CCNE1 mRNA and cyclin E1 protein expression as predictive biomarkers for efficacy of palbociclib plus fulvestrant versus capecitabine in the phase III PEARL study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1014-1014
Author(s):  
Javier Pascual ◽  
Miguel Gil-Gil ◽  
Christoph Zielinski ◽  
Margaret Hills ◽  
Manuel Ruiz-Borrego ◽  
...  
Keyword(s):  
Protein Expression ◽  
Cox Regression ◽  
Statistical Significance ◽  
Predictive Biomarkers ◽  
Phase Iii ◽  
Relative Resistance ◽  
Luminal A ◽  
Luminal B ◽  
Cyclin E1 ◽  
E1 Protein

1014 Background: The randomized PEARL trial found no superiority of palbociclib plus endocrine therapy over capecitabine in patients (pts) with metastatic HR-positive, HER2-negative breast cancer resistant to prior aromatase inhibitors (Martin M, Ann Oncol 2020). Gene expression analysis showed high CCNE1 mRNA ( CCNE1) conferring relative resistance to palbociclib in the PALOMA-3 trial (Turner N, JCO 2019), but further validation is needed. Cyclin E1 protein (cyclin E1) expression in this context has not been studied in randomized trials. We explored CCNE1 and cyclin E1 as predictive biomarkers in tumor samples from the PEARL study. Methods: Formalin-fixed paraffin-embeded tumor samples were retrieved from pts enrolled in PEARL cohort 2 (palbociclib (PAL) + fulvestrant (FUL) vs capecitabine (CAPE)). We measured CCNE1 using the HTG EdgeSeq Oncology Biomarker Panel (HTG Molecular Diagnostics). Cyclin E1 immunohistochemistry (IHC) staining was performed using specific mouse monoclonal antibody HE12 (Abcam) and scored as percentage of invasive nuclei stained (0-100%). CCNE1 and cyclin E1 correlations were explored using Pearson coefficients. Cox regression models were used for progression free-survival (PFS) analyses using expression levels split by median, to define high ( > median values) vs. low expression. Site of disease and prior chemotherapy were used as confounders in multivariate models. Results: Analyses were conducted in 219 pts (47% receiving PAL + FUL and 53% CAPE) with available tumors, with the analysed patients representative of the overall study. Most samples were from the archival primary (72%), obtained > 5 years before this analysisº (74%). CCNE1 and cyclin E1 were only moderately correlated (r = 0.5). Median CCNE1 was higher in metastatic vs primary (7.37 vs 6.94, p < 0.01), and in luminal B and non-luminal subtypes compared to luminal A (p < 0.001). In patients with high CCNE1 expression, median PFS on CAPE was 10.35 and PAL + FUL was 5.68 (HR = 1.63, 95% CI 1.02-2.59, p = 0.042). In patients with low CCNE1 expression, median PFS on CAPE was 9.43 and PAL + FUL was 8.97 (adjusted HR = 0.93, 95% CI 0.59-1.48, p = 0.762, interaction p = 0.072). Median cyclin E1 protein was higher in luminal B and non-luminal subtypes compared to luminal A (p < 0.01). Cyclin E1 protein expression was not predictive of treatment effect (high cyclin E1 expression CAPE vs PAL + FUL HR = 1.17, low cyclin E1 expression CAPE vs PAL + FUL HR = 1.21, interaction p = 0.977). Conclusions: High tumor CCNE1 mRNA expression identified patients with relative resistance to palbociclib plus fulvestrant, validating prior observations although without statistical significance for interaction. Assessment of Cyclin E1 protein expression did not show predictive value. Investigation treatments to enhance CDK4/6 inhibitor efficacy in tumors with high CCNE1 expression is warranted. Clinical trial information: NCT02028507 .

