Positive Early Breast Cancer Patients Research Articles

Abstract GS1-04: Copy number aberration analysis to predict response to neoadjuvant anti-HER2 therapy: Results from the NeoALTTO phase III trial

Abstract Background In the NeoALTTO trial, the combination of trastuzumab and lapatinib for the neoadjuvant treatment of HER2 positive early breast cancer patients (pts) nearly doubled the rate of pathological complete response (pCR) compared with either anti-HER2 treatment alone. In the same trial, pCR was shown to be a surrogate for long-term outcome. Expression of ERBB2, ESR1 and immune signatures were the main drivers of pCR (Fumagalli et al. JAMA Oncol 2016). The main aim of the current study was to investigate the relevance of copy number aberrations (CNAs) for pCR and event-free survival (EFS). Methods For 271 out of the 455 pts enrolled in the study with sufficient tumour content, DNA was hybridized on CytoScan HD arrays. The log2 ratio intensities and B allele frequencies were segmented jointly using the multitrack segmentation algorithm. Integer level estimates of total copy number and major allele were obtained using GAP. Recurrent CNAs were found with GISTIC2. The genome instability index (GII) was defined as the median absolute deviation of the normalized copy number. Tumor infiltrating lymphocytes (TILs) and gene expression were obtained as described previously. The correlations between differents parameters were assessed using Spearman correlations (ρ). The Mann-Whitney test was used to relate binary and numerical features. EFS analysis was performed using the Cox proportional hazard model. Results CNAs estimates were obtained for 185 out of 271 pts. CNA distribution was similar to the ones observed in HER2+ pts from the METABRIC and the TCGA datasets. There were 64% of diploid pts, 26% of triploid and 9% of tetraploid or more. Aneuploidy level was not associated with pCR or EFS. Of interest, there were many significant differences in CNA profiles between ER+ and ER- pts. Those differences mirror those observed between ER+ and ER- among HER2- pts in TCGA (ρ=63%) and METABRIC (ρ=56%). ERBB2 amplification was predictive of high pCR (p=0.0007), albeit less so than ERBB2 expression, and ceased to be significant correcting for ERBB2 expression. The pCR rate increased with the GII (p=0.03), independently of ERBB2 amplification. The effect was stronger in ER+ patients (p=0.01). GISTIC analysis revealed 159 recurrent CNA regions. Amplification of 2 regions on 6q23-24 was significantly associated with higher pCR (p=0.00005 and p=0.00087, FDR=0.006 and 0.05). The most significant segment of 6q23-24 contained 39 genes, some whose expression level also predicted pCR (e.g. MAP3K5, p=10<sup style="font-family: Calibri;">-4). Gene ontology analysis of the genes correlated with this segment highlighted the category 'response to interferon-alpha' (p=4.3x10<sup style="font-family: Calibri;">-7). No amplified region or gene was found to be predictive of EFS, after multiple testing correction. Conclusions The amplification of ERBB2 was shown to be predictive of pCR, however its expression was more predictive. High genomic instability was associated with higher rate of pCR in ER+ subgroup. Of interest, a novel amplified region, involving chromosome 6 was shown to be predictive of pCR, which may warrant further investigation. Citation Format: Sotiriou C, Rothé F, Maetens M, Fumagalli D, Brown DN, Salgado R, Bradbury I, Pusztai L, Harbeck N, Ignatiadis M, Sarp S, de la Pena L, de Azambuja E, Huober J, Nuciforo P, Baselga J, Piccart M, Loi S, Venet D. Copy number aberration analysis to predict response to neoadjuvant anti-HER2 therapy: Results from the NeoALTTO phase III trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS1-04.

Abstract P3-08-09: Impact of gene-expression profiling in patients with early breast cancer when applied outside the guideline directed indication area

