HER2-negative Early-stage Breast Cancer Research Articles

A metastasis biomarker (MetaSite Breast\u2122 Score) is associated with distant recurrence in hormone receptor-positive, HER2-negative early-stage breast cancer

Metastasis is the primary cause of death in early-stage breast cancer. We evaluated the association between a metastasis biomarker, which we call “Tumor Microenviroment of Metastasis” (TMEM), and risk of recurrence. TMEM are microanatomic structures where invasive tumor cells are in direct contact with endothelial cells and macrophages, and which serve as intravasation sites for tumor cells into the circulation. We evaluated primary tumors from 600 patients with Stage I–III breast cancer treated with adjuvant chemotherapy in trial E2197 (NCT00003519), plus endocrine therapy for hormone receptor (HR)+ disease. TMEM were identified and enumerated using an analytically validated, fully automated digital pathology/image analysis method (MetaSite Breast™), hereafter referred to as MetaSite Score (MS). The objectives were to determine the association between MS and distant relapse free interval (DRFI) and relapse free interval (RFI). MS was not associated with tumor size or nodal status, and correlated poorly with Oncotype DX Recurrence Score (r = 0.29) in 297 patients with HR+/HER2- disease. Proportional hazards models revealed a significant positive association between continuous MS and DRFI (p = 0.001) and RFI (p = 0.00006) in HR+/HER2- disease in years 0–5, and by MS tertiles for DRFI (p = 0.04) and RFI (p = 0.01), but not after year 5 or in triple negative or HER2+ disease. Multivariate models in HR+/HER- disease including continuous MS, clinical covariates, and categorical Recurrence Score (<18, 18–30, > 30) showed MS is an independent predictor for 5-year RFI (p = 0.05). MetaSite Score provides prognostic information for early recurrence complementary to clinicopathologic features and Recurrence Score.

Abstract P2-05-06: Analytical and clinical validation of a fully automated tissue-based quantitative assay (MetaSite Breast™) to detect the likelihood of distant metastasis in hormone receptor (HR)-positive, HER2-negative early stage breast cancer (ESBC)

Abstract Background: MetaSite Breast™ is a validated assay to predict risk of distant breast cancer metastasis in patients with HR+/HER2- ESBC. The assay measures the number of MetaSites defined as tumor microanatomic structures composed of MENA protein expressing tumor cells in contact with CD31+ endothelial cells and CD68+ macrophages. Previous studies have demonstrated that an increased number of these microanatomic structures is associated with distant metastasis (DM) in HR+/HER2- ESBC independent of clinicopathologic features. Analytical validation of MetaSite Breast™ demonstrated precision of 97-99% (repeat image analysis of the same slide) and performance of 91-96% (staining and image analysis of serial tumor sections). We sought to further understand the importance of the MetaSite in predicting distant breast cancer metastasis utilizing a fully automated prognostic assay in an independent large patient cohort. Methods: We conducted a nested case-control study within a cohort of 3,760 patients diagnosed between 1980 and 2000 with invasive breast cancer from the Kaiser Permanente Northwest health care system. Cases (n=259) were women who developed a subsequent distant metastasis; controls, selected using incidence density sampling, were matched closely to cases (1:1) on age at and calendar year of primary diagnosis. Of the 481 patient tumor samples evaluated in this study, 57% were HR+/HER2-, 19% were triple negative (TN), and 15% were HER2+ disease. Multivariate models were adjusted for clinical factors including: lymph node status, tumor size, tumor grade, and HRT; as well as matching variables: age and year of diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression. Results: In the HR+/HER2- group, MetaSite Score (MS) ranged from 0-357 and the mean was 44.6. MS was a significant predictor of DM (P=0.039) in patients with HR+/HER2- disease. Cut-points based on tertiles of MS in all 259 controls defined intermediate (13-41) and high (&amp;gt;41) risk groups that were significantly associated with risk of DM versus the low risk group (OR=2.24; 95%CI=1.23-4.13, P=0.009) and (OR=2.94; 95%CI=1.62-5.41, P=0.0005), respectively. Univariate estimates of absolute risk of DM with cutoffs based on 90% sensitivity and specificity were 9.4% for the low risk group (MS&amp;lt;7), 14.1% for the intermediate (MS=7-91), and 23.4% for the high (MS&amp;gt;91). When adjusted for clinical factors, estimates of absolute risk of DM were 6.6%, 14.1%, and 33.0% for the low, intermediate, and high risk groups, respectively. A binary cut-point for the high risk group was determined (MS&amp;gt;14) and was significant with a 2-fold higher risk of DM versus the low risk group and adjusted for clinical covariates (P=0.036). MS was not positively associated with DM in TN or HER2+ disease. Conclusions: MetaSite Breast™ significantly predicted the risk of distant breast cancer metastasis in ESBC patients with HR+/HER2-disease, independent of classical clinicopathologic features. Citation Format: Donovan MJ, Jones JG, Entenberg DR, Condeelis JS, D'alfonso TM, Gustavson M, Molinaro A, Oktay MH, Xue X, Sparano JA, Peterson MA, Podznyakova O, Rohan TE, Shuber AP, Gertler FB, Ly A, Divelbiss ME, Hamilton DA. Analytical and clinical validation of a fully automated tissue-based quantitative assay (MetaSite Breast™) to detect the likelihood of distant metastasis in hormone receptor (HR)-positive, HER2-negative early stage breast cancer (ESBC) [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 P2-05-06.