Breast cancer molecular subtypes association with clinical outcomes and race.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e12575-e12575 ◽  
Author(s):  
Ramses F. Sadek ◽  
Li fang Zhang ◽  
Houssein Talal Abdul Sater
Keyword(s):  
Breast Cancer ◽  
Black Women ◽  
Clinical Outcomes ◽  
Cox Regression ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Cancer Stage ◽  
Luminal A ◽  
Luminal B ◽  
Race Disparity

e12575 Background: Breast Cancer (BC) has been classified into four subtypes: Luminal A (LABC), Luminal B (LBBC), Triple negative (TNBC) and HER2-enriched (HER2e). BC mortality in Black women is significantly higher than in Whites and Asians. BC in Blacks has been characterized by higher grade and later stage. Causes of the Black-White BC survival disparity have been investigated, including differences in: diagnostic stage, socioeconomics, and comorbidities. These have led researchers to investigate the differences in tumor molecular subtype and their association with clinical outcomes and races. Methods: This study used the Surveillance, Epidemiology, and End Results – 18 (SEER-18) Registries research data between 2010 and 2013 that included over 212,000 patients. Descriptive statistics, Odds ratios (OR) and 95%Confidence intervals (CI) were used to study the association between BC stage, grade, and mortality and BC molecular subtypes across different races. We employed Cox regression models to explore the race disparity in BC mortality before and after controlling for BC molecular subtype and other clinical and social factors. Results: TNBC had more high grade cancer compared to HER2e subtype (OR, 1.5; CI, 1.3 - 1.8), LBBC (OR, 4.5; CI, 4.0 - 5.0) and LABC (OR, 12.2; CI, 11.2 – 13.3) for Black. BC mortality was higher in TNBC subtype compared to HER2e subtype (OR, 1.3; CI, 1.1 - 1.6), LBBC (OR, 2.4; CI, 2.0 - 2.9), and LABC (OR, 2.8; CI, 2.4 – 3.2) for Blacks. Results are consistent for all races. HER2e subtype had more late cancer stage compare to LBBC (OR, 1.2; CI, 1.0 - 1.4), TNBC (OR, 1.4; CI, 1.2 - 1.6) and LABC (OR, 2.1; CI, 1.8 - 2.4) in Blacks with similar results in all races. BC mortality in Blacks was higher compare with Whites (HR, 1.9; CI, 1.8 - 2.0) and Asian (HR, 2.7; CI, 2.5 - 3.0). After controlling for cancer subtype and other factors in the Cox regression model, the corresponding HRs ware significantly decreased to 1.2 (CI, 1.1 -1.3) and 1.6 (9CI, 1.5 -1.8). Blacks have heighst percent in stage IV and grade higer grade of disease. Conclusions: Molecular subtypes of BC contribute differently to risks of late cancer stage, high cancer grade and BC specific mortality. These differences are consistent in all races. The molecular subtypes and other social and clinical factors may explain part of the BC mortality race disparity.

Event-free survival analysis of the prospectively randomized phase III ETNA study with neoadjuvant nab-paclitaxel (nab-P) versus paclitaxel (P) followed by anthracycline regimens in women with HER2-negative high-risk breast cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 515-515 ◽  
Author(s):  
Luca Gianni ◽  
Mauro Mansutti ◽  
Antonio Anton ◽  
Lourdes Calvo Martínez ◽  
Giancarlo Bisagni ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Statistical Significance ◽  
Secondary Endpoint ◽  
Phase Iii ◽  
Primary Therapy ◽  
Event Free Survival ◽  
Open Label ◽  
Serious Adverse Events ◽  
Free Survival ◽  
Luminal B

515 Background: The ETNA study showed that substituting P with nab-P did not significantly increase the overall rate of pathological complete response (pCR) (P 18.6%, nab-P 22.5%, p = 0.19). The multivariate analysis revealed that tumor subtype (triple negative vs luminal B-like) was the most significant factor (OR 4.85) influencing treatment outcome (Gianni L et al, JAMA Oncol 2018). Methods: This multicenter open label study (NCT01822314) in collaboration with GEICAM and BCRC-WA randomized 695 patients with centrally-confirmed HER2-negative breast cancer to nab-P 125 mg/m2 (346 patients) or P 90 mg/m2 (349 patients). The two drugs were given on weeks 1, 2 and 3 followed by 1-week rest for 4 cycles before 4 cycles of an anthracycline regimen as per investigator choice. The primary endpoint was pCR (absence of invasive cells in breast and nodes). A secondary endpoint is event-free survival (EFS) defined as the time from randomization to the first date of disease progression while on primary therapy or disease recurrence (local, regional, distant, invasive contralateral breast cancer) after surgery or death due to any cause. Results: The ITT analysis of the secondary endpoint EFS at 5 years is reported below: Clinical trial information: NCT01822314. Overall 5-year survival was 84.8% after P and 87.3% for nab-P. No serious adverse events were documented during the follow-up. Conclusions: The improved 5-year EFS after nab-P failed to reach statistical significance (unadjusted P = 0.245). In the analysis by subgroup the numerical improvement was almost exclusively observed in luminal B and not in TN tumors. So far the data do not support substitution of P with nab-P in the schedule and doses adopted in the ETNA trial. Additional analyses will be based on ongoing molecular studies.[Table: see text]