Abstract Purpose In Dutch guidelines gene expression profiles (GEP) are indicated in estrogen receptor positive early breast cancer patients in whom benefit of chemotherapy (CT) is controversial based on traditional prognostic factors alone. Aim of the current study is to assess the use and impact of GEP on administration of adjuvant CT in breast cancer patients who have according to national guidelines a clear indication to either use or withhold adjuvant chemotherapy (clinical high or low risk). Methods Clinical low- and high risk patients, according to Dutch breast cancer guidelines, diagnosed between 2011-2014 were selected from the Netherlands Cancer Registry (NCR). Influence of GEP use and GEP test result on CT administration was assessed with logistic regression. Results Overall, 26,425 patients were identified; 4.8% of patients with clinical low- risk (444/ 9,354), 7.5% of the patients with a clinical high-risk (1,281/ 17,071) received a GEP. GEP use was associated with a significantly increased odds of CT administration in clinical low-risk patients (OR=2.12 95%CI: 1.44-3.11). In clinical high-risk patients GEP use was associated with a decreased frequency of CT administration (OR=0.55, 95%CI: 0.48-0.63). Adherence to the GEP result was higher in clinical high-risk patients with a discordant GEP result as compared to clinical low-risk patients with a discordant GEP result: 71.7% vs. 52.2%, respectively. Conclusion GEP is frequently used outside the indicated area and significantly influenced the administration of adjuvant CT, although adherence to the test-result was limited. Citation Format: Schreuder K, Kuijer A, Rutgers EJTh, Smorenburg CH, Van Dalen T, Siesling S. Impact of gene-expression profiling in patients with early breast cancer when applied outside the guideline directed indication area [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-08-09.

T-DM1 in the Neo-Adjuvant Treatment of HER2-Positive Breast Cancer: Impact of the KRISTINE (TRIO-021) Trial.

Neo-adjuvant chemotherapy (NAC) can facilitate breast conservation, allows in vivo testing of chemotherapy sensitivity and provides a route to accelerated approval of new therapies. For HER2 positive breast cancer, the anti-HER2 monoclonal antibody, trastuzumab, is a standard component of neo-adjuvant therapy. Pertuzumab is an anti-HER2 monoclonal antibody with a distinct binding site to trastuzumab, which prevents HER2 receptor dimerisation. In early breast cancer, the addition of pertuzumab to docetaxel and trastuzumab resulted in a higher rate of pathological complete response (pCR), leading to accelerated approval in many territories. T-DM1 is a novel antibody-drug conjugate, combining trastuzumab with a potent cytotoxic, DM1, a maytansine derivative, via a stable thioether linker. In advanced breast cancer (ABC), T-DM1 improves survival compared to standard 2nd or 3rd line regimens, but not compared to first line chemotherapy plus trastuzumab. The KRISTINE trial investigated the combination of T-DM1 with pertuzumab compared to standard chemotherapy plus trastuzumab and pertuzumab in early breast cancer. This review summarises the data supporting current standards in the neo-adjuvant treatment of HER2 positive early breast cancer and the impact of the KRISTINE trial results. T-DM1 with pertuzumab did not improve pCR over standard therapy, although the novel combination was better tolerated, and a sub-group of patients (44%) achieved pCR with the systemic chemotherapy-free regimen. This suggests that not all HER2 positive early breast cancer patients require systemic chemotherapy and provides the potential, if these patients can be identified up-front, to de-escalate therapy. Although the KRISTINE trial results have not changed the standard of care for the neoadjuvant management of HER2 positive breast cancer, further research is needed to determine whether T-DM1 could be used to de-escalate NAC for selected patients.

Impact of gene-expression profiling in patients with early breast cancer when applied outside the guideline directed indication area

PurposeIn Dutch guidelines, gene expression profiles (GEP) are indicated in estrogen receptor positive early breast cancer patients in whom benefit of chemotherapy (CT) is uncertain based on traditional prognostic factors alone. Aim of the present study is to assess the use and impact of GEP on administration of adjuvant CT in breast cancer patients who have according to national guidelines a clear indication to either use or withhold adjuvant chemotherapy (clinical high or low risk). MethodsClinical low- and high-risk patients, according to Dutch breast cancer guidelines, diagnosed between 2011 and 2014 were selected from the Netherlands Cancer Registry. Influence of GEP use and GEP test result on CT administration was assessed with logistic regression. ResultsOverall, 26,425 patients were identified; 4.8% of patients with clinical low risk (444/9354), 7.5% of the patients with a clinical high risk (1281/17,071) received a GEP. GEP use was associated with significantly increased odds of CT administration in clinical low-risk patients (OR = 2.12 95% CI: 1.44–3.11). In clinical high-risk patients, GEP use was associated with a decreased frequency of CT administration (OR = 0.55, 95% CI: 0.48–0.63). Adherence to the GEP result was higher in clinical high-risk patients with a discordant GEP result as compared to clinical low-risk patients with a discordant GEP result: 71.7% vs. 52.2%, respectively. ConclusionGEP is frequently used outside the indicated area and significantly influenced the administration of adjuvant CT, although adherence to the test result was limited.

