns of care in axillary surgery for Dutch clinical T1-4N0M0 (cT1-4N0M0) breast cancer patients and to assess the effect of the American College for Surgeons Oncology Group (ACOSOG)-Z0011 and After Mapping of the Axilla: Radiotherapy Or Surgery (AMAROS) trial on axillary surgery patterns in Dutch cT1-2N0M0 sentinel node positive breast cancer patients. Background: Since publication of the ACOSOG-Z0011 and AMAROS trial, omitting a completion axillary lymph node dissection (cALND) in sentinel node positive breast cancer patients is proposed in selected patients. Methods: Data were obtained from the nationwide Nationaal Borstkanker Overleg Nederland breast cancer audit. Descriptive analyses were used to demonstrate trends in axillary surgery. Multivariable logistic regression analyses were used to identify factors associated with the omission of cALND in cT1-2N0M0 sentinel node-positive breast cancer patients. Results: Between 2011 and 2015 in cT1-4N0M0 breast cancer patients, the use of sentinel lymph node biopsy as definitive axillary staging increased from 72% to 93%, and (c)ALND as definitive axillary staging decreased from 24% to 6% (P < 0.001). The use of cALND decreased from 75% to 17% in cT1-2N0 sentinel node-positive patients (P < 0.001). Earlier year of diagnosis, lower age, primary mastectomy, invasive lobular subtype, increasing tumor grade, and treatment in a nonteaching hospital were associated with a lower probability of omitting cALND (P < 0.001). Conclusions: This study shows a trend towards less extensive axillary surgery in Dutch cT1-T4N0M0 breast cancer patients; illustrated by an overall increase of sentinel lymph node biopsy and decrease in cALND. Despite this trend, particularly noticed in cT1-2N0 sentinel node-positive patients after publication of the ACOSOG-Z0011 and AMAROS trial, variations in patterns of care in axillary surgery are still present.

Factors Associated with the Use of Gene Expression Profiles in Estrogen Receptor-Positive Early-Stage Breast Cancer Patients: A Nationwide Study

Background: Breast cancer guidelines suggest the use of gene expression profiles (GEPs) in estrogen receptor-positive (ER+) breast cancer patients in whom controversy exists regarding adjuvant chemotherapy benefit based on traditional prognostic factors alone. We evaluated the current use of GEPs in these patients in the Netherlands. Patients and Methods: Primary breast cancer patients treated between January 1, 2011 and December 31, 2014 and eligible for GEP use according to the Dutch national breast cancer guideline were identified in the Netherlands Cancer Registry: ER+ patients <70 years with grade 1 tumors >2 cm or grade 2 tumors 1-2 cm without overt lymph node metastases (pN0-Nmi). Mixed-effect logistic regression analysis was performed to associate characteristics of patients, tumors and hospitals with GEP use. Results: GEPs were increasingly deployed: 12% of eligible patients received a GEP in 2011 versus 46% in 2014. Lobular versus ductal morphology (OR 0.58, 95% CI 0.47-0.72), pN1mi status (versus pN0, OR 0.52, 95% CI 0.40-0.68), and tumor size (>3 cm vs. >2 cm, OR 0.33, 95% CI 0.14-0.88) were inversely associated with GEP use. High socioeconomic status (SES) (OR 1.32, 95% CI 1.06-1.64) and younger age (OR 0.96/year increasing age, 95% CI 0.95-0.96) were positively associated with GEP use. GEP use per hospital did vary, but no predefined institutional factors remained independently associated with GEP use. Conclusion: GEP use increased over time and was influenced by patient- and tumor-associated factors as well as by SES.

Conventional Pathology Versus Gene Signatures for Assessing Luminal A and B Type Breast Cancers: Results of a Prospective Cohort Study