Analysis of mismatch repair (MMR) proteins expression in a series of malignant pleural mesothelioma (MPM) patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20062-e20062
Author(s):  
Susana Cedres ◽  
Santiago Ponce Aix ◽  
Ana Callejo ◽  
Nuria Pardo ◽  
Alejandro Navarro ◽  
...  
Keyword(s):  
Protein Expression ◽  
Survival Data ◽  
Cox Regression ◽  
Asbestos Exposure ◽  
Performance Status ◽  
Predictive Biomarkers ◽  
University Hospital ◽  
Tumor Biomarker ◽  
Neutrophil Lymphocyte Ratio ◽  
Mmr Proteins

e20062 Background: The increasing incidence and poor outcome associated with MPM demand identification of effective treatment options. Promising results have been reported with immunotherapy (IO) in a small proportion of MPM patients (p). MMR deficiency (dMMR) has been well described in several malignancies and was recently approved as a tumor biomarker for IO with anti-PD-1 checkpoint inhibitor. Next generation sequencing (NGS) data demonstrated that 2% of MPM harbor microsatellite instability. The aim of this study is to characterize MMR by immunohistochemistry (IHC) in a series of MPM p. Methods: Tumors of 159 MPM p from Vall d´Hebron University Hospital and October 12th University Hospital diagnosed between 2002 and 2017 were reviewed. Formalin-fixed, paraffin-embedded tissue was stained for MLH1, MSH2, MSH6 and PMS2 and tumors were classified as dMMR when any MMR protein expression was negative and MMR intact when all MMR proteins were positively expressed. Associations between clinical variables and outcome were assessed with Cox regression models and survival data were calculated by the Kaplan-Meier method. Results: P characteristics: median age: 69 years (29-88 years), males: 71%, performance status (PS) 1:69%, asbestos exposure: 52%, stage III at diagnosis: 42%, epithelial subtype: 65%, systemic treatment 81% (57% chemotherapy with cisplatin plus pemetrexed in first line), 50% received second line and 28% third line. MMR protein expression was analyzed in 158 samples with enough tissue and was positive in all of the cases. The median overall survival (mOS) in all population was 15 months (m) (13.5-18.8m). In a multivariate model factors associated to improved mOS were PS 0 vs PS2 (13 v 2 m, HR 12.8, p < 0.01), neutrophil-lymphocyte ratio (NLR) < 5 (18 v 9 m in NLR ≥5,HR 1.5, p < 0.05) and epitheliod vs sarcomatoid histology (18 vs 4 m HR 4.7, p < 0.01). Thirteen p received IO with anti-CTLA4 or anti-PD-1 blockade in clinical trials, 58% had a response or stable disease for more than 6 m, with median progression-free survival (PFS) of 5.7 m (2.1-26.1m). Conclusions: In our series we were unable to identify any MPM patient with dMMR by IHC. Further studies are needed to elucidate novel predictive biomarkers benefit from IO in MPM.

GAIN-2: Neo-/adjuvant phase III trial to compare intense dose-dense chemotherapy (CT) to tailored dose-dense CT in patients (pts) with high risk early breast cancer (EBC): Results on safety and interim invasive disease-free survival (iDFS).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 516-516
Author(s):  
Volker Moebus ◽  
Hans-Joachim Lueck ◽  
Ekkehart Ladda ◽  
Peter Klare ◽  
Marcus Schmidt ◽  
...  
Keyword(s):  
High Risk ◽  
Cranial Nerves ◽  
Disease Free Survival ◽  
Hazard Ratio ◽  
Phase Iii ◽  
Rank Test ◽  
Luminal A ◽  
Luminal B ◽  
Grade 3 ◽  
Dose Dense