Concurrent versus sequential adjuvant chemo-endocrine therapy in hormone-receptor positive early stage breast cancer patients: a systematic review and meta-analysis

BackgroundAlthough in clinical practice adjuvant chemotherapy (CT) and endocrine therapy (ET) are administered sequentially in patients with hormone-receptor positive breast cancer, the optimal timing, i.e. concurrent or sequential administration, of these treatments has been scarcely investigated. To better clarify this issue we conducted a systematic review and meta-analysis of randomized studies comparing these two modalities of administrations in terms of disease-free survival (DFS) and overall survival (OS). MethodsRelevant studies were identified by searching PubMed, Web of Knowledge and the proceedings of the major conferences with no date restriction up to March 2016.The summary risk estimates (pooled hazard ratio [HR] and 95% confidence intervals [CI]) for DFS and OS were calculated using random effect models (DerSimonian and Laird method). ResultsA total of three randomized studies were eligible including 2021 breast cancer patients. Overall, 755 DFS events were observed, 365 in the sequential arm and 390 in the concomitant arm, with a pooled HR of 0.95 (95% CI = 0.76 to 1.18, P = 0.643).No association between timing of treatment and OS was observed (HR = 0.95; 95% CI = 0.80 to 1.12, P = 0.529). ConclusionOur pooled analysis showed no association between the timing of administration of adjuvant CT and ET and DFS and OS in breast cancer patients candidates for both adjuvant treatments. Because of the small number of published trials, the lack of data on the timing with modern adjuvant treatments, i.e. taxane-containing CT and aromatase inhibitors, this topic remain still controversial and requires further studies to be clarified.

Abstract P6-09-03: Impact of 70-gene signature use on adjuvant chemotherapy decisions in early breast cancer patients: Results of the prospective symphony triple A study

Abstract PURPOSE: gene-expression profiles, such as the 70-gene signature (70-GS), are increasingly used as adjunct to conventional clinicopathological prognostic factors to guide adjuvant chemotherapy (CT) decisions. The Dutch guideline suggests use of validated gene-expression profiles in estrogen-receptor (ER) positive (+) early stage breast cancer patients without overt lymph node metastases. We aimed to assess the impact of the 70-GS on CT decisions in ER+ early stage breast cancer patients. PATIENTS AND METHODS: In this prospective observational multicenter study physicians were asked for their opinion whether to administer or omit adjuvant CT before deployment and after obtaining the test result of the 70-GS in this guideline delineated group of patients. RESULTS: Between January 1 2013 And December 31 2015 660 patients, treated in 31 hospitals, were enrolled. Based on the clinicopathological postoperative findings physicians would administer CT in 41%, withhold CT in 16% of patients and refrained from formulating an advice in the remaining 43% of patients letting their recommendation depend on the result of the 70-GS. Estimated 5-year survival benefit of CT administration was 0.8%, 0.6% and 0.7% respectively (p 0,585). The 70-GS result hardly varied in relation to the initial advice of the physician: 56% and 59% had a low-risk profile in patients in whom CT was recommended or discommended respectively (r =0.021, Table 1). In 51% of patients in whom a pre-test recommendation was formulated incorporation of the 70-GS test result changed the initial advice. Adherence to the test result was high for the three groups (range 94-97%). Table 1. Concordance between pre-test CT recommendation of the oncologist and the 70-gene signature (GS) test result. 70-GS test resultPre-test CT recommendationno. patientsLow RiskHigh RiskNo CT10763 (59%)44 (41%)CT270152 (56%)118 (44%)Depends on 70-GS result283174 (61%)109 (39%)Note. Agreement between pre-test oncologist CT recommendation and the 70-GS test result: Pearsons r = -0,031 95%CI (-0,11 – 0,045). Table 2. CT recommendation before vs. after obtaining the 70-GS test result and the actual administration of CT. Post-test CT recommendationAdherence to test result*Actual administered CTAdherence to test result*Pre-test CT recommendationno. patientsNo CTCT%No CTCT%No CT10769 (65%)38 (35%)94%73 (68%)34 (32%)91%CT207156 (58%)114 (42%)97%162 (60%)108 (40%)90%Depends on 70-GS result283173 (61%)110 (39%)95%185 (65%)98 (35%)91%*Percentage of patients in whom the post-test recommendation/actual administered CT was in line with the 70-GS test result (i.e. no CT in case of a low-risk profile and CT in case of a high-risk profile. Note. Change in CT recommendation in patients with a CT or no CT pre-test recommendation McNemar's chi-square test p < 0.001 and p < 0.001 for actual administered CT CONCLUSION: guideline-directed use of the 70-GS in Dutch ER+ early breast cancer patients influenced CT treatment decision in the majority of patients. The physician's tentative CT advice was not associated with the 70-GS test-result. Citation Format: Kuijer A, Straver M, Elias S, Smorenburg C, Wesseling J, Linn S, Rutgers E, Siesling S, van Dalen T. Impact of 70-gene signature use on adjuvant chemotherapy decisions in early breast cancer patients: Results of the prospective symphony triple A study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-03.