Abstract S4-04: Tumor microenvironment of metastasis (TMEM) score is associated with early distant recurrence in hormone receptor (HR) positive, HER2-negative early stage breast cancer (ESBC)

Abstract Background: Metastasis is the primary cause of death in ESBC. We have shown in mouse models that a subpopulation of tumor cells expressing invasive Mena isoforms stream, form microanatomic structures (“TMEM”) with endothelial cells and macrophages, intravasate into the circulation at TMEM sites, and metastasize (Harney et al. Cancer Discovery, 2015). Further, TMEM sites (“MetaSites”) are identifiable in human ESBC, and “MetaSite score” [MS] is positively associated with distant recurrence in HR+/HER2- ESBC independent of clinicopathologic features, including IHC4 (Rohan et al. JNCI 2014). Here we determined the association between MS and recurrence in an independent ESBC cohort (E2197; NCT00003519). Methods: We evaluated primary tumors from 600 patients (median followup 14.8 years) with ESBC (weighted % = 50% T1, 54% N0, 46% N1) treated with surgery and 4 cycles of adjuvant chemotherapy (AC or AT) and endocrine therapy. Grade, ER, PR, and HER2, and Oncotype DX Recurrence Score (RS) were evaluated in central labs (Badve et al. JCO 2008), and MS was determined in a CLIA-certified lab using an analytically validated, fully automated digital pathology/image analysis method that identifies Mena expressing tumor cells in direct contact with CD68+ macrophages and CD31+ endothelial cells (ie, “TMEMs”, or “MetaSites”). The objectives were to determine the association between MS and distant relapse free interval (DRFI) and relapse free interval (RFI). Kaplan-Meier survival curves were used to estimate time-to-event distributions. Cox proportional hazards models were used to assess hazard ratio associated with MS while controlling for covariates, and allowing time-varying association with MS. Both Kaplan-Meier and Cox regression methods addressed stratified sampling by incorporating proper weights. All analyses were performed in R 3.2.3. Results: MS ranged from 0-199; the weighted mean MS was lower in HR+/HER2- than TN (16.1 vs. 23.8, p=0.001) and HER2+ disease (26.2, p=0.003). MS was not associated with T or N status, and correlated poorly with RS (r=0.29). Proportional hazards models revealed a significant positive association between continuous MS and DRFI (p=0.001) and RFI (p=0.00006) in HR+/HER2- disease in years 0-5 (and by MS tertiles for DRFI [p=0.04] and RFI [p=0.01]), but not after year 5 or in TN or HER2+ disease. Proportional hazards models including clinical covariates (N0 vs. N1; T1 vs. T2; high vs. int. vs. low grade) also revealed significant positive associations for continuous MS with RFI (p=0.04), and borderline association with DRFI (p=0.08). Similar findings for MS (RFI p=0.05;DRFI p=0.10) were noted in a joint model including categorical RS (&amp;lt;18,18-30, &amp;gt;30). Conclusions: MS, a novel metastasis biomarker reflecting interaction between streaming and metastasizing tumor cells and microenvironment, provides prognostic information complementary to classical clinicopathologic features and RS in HR+/HER2- ESBC. Further evaluation is warranted in order to identify patients at highest risk of recurrence within 5 years most likely to benefit from adjuvant chemotherapy or novel therapies. (Supported by BCRF and NCI CA21115, CA180794, CA23318, CA66636, CA180820). Citation Format: Sparano JA, Gray R, Oktay MH, Entenberg D, Rohan T, Xue X, Donovan M, Peterson M, Shuber A, Hamilton D, D'Alfonso T, Goldstein LJ, Gerlter F, Davidson N, Condeelis J, Jones J. Tumor microenvironment of metastasis (TMEM) score is associated with early distant recurrence in hormone receptor (HR) positive, HER2-negative early stage breast cancer (ESBC) [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 S4-04.