516 Background: GAIN-2 (NCT01690702) compared efficacy and safety of intense, dose-dense epirubicin, nab-paclitaxel, and cyclophosphamide (iddEnPC) vs dose-dense, dose-tailored epirubicin/ cyclophosphamide followed by dose-dense, dose-tailored docetaxel (dtEC-dtD) as adjuvant or neoadjuvant CT for node-positive or high risk node-negative EBC. Here, we report safety results and interim analysis (IA) of the primary endpoint iDFS. Methods: Pts (luminal A ≥N2; luminal B N+; HER2+ and TNBC) were randomized between iddEnPC (E 150 mg/m2, nP 330 mg/m2, C 2000 mg/m2, all q2w x 3) or dtEC-dtD (dtEC q2w x 4 followed after 1 week rest by dtD q2w x 4). Primary objective was to compare iDFS. 797 events are needed to detect a hazard ratio of 0.819 with a 2-sided log-rank-test with 80% power and α=0.05. The IA of iDFS was planned after 50% of the events have occurred. Safety and compliance were secondary objectives. Results: Between 10/2012 and 09/2018, 2887 pts were randomized and 2857 started treatment (iddEnPC 1429; dtEC-dtD 1428). Median age was 51 (range 18-75) years. Overall, 18.1% were luminal A, 31.5% luminal B/HER2-, 18.8% hormone-receptor (HR)+/HER2+, 8.5% HR-/HER2+ and 23.2% TNBC. Overall, 88.1% of pts completed all treatment in both arms. 66.8% with iddEnPC vs 58.8% with dtEC-dtD delayed CT dose (p<0.001). Grade 3-4 non-hematological adverse events (AEs) were more frequent with iddEnPC (iddEnPC 50.8% vs dtEC-dtD 45.1%, p=0.002). Grade 3-4 leukopenia, neutropenia, febrile neutropenia, arthralgia, and peripheral sensory neuropathy were significantly higher with iddEnPC. There were 1464 serious AEs (iddEnPC 870 vs dtEC-dtD 594) and 26 (9 vs 17) predefined AEs of special interest (anaphylaxis, any AE affecting cranial nerves, macula edema). Two deaths occurred during dtEC-dtD. After a median follow-up of 45.8 months, there was no difference in iDFS between arms (log-rank p=0.9102, hazard ratio iddEnPC vs dtEC-dtD 1.01, 95% CI 0.83-1.23). Conclusions: No new safety concerns were observed. Use of both iddEnPC and dtEC-dtD appears feasible in the (neo)adjuvant treatment of high risk EBC. Clinical trial information: NCT01690702 .

Tailored endpoints: A proposal for design of future clinical trials in metastatic breast cancer (MBC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13058-e13058
Author(s):  
Caterina Fontanella ◽  
Marta Bonotto ◽  
Pamela Driol ◽  
Francesca Valent ◽  
Lorenzo Gerratana ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Metastatic Breast ◽  
New Drugs ◽  
University Hospital ◽  
Phase Iii ◽  
Consecutive Series ◽  
First Line ◽  
Luminal A ◽  
Her2 Positive ◽  
Luminal B

e13058 Background: Widespread access to active agents against MBC has produced significant improvements in survival, even though few phase III trials are powered to detect overall survival (OS) effects. However, regulatory agencies hold OS as gold standard for approval of new drugs. OS can be portioned into the sum of progression-free survival (PFS) and survival post-progression (SPP). Recent data suggest that OS is a reasonable primary endpoint only when median SPP is short. On the other hand, patients enrolled in first-line trials could have a long life-expectancy. Aim of this study was to evaluate PFS, OS and SPP in a consecutive series of patients with MBC in order to obtain information as a basis for design of future clinical trials. Methods: Four hundred patients with MBC diagnosed from January 2004 to February 2011 at University Hospital of Udine, Italy, were included in the study. We examined the role of potential of disease and patients’ characteristics in influencing the different measures of outcome. Results: Median OS was 33.71 months (mo), in line with the best literature. Median PFS at first-line (PFS1) was 9.33 mo, with linear decrease at second (5.06), third (3.58), and fourth (3.19) line, respectively. Median SPP after first-line (SPP1) was 18.69 mo. Interestingly, differences in outcome were noticed according to immunophenotype. The best prognosis was observed in luminal A disease (OS= 46.72 mo, PFS1= 15.61 mo, SPP1= 25.43 mo). In luminal B disease, median OS was 27.66 mo, PFS1 8.94 mo, and SPP1 13.21 mo, respectively. In patients with HER2-positive disease, mainly treated with anti-HER2 therapy, outcome approached that of luminal A disease (OS= 41.10 mo, PFS= 9.89 mo, SPP1 18.69 mo). Patients with triple negative disease (TNBC) experienced the worst prognosis (OS= 8.54 mo, PFS1= 4.04 mo, SPP1= 2.83 mo). Conclusions: The study demonstrated different results in the measures of outcome according to the line of treatment and specific disease characteristics. As a consequence, endpoints of clinical trials should be tailored taking into consideration prognostic/predictive factors as well as the line of treatment.

