J-M Guinebretière

BIRC5 (survivin): a pejorative prognostic marker in stage II/III breast cancer with no response to neoadjuvant chemotherapy.

PurposeNeoadjuvant systemic therapy (NAC) is currently used in the treatment of stage II/III breast cancer. Pathological complete response as a surrogate endpoint for clinical outcomes is not completely validated for all subgroups of breast cancers. Therefore, there is a need for reliable predictive tests of the most effective treatment.MethodsWe used a combination of predictive clinical, pathological, and gene expression-based markers of response to NAC in a prospective phase II multicentre randomized clinical trial in breast cancer patients, with a long follow-up (8 years). This study concerned the subpopulation of 188 patients with similar levels of pathological response rates to sequential epirubicin/cyclophosphamide and docetaxel to determine predictive marker of pCR and DFS. We used a set of 45 genes selected from high throughput analysis and a standardized RT-qPCR. We analyzed the predictive markers of pathological complete response (pCR) and DFS in the overall population and DFS the subpopulation of 159 patients with no pCR.ResultsIn the overall population, combining both clinical and genomic variables, large tumor size, low TFF1, and MYBL2 overexpression were significantly associated with pCR. T4 Stage, lymphovascular invasion, negative PR status, histological type, and high values of CCNB1 were associated with DFS. In the no pCR population, only lymphovascular invasion and high values of BIRC5 were associated with DFS.ConclusionsWe confirm the importance of ER-related and proliferation genes in the prediction of pCR in NAC-treated breast cancer patients. Furthermore, we identified BIRC5 (survivin) as a main pejorative prognostic factor in patients with breast cancers with no pCR. These results also open perspective for predictive markers of new targeted therapies.

Abstract P2-05-04: Evaluation of intra-tumor heterogeneity, test reproducibility and their impact in breast cancer samples assessed by Prosigna™: Results from a decision impact prospective study and a matched case-control study

Background: Recent molecular biology technologies reveals insight into tumor heterogeneity but quantification and impact on reproducibility of tests is not well known. The objective of this study was to assess the extent to which tumor heterogeneity may affect the prognosis of patients assessed by Prosigna™ (PAM50) gene signature assay compared to test reproducibility. Methods: Reproducibility was measured by testing replicate tissue sections from 186 FFPE breast tumor blocks across 2 sites (Institut Curie, Centre Jean Perrin) following independent pathology review at each site. Consecutive slides came from blocks of patients included in the Decision Impact prospective study which examined whether the Prosigna™ test influences adjuvant treatment decision (Clinical trial information: NCT02395575). To evaluate heterogeneity and its impact in terms of outcome, we selected among T1N0 patients treated in Institut Curie between 2003 and 2008, 32 patients who did recur and 28 matched control group who did not (2 9controls9 recurred during the study). Analyses were performed on two parts of each tumor. NanoString9s Prosigna™ outputs (risk of recurrence (ROR) score, 10 year probability of distant recurrence, risk category, and intrinsic subtype (Luminal A/B, HER2-enriched, Basal-like)) were measured and compared to evaluate heterogeneity (defined as difference in terms of subtype and/or risk category between the two parts) and reproducibility. Correlation between heterogeneity and outcome was performed. Impact was assessed by tumor board analysis. Results: Pearson correlation coefficients for ROR score and probability of distant recurrence predicted were .95 and .97, respectively in the reproducibility study and .82 and .86, in the tumor heterogeneity study. The measured standard deviation (SD) was 5.4 and 8.1 ROR units corresponding to 1.6% and 2.8% in terms of risk of distant metastasis free survival within the reproducibility study and the tumor heterogeneity study, respectively. Kappa coefficients for intrinsic subtype and risk category agreement were 0.88 and 0.87 in the reproducibility study, and 0.67 and 0.58 in the tumor heterogeneity study. Tumor board analysis of discordant cases showed that the impact, in terms of decision of chemotherapy administration, concerns 3% of patients because of reproducibility and 8% because of tumor heterogeneity, comparing favorably with the discordance between Prosigna™ and immunohistochemistry (27%). Probability of distant recurrence was higher in the cases (15%) compared to control (9%) (p=.001) in the tumor heterogeneity study confirming the performance of the Prosigna™ test. Conclusion: We validated in the prospective Decision Impact study the analytical performance of NanoString9s Prosigna™ assay across multiple clinical testing laboratories. We showed in these two studies that tumor heterogeneity has more impact than reproducibility performance. The clinical impact on the decision making based on tumor heterogeneity is however limited, since it does not correlate to outcomes, whereas the Prosigna™ ROR score has been shown to correlate very well to outcomes. Citation Format: Rouzier R, Bonneau C, Cayre A, Hequet D, Gentien D, Bonhomme A, Mouret-Reynier M-A, Dubot C, Cottu P, Roulot A, Morel P, Salomon A, Callens C, Guinebretiere J-M, Penault-Llorca F. Evaluation of intra-tumor heterogeneity, test reproducibility and their impact in breast cancer samples assessed by Prosigna™: Results from a decision impact prospective study and a matched case-control 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 P2-05-04.