21-Gene recurrence score decreases receipt of chemotherapy in ER+ early-stage breast cancer: an analysis of the NCDB 2010-2013.

The purpose of this study was to determine if receipt of chemotherapy was associated with utilization of the 21-gene recurrence score assay (RS assay) or with recurrence score (RS) in eligible patients. Using the National Cancer Data Base (NCDB), we identified female patients eligible for RS assay based on National Comprehensive Cancer Network (NCCN) guidelines: age 18–70, ER-positive and HER2-negative early-stage breast cancer diagnosed during 2010–2013. We excluded patients not meeting testing guidelines. Inclusion required result of RS in patients who underwent RS assay and status for receipt of chemotherapy. Multivariable logistic regression models and propensity matched analysis were used to determine associations between RS assay and RS with receipt of chemotherapy. Among 129,765 patients who were eligible, 74,778 underwent RS assay and had results available. Of these, 59.5 % (44,505) had low-risk, 32.0 % (23,920) had intermediate-risk, and 8.5 % (6353) had high-risk RS. Patients with intermediate- and high-risk RS were more likely to receive chemotherapy [OR 12.9 (CI 12.2–13.6), p <0.001 and OR 87.2 (CI 79.6–95.6), p <0.0001], respectively. In both low- and intermediate-risk groups, increasing RS score was significantly associated with increasing odds of receiving chemotherapy [OR 1.10 (CI 1.09–1.12), p <0.0001 and OR 1.26 (CI 1.25–1.27), p <0.0001, respectively, for each point increase in RS]. Receipt of chemotherapy was more likely in patients who did not undergo RS assay compared to those who did, OR 1.21 (CI 1.175–1.249) p <0.0001. The utilization of RS assay and the RS were both strongly associated with chemotherapy receipt. Patients eligible for chemotherapy, based on NCCN criteria, were more likely to receive chemotherapy if they did not undergo RS assay or they had a high RS.

The West German Study Group Breast Cancer Intrinsic Subtype study: a prospective multicenter decision impact study utilizing the Prosigna assay for adjuvant treatment decision-making in estrogen-receptor-positive, HER2-negative early-stage breast cancer