scholarly journals KK-LC-1 May Be An Effective Prognostic Biomarker for Gastric Cancer

2020 ◽  
Author(s):  
Jun Ji ◽  
Jiahui Chen ◽  
Anqiang Wang ◽  
Yang Liu ◽  
Leping Li
Keyword(s):  
Gastric Cancer ◽  
Overall Survival ◽  
Protein Expression ◽  
Cox Regression ◽  
Statistical Significance ◽  
Good Prognosis ◽  
Chi Square ◽  
S Protein ◽  
Cox Regression Analysis ◽  
Linear Association

Abstract Background: To detect the protein expression of Kitakyushu lung cancer antigen 1 (KK-LC-1) in gastric cancer (GC) specimens, and to analyze the linear association of KK-LC-1 protein expression with clinical pathological data and prognosis.Methods: A total of 94 patients in this study were all GC patients with surgical resection. KK-LC-1’s protein expression in GC tissue was detected by immunohistochemistry. This report applies Histological score (H-score) to evaluate KK-LC-1’s expression. Chi-square test, Kaplan-Meier method and Cox regression were used to analyze the linear association between KK-LC-1 expression and clinicopathological data and prognosis.Results: KK-LC-1’s protein expression in the cytoplasm of tumor tissue was found to be significantly higher than that in normal tissue (P <0.001). If we apply the median value of H-value as the cut-off point, it suggests that overall survival for GC patients with high KK-LC-1 expression levels in the cytoplasm was good (P = 0.016), and still had statistical significance after Cox regression analysis. At the same time, the study found that there was a negative correlation between KK-LC-1’s protein expression and the pathological grade of the tumor (P = 0.036).Conclusions: Our research data shows that KK-LC-1’s expression in GC is higher than that of normal tissues, which is associated with a longer overall survival in GC. KK-LC-1 can be used as a biomarker for GC patients with good prognosis.

scholarly journals Clinicopathologic Features and Survival Analysis of Non-metastatic Breast Cancer Patients in Guatemala

2020 ◽  
pp. 111-118
Author(s):  
Hugo Castro-Salguero ◽  
Luis García Aceituno ◽  
Alba Kihn ◽  
Raúl Jiménez ◽  
Allan Ramos-Esquivel
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Cox Regression ◽  
Clinical Stage ◽  
Metastatic Breast ◽  
Developed Countries ◽  
Clinicopathologic Features ◽  
Breast Cancer Patients ◽  
Luminal A ◽  
Luminal B

Background: Breast cancer (BC) is a leading cause of cancer related death worldwide. Unfortunately, data concerning clinicopathologic features of this malignancy in non-developed countries is scarce. This study aims to characterize a cohort of Guatemalan female patients with non-metastatic BC and to determine risk factors for overall survival (OS).Methods: We retrieved data on consecutive patients from the Instituto Guatemalteco de Seguridad Social that were treated from 2008 to 2014. Clinical features and long-term outcomes were retrieved from medical records. Univariate and multivariate Cox regression analyses were conducted to identify variables associated with OS. Results: 954 BC patients were identified during the time frame. A total of 436 women (46%) were younger than 50 years old. BC molecular subtypes categorized 537 patients (56.3%) with luminal A disease, 186 (19.5%) patients with triple negative tumors, 153 cases (16.1%) with HER-2 enriched tumors, and 78 patients (8.2%) with luminal B tumors. Clinical stage at presentation was stage I: 4.7% (n=45); stage II: 48.1% (n=459), and stage III: 47.2% (n=450). The overall 5-year survival rate was 75.2% (95% Confidence Interval: 72.0–78.3). In the multivariate analysis clinical stage, triple negative tumors and HER2 enriched tumors were independently associated with poor survival.Conclusion: The majority of patients with non-metastatic BC are diagnosed with advanced disease and many of them are younger than 50 years old. OS in this cohort of Guatemalan patients is lower than that reported in developed countries.