Abstract P6-17-02: Evaluation of the impact of oncotype DX test results on systemic therapy in breast cancer patients at the BC cancer agency (BCCA)

Abstract Introduction: The BCCA started funding the Oncotype DX genomic test for node negative, hormone receptor positive and HER2 negative early breast cancer patients in April 2014. Individual requests for the test are reviewed and approved based on predefined BCCA specific eligibility criteria which are, any size grade 3 cancer and any grade 2 cancer over 1cm (later amended to any size) in women 80 and younger, and any grade 1 cancer in women 40 and younger. General consensus is the test result, or Recurrence Score (RS), can be used to guide whether patients should receive endocrine therapy alone (low RS[LRS] <18) or chemoendocrine therapy (high RS[HRS] >30). For patients with intermediate RS (IRS), there is no consensus on whether the benefits of chemotherapy outweigh the risks of potential toxicities. Objectives: To determine (1) the concordance of RS with treatments given to patients with LRS or HRS, (2) the treatments given to patients with IRS, and (3) the reasons for requesting the genomic test for patients outside the eligibility criteria. Methods: This was a retrospective, multi-centre analysis of breast cancer patients for whom the genomic test was requested between June 1, 2014 and May 31, 2015. Charts were reviewed to determine the RS and the therapy given following knowledge of the RS. The primary outcome was the concordance rate between LRS and receipt of endocrine therapy only, and HRS and receipt of chemoendocrine therapy. The discordance rate between RS-based recommendations and treatments given, and the type of therapy received by patients with IRS were also explored. Treatments for those with low IRS (18-24) or high IRS (25-30) were examined separately. Finally, we examined the reasons for requesting the genomic test outside eligibility criteria. Results: 435 requests were received during the study period. 395 requests were approved and test results were not found in 20 cases. Among the 375 RS results, 191 were LRS (51%), 122 were IRS (33%), and 62 were HRS (16%). The concordance rate between RS low and high and given treatments was 96%. Reasons for discordance included: patients with HRS refusing chemotherapy (n=3), patients with LRS receiving chemotherapy (n=3), patients refusing systemic treatment (n=3), and no explanation (n=1). Among the 122 patients with IRS, 81 were low-IRS and 41 were high-IRS. Overall, 27 % of patients with IRS received chemotherapy. Chemotherapy was given in 16 patients (19.7%) with low-IRS and 17 patients (41.4%) with high-IRS. The main reasons for requesting the test for patients outside eligibility criteria were: grade 1 tumors in patients older than 40 years old (n=20), node-positive disease (n=9), and grade 2 tumors less than 11 mm (n=3). Conclusion: Our results showed that the majority of patients with LRS or HRS were treated in accordance to RS-based recommendations. When treatment differed from RS-based consensus, the main reason was treatment refusal by patients. Only a quarter of patients with IRS received chemotherapy. Ongoing prospective trials will determine the utility of IRS in defining optimal therapy. Patients denied for the test were older and with grade 1 tumors, or with node-positive disease. Citation Format: Cheng V, Markarian A, de Lemos M, Schaff K. Evaluation of the impact of oncotype DX test results on systemic therapy in breast cancer patients at the BC cancer agency (BCCA) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-17-02.