Purpose: The West German Study Group (WSG) Breast Cancer Intrinsic Subtype (BCIST) study was designed to assess the influence of Prosigna gene signature assay results on physicians’ adjuvant treatment recommendations by determining the extent of change in pre-test treatment recommendations following assay results. Secondary objectives were to assess the influence of Prosigna results on physicians’ confidence in their therapeutic recommendations and on patients’ decisional conflict status, anxiety levels, and functional status. Methods: This prospective, observational, decision impact study enrolled consecutive postmenopausal patients with estrogen-receptor (ER)-positive, HER2-negative, lymph-node-negative early-stage breast cancer in 11 centers in Germany. Physicians based their pre-test adjuvant treatment recommendations on standard clinico-pathological parameters. Tumor specimens were assayed using the Prosigna test in a WSG central pathology laboratory following manufacturer’s guidelines. An independent pathology laboratory performed subsequent Prosigna assays on tumor sections to assess assay result concordance with the central laboratory. Physicians completed treatment confidence questionnaires prior to and after receiving Prosigna test results. Patients completed standardized questionnaires on decisional conflict, anxiety, and health status both before and after Prosigna testing. Results: The present study population consisted predominantly of low-to-intermediate risk patients (N = 198). Prosigna had 29.3% discordance in intrinsic subtyping with local immunohistochemistry test results. After Prosigna test results, a change in the adjuvant therapy recommendation occurred in 36 (18.2%) patients; 22 (11.1%) patients switched from no chemotherapy to chemotherapy. After Prosigna test results, physicians expressed increased confidence in their prognostic assessment in 87.9% of patients, and increased confidence in their treatment recommendation in 89.4%. Patients reported improved anxiety and emotional/functional well-being after receiving Prosigna test results. Conclusions: Use of the Prosigna assay led to a change in 18.2% of adjuvant treatment decisions. Prosigna testing was associated with increased patient and physician confidence in treatment decisions, and with decreased patient anxiety and improved well-being. Any comparison of the therapeutic decision-making impacts of different genomic assays must account for potential confounding factors.

Increased Expression of Tumor Proliferation Genes in Hispanic Women with Early-Stage Breast Cancer

Hispanic women have higher breast cancer mortality compared to non-Hispanic whites. We evaluated for Proliferation Axis Score differences, as determined by Oncotype Dx, in Hispanic and non-Hispanic white women with newly diagnosed breast cancer. We matched 219 women, based upon age, stage, and nodal status. Compared to non-Hispanic whites, Hispanic women with hormone-sensitive, HER2-negative early-stage breast cancer had a higher Proliferation Axis Score. No differences were seen in Recurrence Score, ER, PR, or HER2 by Oncotype DX. CCNB1 and AURKA were significantly higher in Hispanic women. These tumor differences may help explain breast cancer outcome differences between the two ethnicities.

Estrogen Receptor and Receptor Tyrosine Kinase Signaling: Use of Combinatorial Hormone and Epidermal Growth Factor Receptor/Human Epidermal Growth Factor Receptor 2–Targeted Therapies for Breast Cancer