Quantitative hormone receptors, triple-negative breast cancer (TNBC), and molecular subtypes: A collaborative effort of the BIG-NCI NABCG.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1008-1008 ◽  
Author(s):  
Maggie Chon U. Cheang ◽  
Miguel Martin ◽  
Torsten O. Nielsen ◽  
Aleix Prat ◽  
Alvaro Rodriguez-Lescure ◽  
...  
Keyword(s):  
Hormone Receptors ◽  
Tumor Biology ◽  
Intrinsic Subtype ◽  
Phase Iii ◽  
Her2 Status ◽  
Luminal A ◽  
Exact Test ◽  
Borderline Cases ◽  
Luminal B ◽  
Three Phase

1008 Background: Most TNBC trials focusing on biology of the basal-like subtype (BLBC) allow borderline (1-10% staining) estrogen receptor (ER) and progesterone receptor (PgR) expression by immunohistochemistry (IHC); however the optimal ER and PgR cut points to enrich for non-luminal subtypes has not been studied. In this study,we compared quantitative ER/PgR status with gene expression-based intrinsic subtype in order to determine if borderline cases should be included in TNBC trials. Methods: ER, PgR, and HER2 status was determined by central review of tumors collected from three phase III randomized trials: GEICAM 9906 (n=820), NCIC CTG MA.5 (n=476) and MA.12 (n=398). PAM50 intrinsic subtyping (BLBC, HER2-enriched, Luminal A, Luminal B and Normal-like) was performed using the qRT-PCR-based assay. Quantitative ER/PgR expression by IHC and subtype was tested using ANOVA and Fisher’s exact test. Results: Of 1,694 tumors, 15% were BLBC, 21% HER2-Enriched, 33% Luminal A, 25% Luminal B and 4% Normal-like. BLBC subtypes were significantly associated with low expression of ER and PgR (median = 0.05%) compared to other subtypes (p < 0.001). The vast majority of BLBC (96%) did not express any ER or PgR protein by IHC. BLBC represented 73% of TNBC (borderline cases not included) and significantly more than the additional TNBC with borderline ER/PgR (p < 0.001). Within borderline ER/PgR and HER2-negative cases only, 17% were BLBC and 46% were luminal subtypes (Table). Conclusions: BLBC rarely express ER or PgR by IHC. The majority of borderline TNBC (1-10% ER/PgR) are not BLBC; half of them are categorized as luminal categories that may be endocrine sensitive. TNBC trials seeking to target BLBC tumor biology should use the ASCO/CAP guidelines of 0% as the cutoffs for ER and PgR negativity. [Table: see text]

ESR1 gene amplification and protein expression in 946 patients with resected breast cancer: A Hellenic Cooperative Oncology Group (HeCOG) translational research study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 592-592
Author(s):  
George E. Pentheroudakis ◽  
Anna Batistatou ◽  
Urania Dafni ◽  
Mattheos Bobos ◽  
Eleftheria Tsolaki ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Expression ◽  
Gene Amplification ◽  
Cox Regression ◽  
Phase Iii ◽  
Gene Gain ◽  
Clinicopathologic Characteristics ◽  
Cox Regression Analysis ◽  
Allred Score ◽  
Esr1 Gene