PCN67 - Economic Assessment of Routine Oncotype DX Testing of Estrogen Receptor Positive (ER+) Early Breast Cancer (EBC) Patients with Grade 2 Tumours in Czech Republic

PCN67 - Economic Assessment of Routine Oncotype DX Testing of Estrogen Receptor Positive (ER+) Early Breast Cancer (EBC) Patients with Grade 2 Tumours in Czech Republic

177P - The impact of the 21-gene assay in the Czech Republic on adjuvant chemotherapy (CT) recommendations and costs in estrogen receptor positive (ER+) early stage breast cancer (ESBC) patients with grade 2 tumors and risk factors

177P - The impact of the 21-gene assay in the Czech Republic on adjuvant chemotherapy (CT) recommendations and costs in estrogen receptor positive (ER+) early stage breast cancer (ESBC) patients with grade 2 tumors and risk factors

88. Validity of Oncotype Dx recurrence score in predicting recurrence in hormone receptor positive and node negative early breast cancer patients

88. Validity of Oncotype Dx recurrence score in predicting recurrence in hormone receptor positive and node negative early breast cancer patients

Prognostic impact of progesterone receptor status in 3030 Chinese estrogen receptor positive early breast cancer patients.

e12002Background: Estrogen receptor (ER) and progesterone receptor (PR) have been used as indicators of endocrine system since the mid-1970s in the breast cancer. The predictive role of ER in endocrine therapy is undisputed, but the prognostic value of PR is still debated.The objective of this study was to investigate the clinical characteristics and prognosis of ER+ early breast cancer in different PR expression. Methods: A population cohort of 3030 ER+ primary invasive breast cancer with curative intent patients presenting to a single Cancer Centre over 6 years (2004–2010) underwent surgery and received adjuvant endocrine therapy. Age, menopausal status, tumor size, histology, lymph node status, PR status, Her-2, and Ki-67 were collected. The follow-up data for disease-free survival (DFS) and overall survival (OS) was obtained and distribution of factors was compared using the standard Chi-Square test. Univariate Cox hazard models were used to assess the effects of treatment and predictive factors on cl...

Association of discovered novel SNPs of FGFR2 and MAP3K1 genes from next-generation sequencing with the prognosis of hormone receptor-positive early breast cancer patients.

e12054Background: We and other investigators have demonstrated that CYP19TTTA repeat polymorphism, MAP3K1 rs889312, FGFR2 rs2981582, ABCB1 rs2032582, and TOX3 rs3803662 are associated with the prognosis of hormone receptor (HR)-positive early breast cancer patients. In this study, we assessed whether undiscovered single nucleotide polymorphisms (SNPs) of CYP19A1, MAP3K1, FGFR2, ABCB1, and TOX3are associated with clinical outcome of these patients. Methods: Using next-generation sequencing (NGS), we performed target region re-sequencing to analyze unidentified SNPs located in the candidate genes of CYP19A1, MAP3K1, FGFR2, ABCB1, and TOX3 in 84 HR+ early breast cancer patients with negative or 1 to 3 lymph nodal (LN) metastases. Among them, 74 (88.1%) with grade 1-2, 15 (17.9%) with HER2, and 16 (19.0%) with positive LN. The multivariate-adjusted hazard ratio of overall survival (OS) associated with the individual genotypes was assessed after adjusting for age, tumor size, tumor grade, HER2 status, and chem...

The impact of the 21-gene assay in the Czech Republic on adjuvant chemotherapy (CT) recommendations and costs in estrogen receptor positive (ER+) early stage breast cancer (ESBC) patients with grade 2 tumors and risk factors.

e12061Background: Conventional clinical risk factors are imprecise for determining recurrence risk. Multigene classifiers may provide useful information to resolve treatment decisions in the presen...

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.