Estrogen receptor (ER ) is expressed in nearly 70% of breast cancers and is a key driver of growth in ER-positive breast tumors. ER is primarily a nuclear protein that, when activated by estrogens, acts as a ligand-dependent transcription factor and promotes the expression of several genes that enhance cell survival, proliferation, and tumor progression (Fig 1). Examples of gene products upregulated by ER’s genomic actions include Bcl-2, cyclin D1, and the insulin-like growth factor 1 (IGF-1) receptor. Activated ER can also be localized to the cellular membrane and exert rapid, nongenomic effects. Here ER can colocalize with numerous different signaling molecules that lead to activation of growth and survival-promoting pathways, including the mitogen-activated protein kinase (MAPK) and Akt pathways. The use of hormone therapies, including aromatase inhibitors and selective estrogen receptor modulators, that target and downregulate ER signaling in the breast is a mainstay of treatment for patients with ER-positive breast cancers. Although these agents are extremely effective, a significant proportion of patients exhibit de novo or acquired resistance to hormone therapy. A proposed mechanism of resistance to hormone therapy is signaling crosstalk between ER and growth factor receptor tyrosine kinases (RTKs). In an accompanying article, Guarneri et al report the results of a randomized, double-blind, placebo-controlled, multicenter phase IIb neoadjuvant study of the aromatase inhibitor letrozole combined with the dual epidermal growth factor receptor/human epidermal growth factor receptor 2 (EGFR/ HER2) inhibitor lapatinib in postmenopausal hormone receptor– positive, HER2-negative early-stage breast cancer. Their results show that clinical response rates were similar for patients who received a combination of letrozole and lapatinib compared with patients receiving letrozole and placebo (70% v 63%, respectively). However, on further subset analysis, they found that patients with a PIK3CA mutation (37%) had a significantly higher likelihood of clinical response to the letrozole-lapatinib combination therapy versus those patients without PIK3CA mutations (overall response rate of 93% for patients with mutant PIK3CA v 63% for patients with wild-type PIK3CA). PIK3CA is the gene that encodes the PI3K catalytic subunit p110 , and the PI3K pathway is the most commonly mutated pathway in breast cancers, with PIK3CA recurrent hotspot mutations found at high frequency in ER-positive breast tumors. PI3K has been implicated as a key mediator of hormone resistance in preclinical models, and evidence suggests that hyperactivation of PI3K may enhance estrogen-independent and -dependent ER transcriptional activity. Although inhibition of the PI3K pathway has been postulated to sensitize cells to hormone therapy, several retrospective clinical studies have shown that activating mutations in PIK3CA paradoxically predict for a better long-term prognosis in patients with ER-positive breast cancers treated with hormonal therapy although other studies have shown contradictory results. It is known that activated RTKs and their downstream signaling partners can directly interact with ER and cause phosphorylation of key residues in the AF-1 domain of ER. This phosphorylation results in activation of ER in a ligand-independent fashion to promote cell growth and survival. In addition, membrane-activated ER can activate the EGFR pathway by increasing the production of the EGFR ligand heparin-binding epidermal growth factor. Furthermore, in vitro studies have shown that breast cancer cell lines with acquired resistance to hormone therapy have increased expression and activation of EGFR and HER2 along with their downstream signaling pathways. The use of ErbB-targeted tyrosine kinase inhibitors or the anti-HER2 monoclonal antibody trastuzumab significantly inhibits the growth of these cells after development of resistance to hormone therapies. In addition, sensitivity to hormone therapies can be restored when resistant cells are treated with lapatinib, a dual EGFR/ HER2 inhibitor. Together, these data suggest that enhanced RTK signaling and activationofPI3Ksignalingmaybekeycontributorstoresistancetohormone therapies in breast cancer. This provides the rationale for the dual JOURNAL OF CLINICAL ONCOLOGY U N D E R S T A N D I N G T H E P A T H W A Y VOLUME 32 NUMBER 10 APRIL 1 2014

21-gene Recurrence Score testing and subsequent treatment decisions in patients (pts) with estrogen-receptor-positive (ER+) early-stage breast cancer (ESBC).

30 Background: The utilization of the 21-gene Recurrence Score (Oncotype DX) in community settings is now well established for ER+, node negative (N-) pts with ESBC. The utility of the Recurrence Score result is to guide treatment decisions and spare exposure to chemotherapy (CT) in pts that have little likelihood of benefitting. To better understand physician behavior as it relates to OncotypeDX testing, we examined the characteristics of pts tested versus not tested, the Recurrence Score distribution and treatment patterns in approximately 160 pts with ESBC seen in 2010. In addition, provider utilization and treatment patterns were also assessed. Methods: Using data from 2010, the number of pts who were eligible to undergo OncotypeDX testing was compared to the number of pts who underwent testing. Pts were considered eligible for testing if they had node-negative, ER+, HER2-negative ESBC. We determined the number of pts with a Recurrence Score value in the low (RS &lt;18), intermediate (int; RS 18-30), and high-risk (RS ≥31) groups along with the number of pts who subsequently received chemotherapy in each category. Results: Of the 233 pts identified with ESBC, 158 were eligible for OncotypeDX testing and 107 (67.7%) underwent testing. Fifty-five percent of pts were low, 37% int, and 7.7% high-risk, respectively. Nineteen percent of low, 56% of int, and 100% of high-risk pts received CT. In the 11 pts with a low Recurrence Score result that received CT, the reason cited was pt decision in 4 and young age in 3. Conclusions: Oncotype DX use in the community is well established. Recurrence Score-guided use of CT in the low- and int-risk groups was as expected based on adjuvant chemotherapy guidelines; however, there were still some physicians treating low Recurrence Score pts with CT-mostly based on younger age or larger tumors. Data from 2011 and 2012 will be included in the final presentation allowing greater insight into pt groups less represented in the single year experience.

