Bleznak, Aaron D, MD, FACS

Burke, Emily

Chao, Calvin

Chung, Heiwon, MD, FACS

Davison, D S

Dellers, Elizabeth A., MD

Kimmel, Sharon R, PhD, MHA

Porter, B G

Yoshizawa, Carl N

English

Lehigh Valley Health Network: LVHN Scholarly Works

Lehigh Valley Health NetworkLVHN Scholarly WorksDepartment of Pathology & Laboratory MedicineA Non-randomized, Observational Trial of Short-term Pre-operative Endocrine Therapy in ERPositive Breast Cancer to Investigate Changes inGenomic Expression Using the Oncotype DX®Recurrence Score®Aaron D. Bleznak MD, FACSLehigh Valley Health NetworkElizabeth A. Dellers MDLehigh Valley Health Network, Elizabeth.Dellers@lvhn.orgB G. PorterLehigh Valley Health Network, Bernadettee.GI-Porter@lvhn.orgSharon R. Kimmel PhD, MHALehigh Valley Health Network, Sharon.Kimmel@lvhn.orgHeiwon Chung MD, FACSLehigh Valley Health Network, heiwon.chung@lvhn.orgSee next page for additional authorsFollow this and additional works at: https://scholarlyworks.lvhn.org/pathology-laboratory-medicinePart of the Medical Pathology Commons, and the Pathology CommonsThis Poster is brought to you for free and open access by LVHN Scholarly Works. It has been accepted for inclusion in LVHN Scholarly Works by anauthorized administrator. For more information, please contact LibraryServices@lvhn.org.Published In/Presented AtBleznak, A.D., Dellers, E.A., Glenn-Porter, B., Kimmel, S., Chung, H., Yoshizawa, C., Burke, E., Davison, D.S., Chao, C., (2011,September). A Non-randomized, Observational Trial of Short-term Pre-operative Endocrine Therapy in ER Positive Breast Cancer toInvestigate Changes in Genomic Expression Using the Oncotype DX® Recurrence Score. Poster presented at: The American Society ofClinical Oncology Breast Symposium.AuthorsAaron D. Bleznak MD, FACS; Elizabeth A. Dellers MD; B G. Porter; Sharon R. Kimmel PhD, MHA; HeiwonChung MD, FACS; Carl N. Yoshizawa; Emily Burke; D S. Davison; and Calvin ChaoThis poster is available at LVHN Scholarly Works: https://scholarlyworks.lvhn.org/pathology-laboratory-medicine/1A Non-randomized, Observational Trial of Short-term Pre-operative Endocrine Therapy in ER Positive Breast Cancer to Investigate Changes in Genomic Expression Using the Oncotype DX® Recurrence Score®Bleznak A. D.,1,2 Dellers E. A.,1 Glenn-Porter B.,1 Kimmel S.,1 Chung H.,1 Yoshizawa C.,3 Burke E.,3 Davison D. S.,3 Chao C.3 (1Lehigh Valley Health Network, Allentown, Pa.; 2University of South Florida School of Medicine, Tampa, Fla.;  3Genomic Health, Inc., Redwood City, Calif )L E H I G H  V A L L E Y  H E A L T H  N E T W O R KBackground•  Pre-operative systemic treatment is commonly employed for women with locally  advanced breast cancer. Women with early-stage, hormone receptor-positive breast cancer whose resections may be delayed for 30 to 60 days while they undergo pre- operative evaluation, may benefi t from receiving pre-operative endocrine therapy while awaiting surgery. •  Short-term neoadjuvant endocrine therapy has been reported to be well tolerated and results in a modest clinical response. 1,2•  One rationale for not initiating such treatment is that the cancer may be rendered less chemosensitive should fi nal pathology dictate that adjuvant chemotherapy would be benefi cial. •  The 21-gene Recurrence Score (RS) assay has been shown to be a predictor of both chemo- and endocrine-therapy responsiveness and may be useful as an indicator of sensitivity during and after neoadjuvant therapy.3-6Objective•  Compare core biopsy and excisional surgical specimens with respect to RS and single gene RT-PCR scores for ER, PR and HER2, in a cohort of women receiving short-term, pre-operative endocrine therapyMaterials and Methods•  Treatment: 4-8 weeks of daily letrozole (2.5 mg ) for post-menopausal women or tamoxifen (20 mg) for pre-menopausal women•  Clinical response was assessed by ultrasound (US) and clinical examination.   