Abstract OT2-03-02: DI study: Decision impact of the NanoString® Technologies Prosigna™ in early breast cancers

Backgrounds: More than a decade of research, clinical studies, and peer reviewed publications support the value of molecular subtyping based on gene expression analyses to assess prognosis and treatment options for patients with early-stage breast cancer. Therefore, genomic assays are now being introduced to supplement the conventional diagnostic tools. Prosigna is a standardized test that measures the expression levels of 50 classifier genes in formalin-fixed, paraffin-embedded (FFPE) breast tumor tissue samples and provide a subtype classification based on the fundamental biology of individual patient9s tumor (referred to as molecular subtyping), as well as a prognostic score (referred to as risk of recurrence (ROR) score) that predicts the probability of cancer recurrence over 10 years. The primary objective of this study is to assess the extent to which Prosigna affects the medical oncologist9s treatment recommendations regarding adjuvant chemotherapy and actual treatments received for patients with early-stage breast cancer. Changes will include hormonal therapy alone, hormonal therapy plus chemotherapy, and changes in types of chemotherapy if chemotherapy was recommended before and after the test. Secondary objectives will be to elicit information on investigators9 confidence in the recommendations before and after the test, and by cancer recurrence risk groups, rate of chemotherapy related adverse events stratified by administration of chemotherapy, and patients9 decisional conflict status, anxiety levels, and functional status before and after Prosigna results. Multicentric prospective study. Prosigna will be performed on operative piece for all consecutively postmenopausal women matching the inclusion criteria and having signed an informed consent. Data on patient demographics, disease status, intended cancer-specific postoperative management before and after the test, tests results, investigators and patients9 confidence in the treatment and in the test, will be recorded in the inclusion visit, after the tests results and 6 month post-assay. Inclusion criteria: Postmenopausal patients with resected node-negative, estrogen-receptor-positive, HER2-negative (by the local laboratory) early-stage invasive breast cancer (T1-T2, N0, pN0 (i+), pN1 (micrometastatic), M0), able to give consent, eligible for treatment of breast cancer with adjuvant chemotherapy and with ECOG performance status of 0 or 1. Statistical methods: The clinical and demographic characteristics of the study sample will be described using mean, median, standard deviation, and range for continuous/ordinal variables and frequency and proportion for categorical variables. Bivariate plots and crosstabs will be performed to inspect bivariate associations between variables. The proportion of patients for whom the physicians9 choice of treatment changed from baseline to follow-up will be calculated along with the 95% confidence interval. The change in investigator confidence in treatment recommendations before and after Prosigna results were known will be analyzed by calculating the mean and 95% CI for the question regarding whether a physician is more confidence in treatment recommendation after ordering Prosigna. 47 patients have been included on 200 scheduled. Citation Format: Lerebours F, Hequet D, Guinebretiere J-M, Roulot A, Callens C, Gentien D, Penault-LLorca F, Zilberman S, Salmon R, Foa C, Berseneff H, Huchon C, Katz G, MacDonald M, Morel P, Bieche I, Dubot C, Rouzier R. DI study: Decision impact of the NanoString® Technologies Prosigna™ in early breast cancers. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT2-03-02.