252PD - Meta-Analysis of Prospective European Studies Assessing the Impact of Using The 21-Gene Recurrence Score Assay on Clinical Decision Making in Women With Er-Positive, Her2-Negative Early Stage Breast Cancer

ABSTRACT Background The Oncotype DX® Recurrence Score is a validated assay to help inform the appropriate treatment of estrogen receptor-positive (ER+), early stage breast cancer. Adjuvant treatment traditions vary significantly among different countries. Prospective studies assessing the impact of the Oncotype DX test on adjuvant treatment decisions have been performed in several European countries. This is a meta-analysis of these studies. Methods Four prospective studies assessing the impact of using the Recurrence Score result on clinical decision making in patients with node negative and pN1 (mi) disease were identified. Node positive patients were excluded. The identified studies had a similar study design with consecutive patients and treatment recommendations before and after having the Recurrence Score results were recorded. In three of the studies, medical oncologists completed questionnaires regarding their confidence in their recommendation before and after knowing the patient's Recurrence Score result. The final results of the studies in Germany, Spain and the UK have been presented and final data from the French study will be presented at ASCO 2012. Results A total of 589 patients with node negative or pN1 (mi) ER pos HER2 negative early breast cancer were included in the four identified studies. Overall, 45% (range 36-52%) of patients in these studies were recommended chemo-endocrine and 55% endocrine treatment alone. After having the Recurrence Score result, 47% (range 38-60%) of patients recommended chemotherapy were changed to endocrine treatment alone and 17% (range 11-22%) of those recommended endocrine treatment alone were recommended chemo-endocrine treatment. There was a significant improvement in physician confidence in treatment recommendations when using the assay. Conclusion Using Oncotype DX® is associated with a significant change in treatment decisions and a reduction in chemotherapy use in studied European countries despite differences in therapeutic traditions. The consistency of the results from different countries underlines the tests utility. Disclosure J. Albanell: Participated advisory board (Genomic Health). S. Holt: Participated as a speaker, and in advisory board for Genomic Health. J. Gligorov: Has participated as speaker for Genomic Health. W. Eiermann: Participated as speaker and in advisory board for Genomic Health. C. Svedman: Employee and stocks in Genomic Health.

292P - Serum Levels of VEGF Pre- and Post-Treatment With Bevacizumab (BEV) for Early Stage Breast Cancer (ESBC): ICORG 08-10

ABSTRACT Background Angiogenesis, partly mediated by vascular endothelial growth factor (VEGF), promotes metastases. BEV, an anti-VEGF monoclonal antibody which has some efficacy in metastatic BC is being studied as an adjuvant treatment for ESBC. However, there are no validated biomarkers, and the effects of BEV on VEGF levels in pts with ESBC is unknown. We studied VEGF serum concentration in ESBC receiving BEV. Methods 106 pts with HER-2 negative ESBC were included in this study. Patients received 4 cycles of docetaxel (75 mg/m2) + cyclophosphamide (600 mg/m2) with BEV (15 mg/kg) once every three weeks for one year. Serum samples were collected prior to commencement of treatment, at 6 months and 12 months. The VEGF levels in serum samples were determined, at each time point, using a VEGF enzyme-linked immunosorbent assay (ELISA). Results VEGF concentration was determined in serum samples from 65 patients. Serum VEGF was detectable in 62 of 65 patients and the median level in untreated patients was 325.4 pg/ml (range 0.1 - 924.8 pg/ml). All of the 62 patients showed a significant decrease in VEGF concentration after 6 and 12 months of treatment (median 9 ± 42.1 pg/ml, p Conclusion Adjuvant therapy with chemotherapy and BEV is associated with a significant reduction in VEGF levels at 6 months. Disclosure All authors have declared no conflicts of interest.