269P - The Relationship Between Serum E2 Level and Recurrence During Endocrine Therapy for Er Positive Pre-Menopausal Early Breast Cancer Patients

ABSTRACT Aim: 10-year tamoxifen as adjuvant endocrine therapy become common for pre-menopausal ER-positive breast cancer patients according to the report from ATLAS trial (SABCS 2012) or aTTom study (ASCO 2013). On the other hand, it is generally believed that exposure to estradiol is strongly associated in breast cancer, however there are different opinions among experts voting in the duration of using LHRH agonist. The aim of this study is to evaluate the recurrence factor for endocrine therapy in ER positive pre-menopausal breast cancer patients. Methods: We chose 193 cases of premenopausal ER-positive early-stage breast cancer patients who received LHRH agonist and tamoxifen with 45 year-old or more younger onset. The median age was 40 years old (24-45) when the treatment started. They included 98 cases who were received pre-operative or post-operative chemotherapy as adjuvant systemic therapy. We studied about the relationship of local recurrence or distant metastasis and the duration of administration of the drug. We monitored of E2, FSH concentrations in blood before, during and after treatment. The median follow up period was 68 months (9-324 months). Results: We obtained the data of E2 dynamics during endocrine therapy from patients' sample. During LHRH agonist and tamoxifen therapy, serous E2 level decreased to the postmenopausal level, less than 31.0 pg/ml. However E2 concentration with tamoxifen and without LHRH agonist elevated to the average 58.1 pg/ml (10.0-5248.0 pg/ml). The duration of LHRH agonist was not the most important factor of breast cancer recurrence. There was a relation between continuous high serum level of E2 after LHRH agonist and metastasis regardless of the menstruation state. This phenomenon could be explained by the similar mechanism of low dose estrogen therapy after AI therapy for metastatic breast cancer. Conclusions: There might be association with breast cancer recurrence and E2 concentration in premenopausal ER-positive early-stage breast cancer. Disclosure: All authors have declared no conflicts of interest.

Effect of adjuvant endocrine therapy on hormonal levels in premenopausal women with breast cancer: the ProBONE II study

Endocrine therapy (ET) is a key treatment modality in hormone receptor positive (HR+) early breast cancer (BC) patients. Although the anticancer activity of adjuvant ET + zoledronic acid (ZOL) has been investigated, the potential effects of ET ± ZOL on endocrine hormones in premenopausal women with HR+ early BC are not well understood. ProBONE II was prospective, double-blind, randomized controlled trial. Premenopausal patients with histologically confirmed invasive BC with no evidence of metastases and a T score >-2.5 received ET ± ZOL 4 mg every 3 months for 2 years. Serum levels of estradiol (E2), follicle-stimulating hormone, anti-muellerian hormone (AMH), inhibins A and B, sex hormone-binding globulin, parathyroid hormone, total testosterone, and vitamin D were evaluated at baseline and at every scheduled visit. Of 71 women enrolled, 70 were evaluable (n = 34, ZOL; n = 36, placebo). No statistically significant differences were observed in hormone levels, except E2 and AMH, which showed minor differences. These included decreases in serum E2 levels, which reached a nadir after 3 and 9 months in placebo and ZOL groups, respectively, and decrease in serum AMH levels throughout the study with ZOL, but remained constant with placebo after 6 months. Adverse events in ZOL-treated group were influenza-like illness (32.4 %), bone pain (32.4 %), chills (20.6 %), and nausea (23.5 %). ET ± ZOL was well tolerated. This study showed no influence of ZOL on hormonal level changes that accompany ET, supporting inclusion of ZOL in adjuvant therapy for premenopausal women with HR + BC.

Abstract P3-06-05: HER2/HR positive early breast cancer patients have nowadays the highest disease-free survival: Results from the south-east of the Netherlands