Complete response (CR): no tumor on palpation and/or imaging   Partial response (PR): ≥30% reduction   Progressive disease (PD): >20% increase   Stable disease (SD): other than above•  The Oncotype DX breast cancer assay was performed on core biopsy and excisional specimens by standardized methods in the Genomic Health Clinical Laboratory.    All samples were reviewed by board certifi ed pathologists. When necessary, samples were manually micro-dissected to enrich for tumor.    The 21-gene RS assay, including ER, PR, and HER2 gene expression, was assessed by RT-PCR.•  Single gene cut-point values (reference normalized expression, log2 scale):   ER: Negative <6.5, Positive ≥6.5   PR: Negative <5.5, Positive ≥5.5   HER2: Negative <10.7, Equivocal 10.7 - <11.5, Positive ≥11.5•  This is an exploratory, hypothesis-generating study. Scatter plots of core biopsy vs  excisional specimen results were produced. Pearson correlation coeffi cients and 95% confi dence intervals (CI) were calculated to assess correlation from core biopsies to  excisional specimens. Paired t-tests were performed on a post-hoc basis to examine if there were any directionally consistent changes.References1  Dunbier AK, Anderson H, Ghazoui Z, et al. Association between breast cancer subtypes and response to neoadjuvant anastrozole. Steroids. 2011; 76: 736-40.2  Mattar A, Logullo A, Facina G, et al. Short-term anastrozole therapy reduces Ki-67 and progesterone receptor expression in invasive breast cancer: a prospective, placebo-controlled, double-blind trial. J Cancer Res Clin Oncol. 2011; 137: 897-905.3  Akashi-Tanaka S, Shimizu C, Ando M, et al. 21-Gene expression profi le assay on core needle biopsies predicts responses to neoadjuvant endocrine therapy in breast cancer patients. Breast. 2009; 18: 171-4.4  Chang J, Powles TJ, Allred DC, et al. Prediction of clinical outcome from primary tamoxifen by expression of biologic markers in breast cancer patients. Clin Cancer Res. 2000; 6: 616-21.5  Gianni L, Zambetti M, Clark K, et al. Gene expression profi les in paraffi n-embedded core biopsy tissue predict response to chemotherapy in women with locally advanced breast cancer. J Clin Oncol. 2005; 23: 7265-7277.6  Paik S, Tang G, Shak S, et al. Gene expression and benefi t of chemotherapy in women with node-negative, estrogen receptor -positive breast cancer. J Clin Oncol. 2006; 24: 3726-34.7  Dowsett M, Ebbs SR, Dixon JM, et al. Biomarker changes during neoadjuvant anastrozole, tamoxifen, or the combination: infl uence of hormonal status and HER-2 in breast cancer–a study from the IMPACT trialists. J Clin Oncol. 2005; 23: 2477-92.8  Ellis MJ, Suman VJ, Hoog J, et al. Randomized Phase II Neoadjuvant Comparison Between Letrozole, Anastrozole, and Exemestane for Postmenopausal Women With Estrogen Receptor-Rich Stage 2 to 3 Breast Cancer: Clinical and Biomarker Outcomes and Predictive Value of the Baseline PAM50-Based Intrinsic Subtype–ACOSOG Z1031. J Clin Oncol.2011; 29: 2342-9.9  Miller WR, White S, Dixon JM, et al. Proliferation, steroid receptors and clinical/pathological response in breast cancer treated with letrozole. Br J Cancer. 2006; 94: 1051-6.Results•  21 patients consented to this study and initiated short-term neoadjuvant therapy:   19 completed therapy, underwent surgery, and had evaluable core biopsy and excisional specimens   2 patients were excluded from this analysis:  •  1 patient had no residual cancer in the excisional specimen  •  1 patient did not have evaluable core and excisional specimensStrengths and LimitationsStrengths•  Prospective study of changes in  biomarkers in early-stage, ER+ breast cancer treated with endocrine therapyLimitations•  Small sample size (n=19)•  Only 3 pre-menopausal patients; too few to examine potential differences by  menopausal status. •  Potential selection bias•  Only 1/19 patients in high RS group.•  Hypothesis tests not pre-specifi edSummary and Discussion•  Expression levels of ER, PR, and HER2 from core biopsies and excisional specimens were correlated (Pearson correlation coeffi cients, r = 0.87, 0.72, and 0.77, respec-tively), as was RS (r = 0.89), following short term neoadjuvant endocrine therapy.