Serum VEGF in patients (PTS) receiving bevacizimab (BEV) for early-stage breast cancer (ESBC): ICORG 08-10.

e13520 Background: Approximately 30% of pts with ESBC develop metastasis despite apparently curative loco-regional therapy. Angiogenesis, partly mediated by vascular endothelial growth factor (VEGF), may promote metastases. BEV, an anti-VEGF monoclonal antibody which has some efficacy in metastatic BC is being studied as an adjuvant in ESBC, but there are no validated biomarkers, and the effect on VEGF levels in pts with ESBC is unknown. We studied VEGF serum concentration in ESBC receiving BEV. Methods: 106 pts with HER-2 negative ESBC were included in this study. Patients received 4 cycles of docetaxel (75 mg/m2) + cyclophosphamide (600 mg/m2) with BEV (15 mg/kg) once every three weeks for one year. Serum samples were collected prior to commencement of treatment, at 6 months and 12 months. The VEGF levels in serum samples were determined, at each time point, using a VEGF enzyme-linked immunosorbent assay (ELISA). Results: VEGF concentration was determined in serum samples from 65 patients. Three pts (5%) had no detectable VEGF at 0, 6 and 12 months. The median level of serum VEGF in the remaining 62 patients was 325.4 ± 244 pg/ml. These 62 patients showed a significant decrease in VEGF concentration after 6 and 12 months of treatment (median 9 ± 42.1 pg/ml, p&lt;0.001 and 9 ± 43.9 pg/ml, p&lt;0.001 respectively). However, no significant change in VEGF levels were observed at 12 months compared to 6 months (median 0 ± 60.3 pg/ml, p=0.704). Conclusions: Adjuvant therapy with chemotherapy and BEV is associated with a significant reduction in VEGF levels at 6 months.

Evaluation of Oncotype DX testing and subsequent patterns of care in patients (pts) with early-stage breast cancer (ESBC).

569 Background: Cardinal Health Specialty Solutions (CHSS) partners with payers to manage clinical care pathways in oncology and rheumatology. Observations from one such pathway with CareFirst BlueCross BlueShield revealed that pts with estrogen receptor-positive ESBC who underwent Oncotype DX testing and were found to have high-risk Recurrence Scores (RS) received less chemotherapy than expected. To better understand physician behavior as it relates to Oncotype DX testing, CHSS examined patterns of Oncotype DX use in a large private practice oncology group with a robust electronic medical record (EMR), Georgia Cancer Specialists (GCS). We aimed to determine the RS risk distribution among pts who received Oncotype DX testing and assess the patterns of care that followed. Methods: Using GCS EMR data from 2009 to 2011, the number of pts who were eligible to undergo Oncotype DX testing was compared to the number of pts who underwent testing. Pts were considered eligible for testing if they had node-negative, estrogen receptor-positive, HER2-negative ESBC. We determined the number of pts with a RS value in the low- (RS &lt;18), intermediate- (RS 18-30), and high-risk (RS ≥31) groups along with the number of pts who subsequently received chemotherapy in each category. Results: Of the 1908 patients identified with ESBC, 788 were eligible for Oncotype DX testing and 288 (37%) underwent testing. Fifty percent of pts were in the low-, 34% in intermediate-, and 16% in the high-risk groups. Six percent of low-, 41% of intermediate-, and 83% of high-risk pts received chemotherapy. Seventeen percent of pts in the high-risk group did not receive chemotherapy. Conclusions: The use of chemotherapy in the low- and intermediate-risk groups was as expected based on adjuvant chemotherapy guidelines; however, an under utilization of chemotherapy was found in high-risk pts. There also appears to be a noteworthy underuse of Oncotype DX testing in eligible pts. Further data analysis is needed to understand the low use of Oncotype DX testing in eligible pts and to explain the lower than expected use of chemotherapy in high-risk pts.