Abstract Background Adjuvant systemic therapy choices in early breast cancer largely depend on human epidermal growth factor receptor 2 (HER2) and hormone receptor (HR) status. Overexpression of HER2 has been shown to be associated with a worse outcome (Slamon et al, Science, 1987). With this cohort study, we aimed to assess the outcome of early breast cancer patients per subtype based on HER2 and HR status in daily practice treated in a time period of routine use of anti-HER2 treatment. Patients and methods Patients diagnosed with early breast cancer during the years 2005-2007 in five participating hospitals in the South-East part of the Netherlands were included. Patients with primary metastatic breast cancer were excluded. Information regarding disease characteristics and treatment was collected. Patients were categorized in 4 subtypes based on the HER2 and HR status of the primary tumor: HER2 positive (+)/HR positive (+), HER2 negative (-)/HR+, HER2+/HR-, and triple negative (TN) (i.e. HER2- and HR-). Disease-free survival (DFS) was estimated using the Kaplan-Meier method. Cox proportional hazards model was used to determine the prognostic impact of breast cancer subtype, adjusted for possible confounders. Results A total of 2579 patients were included with a median follow-up of 52.6 months. Median 5-year DFS rate was highest for the HER2+/HR+ subtype (comprising of 13% of all patients) with 78%, compared to 68% for the HER2+/HR- subtype (5% of all patients), 75% for the HER2-/HR+ subtype (70% of all patients) and 64% for the TN subtype (12% of all patients). In multivariate analysis, subtype was confirmed to be an independent prognostic factor. Compared to the HER2+/HR+ subtype, the HER2+/HR- subtype was associated with a worse DFS (HR 2.05, 95% CI 1.21-3.46, P = 0.008) and the HER2-/HR+ was associated with a similar DFS (HR 1.09, 95% CI 0.79-1.52, P = 0.6). Furthermore, classical clinicopathological parameters were all confirmed to be of independent prognostic relevance, as well as the use of adjuvant systemic therapy. At the meeting, we will show the results according to the type of adjuvant systemic treatment used. Conclusion In this cohort, we noted that 13% of patients had HER2+/HR+ early breast cancer. These had the highest 5-year disease-free survival of all subtypes, significantly better than the HER2+/HR- subgroup. This may indicate a differential prognostic impact of HER2 according to HR status, with HR+ having a positive prognostic impact, irrespective of the presence of HER2 overexpression. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-06-05.

Abstract P1-13-12: Intermittent letrozole as adjuvant treatment in postmenopausal hormone-receptor positive early breast cancer patients

Abstract Background: Low-dose estrogen might induce apoptosis in breast cancer cells that develop resistance to antihormonal therapy. Letrozole withdrawal for 3-month might permit estrogenic stimulation in residual resistant disease susceptible to letrozole reintroduction. We investigated the impact of a 3-month letrozole free interval on serum Estradiol levels in patients with early stage breast cancer. Patients and methods: Postmenopausal women with ER and/or PgR ≥ 10% of the cells, node-negative early breast cancer were eligible. Patients (pts) received letrozole (2.5 mg daily) for five years with a 3-month treatment free interval after the 1st year of therapy. The primary endpoint was to evaluate the increase in serum estradiol absolute levels after 3-month treatment free interval. The secondary endpoints were the evaluation of others biological markers (e.g. FSH, LH, Cholesterol, HDL, triglycerides, osteocalcin). Estradiol levels were quantified by ECLIA assay that measured estradiol concentrations with a 5 pg/ml lower detection limit. FSH and LH levels (mU/ml) were measured by ECLIA assay, Osteocalcin (ng/ml) by RIA assay, Cholesterol, HDL, and Triglycerides (mg/ml) by colorimetric assay. Results: From November 2007 to February 2012, 130 evaluable pts were enrolled. The median age was 61 years. One-hundred ten pts (85%) had pT1 tumor, 88 pts (68%) presented grade 2 and 83 pts (64%) showed a Ki-67 LI &amp;lt;20%. Mean values of estradiol levels at time of discontinuation were 5.6 pg/ml (standard deviation: 1.7). Estradiol levels increased after a 3-month free interval by a mean of 3.3 pg/ml (66%; P &amp;lt;0.0001). FSH and LH levels decreased from baseline by a mean of 7.5 mU/ml (P&amp;lt;0.0001), and 1.4 mU/ml (P = 0.0062) respectively. Triglycerides decreased from baseline by a mean of 8.6 mg/dl (P = 0.036), and osteocalcin increased by a mean of 2.8 ng/ml (P = 0.013). Conclusions: Intermittent Letrozole significantly impact on estradiol levels. This study provides further evidence supporting the role of intermittent letrozole in the adjuvant treatment of postmenopausal patients with endocrine responsive breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-13-12.