592 Background: Discrepant data have been reported on the incidence of ESR1 gene amplification in breast cancer, its correlation to clinicopathologic characteristics and its impact on prognosis. Methods: Formalin-fixed paraffin-embedded (FFPE) tumor tissue samples from 946 patients participating in two adjuvant chemotherapy phase III trials (HE10/97 and HE10/00) were centrally assessed in tissue microarrays by immunohistochemistry (IHC) for estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER2). FISH was also performed for HER2, TOP2A and ESR1 using commercially available dual (for ESR1) and triple (for HER2 and TOP2A) hybridization probes. Results: The majority of patients had >T2 (69%), node-positive, ER-positive (>1% stained cells, 73%) tumors managed with resection, chemotherapy and hormonotherapy (76%). Only 38 tumors (4.0%) had ESR1 gene amplification (ESR1/CEN6 ratio >2) and 514 (54.3%) ESR1 gene gain (1<ratio<2). The number of ESR1 gene copies was 3-4 in 251 (26.5%) and 5-10 in 42 (4.4%) of cases. HER2 and TOP2A gene amplification was seen in 234 (25.3%) and 101 (10.9%) of tumors, respectively. We studied the immunohistochemical expression of ER protein by evaluating the percentage of stained cells, the Allred score (0-2, 26.8%; 3-6, 62.5%; 7-8, 10.7% of tumors) and the semiquantitative H-Score (50-100, 13.8%; 101-200, 36.8%; 201-300, 15% of tumors). ESR1 gene amplification was significantly associated with taxane therapy, age >50, postmenopausal status, grade III-IV, absence of HER2 amplification and ER protein expression (p<0.05). At a median follow-up of 92 months, univariate Cox regression analysis showed that ER protein expression, but not ESR1 gene status, was a predictor of favorable outcome. In multivariate analysis, tumor size >5 cm, >4 involved nodes and negative/low ER protein expression by Allred score were independent adverse prognostic factors. Conclusions: Our data showed a rather low incidence of ESR1 gene amplification and failed to confirm its prognostic/predictive utility. ESR1 mRNA expression data will be presented at the meeting.

Genomic-based predictive biomarkers to anti-HER2 therapies: A combined analysis of CALGB 40601 (Alliance) and PAMELA clinical trials.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 571-571 ◽  
Author(s):  
Aranzazu Fernandez-Martinez ◽  
Maki Tanioka ◽  
Cheng Fan ◽  
Joel S. Parker ◽  
Katherine A. Hoadley ◽  
...  
Keyword(s):  
Gene Expression ◽  
Clinical Trials ◽  
Predictive Biomarkers ◽  
Specific Gene ◽  
Mrna Levels ◽  
Clinical Implementation ◽  
Luminal A ◽  
Her2 Positive ◽  
Luminal B ◽  
Erbb2 Mrna

571 Background: In HER2-positive breast cancer, new biomarkers of response are needed in order to direct multi-agent anti-HER2 combinations towards patients in whom they are truly needed. CALGB 40601 and PAMELA trials tested neoadjuvant dual HER2 blockade and included gene expression analysis aimed to evaluate different genomic biomarkers of trastuzumab and/or lapatinib benefit. Methods: Gene expression by mRNA sequencing (RNAseq) was performed on 265 and 142 pre-treatment tumors of the CALGB 40601 and the PAMELA clinical trials respectively. Intrinsic subtypes were determined by nCounter PAM50-predictor on the PAMELA samples. A new HER2-positive specific gene-centering method was trained on the PAMELA RNAseq data, and showed a higher concordance with PAM50 predictions obtained from nCounter platform. This method was then applied to CALGB 40601 samples. Results: In the combined cohort, the subtype distribution was 10% Luminal A, 8% Luminal B, 62% HER2-enriched (HER2-E), 10% Basal and 10% Normal-like. The pCR rate was significantly higher in HER2-E vs. not HER2-E subtypes (48.6% vs. 20.7%; P < 0.001). HER2-E subtype correlation, ERBB2 amplicon and B-cell genomic signatures were associated with pCR, while luminal signatures were associated with non-responders. In multivariate analysis HER2-E subtype, ERBB2 mRNA and IgG signature expression were independent predictors of response to paclitaxel + trastuzumab +/-lapatinib (OR = 1.98, OR = 1.51, OR = 1.48, respectively, P <0.05). The event free survival analysis at 5 years in the CALGB 40601 cohort showed a benefit of dual vs single anti-HER2-blockade (HR 0.35, P <0.05). Within the HER2-E, ERBB2-high and IgG–high subpopulations, there were also a benefit of dual vs. single anti-HER2 treatment (HR = 0.32, HR = 0.15, HR =0.15, respectively, P <0.05). Conclusions: Intrinsic subtype, ERBB2 mRNA levels, and IgG genomic signature are independent predictive biomarkers of response in the combined cohort. The clinical implementation of these biomarkers could help to design future escalation/de-escalation clinical trials in the HER2-positive neoadjuvant setting. Support: U10CA180821, U10CA180882, U24CA196171, P50-CA58223, GSK, SPORE, BCRF and SEOM. https://acknowledgments.alliancefound.org .

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