•  In this study, on average, therapy reduced the expression of ER and PR, while HER2  expression was unchanged. The changes in ER and PR expression contributed to a modest increase (mean = 2.8 units, p = 0.003) in the Oncotype DX RS. •  The prognostic and predictive capability of the Oncotype DX RS in ER-positive, early-stage breast cancer has been demonstrated in multiple clinical studies; none of these patients had received  neoadjuvant therapy.   There are no data on the prognostic or predictive ability of the RS from tumor  samples obtained after neoadjuvant therapy.   The clinical signifi cance of the changes in ER, PR and RS observed in this study is therefore unclear.ConclusionsIn this small, hypothesis-generating study:•  Expression of ER and PR both decreased by small but statistically signifi cant amounts, which  contributed to a small but statistically signifi cant increase in RS (2.8 units).  •  The clinical signifi cance of these observed changes are unclear.•  Decreases in ER have been observed following short term aromatase inhibitor  treatment in some studies,7-8 but not others.9Table 1: Study Eligibility Criteria† Assessed by IHC * HER2 status 0 or 1+ by IHC or negative by FISHCriterion Description Eligible ValuesAge 35 – 85 YearsECOG Performance Status (PS) 0 , 1, or 2Tumor Size Greater than 0.5 cm in diameter, sonographically visibleHER2 Status* NegativeTable 2: Baseline Characteristics for 19 T1, N0, M0 Patients† Assessed by IHC *Assessed by IHC/FISHVariable n (%) Variable n (%)Single Gene Status Menopausal StatusER Positive† 19 (100%) Pre 3 (16%)PR Positive† 19 (100%) Post 16 (84%)HER2* Age (years)0,1+ 17 (89%) <50 4 (21%)2+/FISH- 2 (11%) 50-59 3 (16%)Tumor Grade 60-69 7 (37%)Well Differentiated 9 (47%) 70-79 5 (26%)Moderately Differentiated 8 (42%) Endocrine TherapyPoorly Differentiated 2 (11%) Tamoxifen 3 (16%)Letrozole 16 (84%)Figure 1: Clinical Response by US/Exam0 2 4 6 8 10Partial Response: 9 (47%)Number of PatientsStable Disease: 4 (21%)Progressive Disease: 6 (32%)Figure 2: Correlation of  Pre-Neoadjuvant RS with  Post-Neoadjuvant RSMean change in RS = 2.8 unit (normalized expression, log2 scale)  increase (95% CI 1.1-4.6), p=0.003 from paired t-test0 5 10 15 20 25 30 35 40 45 5005101520253035404550RS from Excisional SpecimenRS from Core Biopsy LOW INTERMEDIATE HIGHPearson r=0.89Clinical Response PR SD PDFigure 3: Correlation of  Pre-Neoadjuvant ER with  Post-Neoadjuvant ERMean change in ER = 0.64 unit (normalized expression, log2 scale) decrease (95%CI 0.32-0.96), p<0.001 from paired t-testTrend toward higher ER in PR vs SD/PD (mean difference= 0.8 units, p=0.064).3 4 5 6 7 8 9 10 11 12 13345678910111213ER from Excisional SpecimenER from Core Biopsy NEGATIVE POSITIVEPearson r=0.87Clinical Response PR SD PDFigure 4: Correlation of  Pre-Neoadjuvant PR with  Post-Neoadjuvant PRMean change in PR = 1.25 unit (normalized expression, log2 scale) decrease (95% CI 0.64-1.86), p<0.001 from paired t-test3 4 5 6 7 8 9 10 11 12 13345678910111213PR from Excisional SpecimenPR from Core Biopsy NEGATIVE POSITIVEPearson r=0.72Clinical Response PR SD PDFigure 5: Correlation of  Pre-Neoadjuvant HER2 with  Post-Neoadjuvant HER2No change in HER2 ([mean change = 0.09 unit (normalized expression, log2 scale]), 95% CI -0.16 to 0.35, p=0.45 from paired t-test3 4 5 6 7 8 9 10 11 12 13345678910111213HER2 from Excisional SpecimenHER2 from Core BiopsyNEGATIVEEQUIVOCALPOSITIVEPearson r=0.77Clinical Response PR SD PD

A Non-randomized, Observational Trial of Short-term Pre-operative Endocrine Therapy in ER Positive Breast Cancer to Investigate Changes in Genomic Expression Using the Oncotype DX® Recurrence Score®

https://scholarlyworks.lvhn.org/cgi/viewcontent.cgi?article=1000&context=pathology-laboratory-medicine

A Non-randomized, Observational Trial of Short-term Pre-operative Endocrine Therapy in ER Positive Breast Cancer to Investigate Changes in Genomic Expression Using the Oncotype DX® Recurrence Score®

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