Efficacy of zoledronic acid in postmenopausal Japanese women with early breast cancer receiving adjuvant letrozole: 36-month results.

e20510 Background: We reported 12-month results of upfront zoledronic acid (ZOL) therapy, which prevented bone loss in postmenopausal Japanese women who were receiving adjuvant letrozole, confirming the Z-FAST and ZO-FAST studies results. But the examination in the long term of aromatase inhibitor-associated bone loss has not been proved in the Japanese or Asia women. Methods: Postmenopausal women with hormone receptor positive early breast cancer (BC) patients receiving adjuvant letrozole were randomly assigned to receive either upfront or delayed-start ZOL (4mg intravenously every 6 months) for 5 years. The delayed group received ZOL when lumbar spine (L2-L4) BMD decreased to less than young adult mean (YAM) – 2.0 S.D or when a nontraumatic fractured occurred. The primary endpoint of this study was to compare the changes in L1-L4 BMD at month 12 between the groups. Secondary endpoints, measured at other predetermined timepoints, included comparing changes in L1-L4, L2-L4and total hip (TH) BMD and markers of bone turnover, fracture incidence, and time to disease recurrence. We report the results of 36-month interim analysis. Results: At 36 months, mean change in L1-L4 BMD was 10.7% higher in the upfront group than in the delayed group ( 95% CI, 9.2% to 12.1%; p&lt; 0.001 ), L2-L4BMD was 10.9% higher ( 95% CI, 9.3% to 12.5%; p&lt; 0.001 ), and TH BMD was 6.7% higher ( 95% CI, 5.3% to 8.1%; p&lt; 0.001 ). The incidence of fracture was not significantly different between each group (upfront, 1(1.0%) vs. delayed, 4(4.1%)). Disease recurrence was reported in 3 upfront (3.1%) and 1 delayed (1.0%) patients. By month 36, 11 patients (11.3%) in the delayed group initiated ZOL therapy. There was no significant difference of adverse events other than fever with ZOL at the first treatment between the two groups. Conclusions: Upfront ZOL seems to be the preferred treatment strategy versus delayed administration, as it significantly and progressively increases BMD in postmenopausal Japanese women with early BC who were receiving adjuvant letrozole for 36 months. Clinical trial information: UMIN000001104.

Abstract P5-03-11: Possible role for cancer stem cells: results from a pilot neoadjuvant trial of HER-2 positive breast cancer patients treated with a combination of (Nab)-paclitaxel and lapatinib.

Abstract Background: Lapatinib, a dual kinase inhibitor against both epidermal growth factor (EGFR) and human epidermal factor 2 (HER-2) and nanoparticle albumin bound (nab) paclitaxel was recently used by our group in a pilot study of early stage HER-2 positive breast cancer. We reported that the combination was well tolerated and showed good efficiency in this patient group. Cancer stem cells were recently identified in solid tumors including breast carcinomas. These tumor initiating stem cells are reported to be increased in HER-2 positive breast cancers. Lapatininb is postulated to reduce the percentage of breast cancer stem cells following HER-2 inhibition. This study aimed to investigate such an effect in this patient population of early stage HER-2 positive breast cancer cases uniquely treated by a combination of nab-paclitaxel and lapatininb. Design: 30 patients with stage I-III HER-2 positive breast cancer were treated in a neoadjuvant setting with lapatinib 1,000mg/day and nab-paclitaxel 260 mg/m2 every 2 weeks for 4 cycles. The expression of the stem cell markers aldehyde dehydroganase (ALDH1) (BD), CD24 and CD44 (both Santa Cruz Biotechnology) was assessed immunohistochemically in breast cancer specimens prior to treatment and at the time of definitive surgery. Staining was considered negative if &amp;lt; or = 1%, and positive if &amp;gt;1%. Results: Of the 30 patients, 28 underwent surgery and were evaluated for pathologic response. Complete pathologic response (pCR) was observed in 5/28 (17.9%) of the patients. Of the 17 patients for whom pre-treatment material was available 13 (76.5%) were positive for ALDH1 expression and 4 (23.5%) were negative. Of the 22 patients with material available for testing at the time of surgery, 5 showed pCR, 3 were negative and 14 (63.6%) were positive for ALDH-A1 expression. The CD44+/CD24- phenotype was variable and showed no difference between groups. Conclusions: 1. Combination of lapatinib and nab-paclitaxel resulted in a complete pathologic response in almost 1/5 of the HER-2 positive early stage breast cancer patients. 2. Overall, there is a reduction in the number cancer stem cells following neoadjuvant treatment with lapatinib and nab-paclitaxel. Our results support the hypothesis that lapatinib may have an effect in manipulating the numbers of cancer stem cells in patients with HER-2 positive breast cancer. Additional studies are currently under way to further characterize these findings. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-03-11.