In this study, in estrogen receptor positive (ER+) early stage breast cancer patients who were considered candidates for 70-gene signature (70-GS, “MammaPrint”) use, we compared molecular subtyping (MS) based on the previously validated 80-gene signature (80-GS, “BluePrint”) versus surrogate pathological subtyping (PS). Between 1 January 2013 and 31 December 2015, 595 clinical intermediate risk ER+ early stage breast cancer patients were enrolled. Hormone receptor (HR) and HER2 receptor status were determined by conventional pathology using immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH). Ki67 was assessed in a subset of patients. The overall concordance between PS and MS for luminal type cancers (A and B together) was 98%. The concordance between PS and MS for luminal A and luminal B type cancers based on the Bloom Richardson histological grade (BR) (n = 586) or Ki67 (n = 185) was low: 64% (Kappa 0.20 [95% CI 0.11–0.28]) and 65% (Kappa 0.22 [95% CI 0.062–0.37]), respectively. In this prospective study (NCT02209857) of a selection of ER+ and predominantly HER2− early-stage breast cancer patients, the additional ability of the 80-GS to distinguish between luminal, HER2-type and basal-like cancers was inherently very limited. The distinction of luminal-type tumors into A and B according to Ki67 status or BR grade versus the 70-GS revealed poor concordance.

The influence of socioeconomic status and ethnicity on adjuvant systemic treatment guideline adherence for early-stage breast cancer in the Netherlands

Background We aimed to assess whether socioeconomic status (SES) and ethnicity affect adjuvant systemic therapy (AST) guideline adherence in early breast cancer patients in a health care setting with assumed equal access to care. Methods Data from all female patients surgically treated for primary unifocal early breast cancer between January 2005 and December 2014 were retrieved from the Netherlands Cancer Registry. We assessed the association between SES, ethnicity and non-adherence to adjuvant chemotherapy (CT) or endocrine therapy (ET) guideline indications with Poisson regression models, adjusting for clinicopathological variables. Results A total of 104 201 patients were included in the current analysis. Of patients without an indication, 4% and 13% received adjuvant CT or ET (overtreatment), whereas 39% and 14% of patients with an indication did not receive CT or ET (undertreatment). Medium and low SES patients were 1.01 (95% CI 1.00-1.01) and 1.01 (95% CI 1.00-1.01) times more likely to be undertreated and 0.85 (95% CI 0.76-0.94) and 0.67 (95% CI 0.60-0.75) times more likely to be overtreated with CT compared with high SES patients [resulting in an overall relative risk of CT use of 0.94 (95% CI 0.92-0.96) and 0.85 (95% CI 0.83-0.87), respectively]. No association between SES and ET guideline adherence or ethnicity and CT/ET guideline adherence was observed. Conclusion In the Netherlands, minimal SES disparities in CT guideline adherence were observed: low SES patients are less likely be overtreated and marginally more likely to be undertreated with CT resulting in an overall decreased risk of receiving CT. No ethnical disparities in AST guideline adherence were observed.

Abstract P6-08-17: The 70-gene signature affects adjuvant systemic treatment decisions in breast cancer patients: A population-based, observational study

Background Gene signatures (GS), such as the 70-gene signature (MammaPrint™), are used as an adjunct to clinicopathological factors to predict outcome in breast cancer patients. According to the current Dutch national guidelines GS can be used in case of ambivalence regarding the benefit of adjuvant chemotherapy (ACT). While the impact of GS on the individual patient is well established, less is known about the impact on predefined patient cohorts in terms of an increase or decrease of the proportion of patients who receive ACT. Methods Patients surgically treated for primary breast cancer between November 2011 and April 2013 were selected from the Netherlands Cancer Registry. The administration of ACT in these patients was evaluated in relation to the use of the 70-gene signature (In the Netherlands the 70-gene signature is the most frequently used gene expression profile). Based on the Dutch guidelines clinicians might be ambivalent regarding the administration of ACT in the following subgroups: patients 2cm (group A), patients 1cm (group B) and patients Results A total of 13.122 patients were identified in the Cancer Registry. The 70 –gene signature was used in 794 patients; 19 in group A, 227 in group B, 62 in group C, and 456 (57.4%) did not fulfil the ambivalence criteria. In the latter patients, clinicopathological characteristics were contributed as follows: BR III tumours > 1cm (n=204), age > 70 (n=71), tumours Conclusion The proportion of patients who receive ACT decreased when a GS was used in predefined cohorts of patients for whom ambivalence exists regarding the use of ACT. The majority of patients for whom a GS was used did not fit these predefined categories and in subsets an inverse relation was seen: the use of a gene signature was associated with a higher chance of receiving ACT. Citation Format: Anne Kuijer, Annelotte CM van Bommel, Margriet van der Heiden- van der Loo, Carolien A Drukker, Thijs van Dalen. The 70-gene signature affects adjuvant systemic treatment decisions in breast cancer patients: A population-based, observational study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-08-17.