Neoadjuvant Chemotherapy and Bevacizumab for HER2-Negative Breast Cancer

BackgroundBevacizumab, a monoclonal antibody against vascular endothelial growth factor A, has shown clinical efficacy in patients with human epidermal growth factor receptor 2 (HER2)–negative metastatic breast cancer. We evaluated the efficacy, measured according to the rate of pathological complete response (absence of invasive and intraductal disease in the breast and the axillary lymph nodes), and the safety of adding bevacizumab to neoadjuvant chemotherapy in patients with early-stage breast cancer.MethodsWe randomly assigned 1948 patients with a median tumor size of 40 mm on palpation to receive neoadjuvant epirubicin and cyclophosphamide followed by docetaxel, with or without concomitant bevacizumab. Patients with untreated HER2-negative breast cancer were eligible if they had large tumors, hormone-receptor–negative disease, or hormone-receptor–positive disease with palpable nodes or positive findings on sentinel-node biopsy, and no increased cardiovascular or bleeding risk.ResultsOverall, the rates of pathological complete response were 14.9% with epirubicin and cyclophosphamide followed by docetaxel and 18.4% with epirubicin and cyclophosphamide followed by docetaxel plus bevacizumab (odds ratio with addition of bevacizumab, 1.29; 95% confidence interval, 1.02 to 1.65; P=0.04); the corresponding rates of pathological complete response were 27.9% and 39.3% among 663 patients with triple-negative tumors (P=0.003) and 7.8% and 7.7% among 1262 patients with hormone-receptor–positive tumors (P=1.00). Breast-conserving surgery was possible in 66.6% of the patients in both groups. The addition of bevacizumab, as compared with neoadjuvant therapy alone, was associated with a higher incidence of grade 3 or 4 toxic effects (febrile neutropenia, mucositis, the hand–foot syndrome, infection, and hypertension) but with a similar incidence of surgical complications.ConclusionsThe addition of bevacizumab to neoadjuvant chemotherapy significantly increased the rate of pathological complete response among patients with HER2-negative early-stage breast cancer. Efficacy was restricted primarily to patients with triple-negative tumors, in whom the pathological complete response is considered to be a reliable predictor of long-term outcome. (Funded by Sanofi-Aventis and Roche, Germany; ClinicalTrials.gov number, NCT00567554.)

Cost-effectiveness of targeting chemotherapy with the 70-gene prognostic signature in early-stage breast cancer (ESBC) patients

6570 Background: The 70-gene microarray test (MammaPrint) has been shown to provide additional prognostic information to clinicopathologic risk assessment for women ESBC; however, the cost-effectiveness of this strategy is not well understood. Methods: The objective of this analysis was to estimate the incremental benefits, costs, and cost-effectiveness of the treatments guided by the 70-gene signature versus Adjuvant! Software (AS) to decide on the use of adjuvant chemotherapy for women ≤61 years with lymph node negative, HER-2 negative ESBC with estrogen receptor (ER) positive or negative disease. A Markov model with a lifetime horizon and three health states (alive without recurrence, death from cancer and death from other causes) was constructed using TreeAge Pro software. Risk classification and patient outcomes data were based on a multi-center 70-gene signature validation study. Efficacy of chemotherapy derived from published meta-analysis of clinical trials. Costs and health utilities were obtained from the literature. Costs and benefits were discounted 3%/year. Results: Compared to AS, the 70-gene signature strategy resulted in 35% of patients being reassigned to a different risk classification and avoided chemotherapy in 9% of patients. In the base case, the 70-gene signature strategy was cost neutral (lifetime costs per patient: $178,811 versus $178,893 for the 70-gene signature and AS strategy). Moreover the 70-gene signature strategy was associated with an increase of 0.13 life years (LYs) and 0.16 quality adjusted life years (QALYs). The model results were sensitive to the cost of 70-gene signature test, cost of adjuvant chemotherapy, and relative risk reduction associated with chemotherapy; however, the 70-gene strategy remained cost-effective across a wide range of assumptions. Conclusions: In this analysis, the 70-gene signature was associated with a reduction in chemotherapy use and an increase in life expectancy. The 70-gene signature appears to be a cost-effective strategy for obtaining additional information to guide the decision to use adjuvant chemotherapy in patients with lymph node negative ESBC. [Table: see text]