Abstract P1-14-09: Long term survival of locally advanced breast cancers (LABC) treated with neoadjuvant treatment, results of a multicenter randomised phase II study (Remagus 02 trial)

Backgound : The primary analysis of the REMAGUS-02 multicenter randomized phase II trial demonstrated that celecoxib did not improve pCR rates in pts with HER2-negative localized invasive breast cancer (BC), whereas trastuzumab increased pCR rates in HER2-positive ones [Pierga BCRT 2010]. We report here the long-term follow-up results of this trial for disease free survival (DFS) and overall survival (OS). Patients and methods: From May 2004 to October 2007, 340 stage II-III BC patients were randomly assigned to receive 4 cycles (c) of epirubicin–cyclophosphamide q 3 w followed by 4 c of docetaxel q 3 w +/- trastuzumab in HER2 positive pts (120 pts) or +/- celecoxib in HER2 negative pts (n=220). From September 2005, all pts with HER2 positive BC received adjuvant T for a total of 18 c (n=106). Patients with hormone receptors (HR) positive tumor received adjuvant endocrine treatment according to menopausal status Results: With a median follow up of nearly 8 years (94.4 months, 20-127m), 112 relapses and 75 deaths have been observed (median DFS and OS not reached). Eight years DFS and OS were respectively 63 % [57%-71%] and 75 % [70%-81%] in HER2 negative group; and 75% [67%-83%] and 82 % [74%-90%] in HER2 positive group. DFS was significantly higher in HER+ pts than in HER2-(HR: 0.64 [0.42-0.99], p=0.042), whereas OS did not differ significantly (HR: 0.67, [0.41-1.11], p=0.123). In the overall population, progesterone receptor (PgR) positivity was associated with a better DFS (p=0.012) and OS (p In the HER2- subgroup, no effect of neoadjuvant celocoxib was observed on survival, neither in intention to treat (ITT) nor in per protocol analyses. In the multivariate analysis clinical stage (T3/T4 versus T2, HR: 1.92 [1.209 - 3.05], p=0.006), PgR status (positive versus negative HR : 0.52, [0.32-0.84], p=0.007) and pCR (yes vs no, HR : 0.213 [0.066-0.687], p=0.01) were significant predictors of DFS. In the HER2+ subgroup, neoadjuvant versus adjuvant trastuzumab was not significantly associated with DFS, neither in the ITT, nor in the per protocol analysis. Conclusion: Celecoxib was not associated with pCR or survival benefit when added to conventional neoadjuvant CT in Her2-negative BC pts. Lack of PgR expression is a major prognostic factor for survival. Neoadjuvant versus adjuvant trastuzumab increased pCR rates but did not change significantly DFS and OS of HER2 positive BC pts. Citation Format: Giacchetti S, Hamy-Petit A-S, Delaloge S, Brain E, Berger F, Mathieu M-C, de Cremoux P, Bertheau P, Guinebretiere J-M, Saghatchian M, Tembo O, Marty M, Pierga J-Y. Long term survival of locally advanced breast cancers (LABC) treated with neoadjuvant treatment, results of a multicenter randomised phase II study (Remagus 02 trial). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-14-09.

Abstract P3-07-63: Ki67 cut-off point to predict the benefit of adjuvant chemotherapy in ER+ HER2- breast cancer patients

BACKGROUND: The benefit of chemotherapy for patients with estrogen receptor(ER)+ HER2- breast cancers is an ongoing question. The evaluation of the tumor9s proliferation by Ki67 may guide the indication but no consensual predictive cut-off has been set yet. MATERIALS AND METHODS: This study included women with a first ER+HER2- invasive breast cancer treated by primary surgery between 2003 and 2008. Data was collected prospectively. Ki67 cut-off was sequentially set each 1% from 5% to 30%. For each threshold, the interaction between Ki67 and adjuvant chemotherapy was integrated in a multivariate Cox model to determine when it became statistically significant in predicting distant-disease free survival (DDFS). Using different Ki67 cut-offs, we also compared DDFS of patients who had or not an indication of chemotherapy, depending on whether they actually received it or not. RESULTS: Among the 3221 breast cancers, median Ki67 was 10%, with a mean of 15% (S.D = 14). Ki67 was an independent prognosis factor whether the cut-off was set to 14% or to 20% (p CONCLUSION: In ER+ HER2- breast cancers, a Ki67 level of expression >= 20% was predictive of benefit from adjuvant chemotherapy. A threshold at 14% was not as discriminant. Based on this large cohort study, we recommend the use of a cut-off at 20% to decide whether patientes with ER positive tumors should receive chemotherapy or not/. Citation Format: Rouzier R, Rossi L, Lerebours F, Savignoni A, Falcou M-C, Bonneau C, Pierga J-Y, Guinebretiere J-M. Ki67 cut-off point to predict the benefit of adjuvant chemotherapy in ER+ HER2- breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-63.

Abstract P3-06-19: Large-scale retrospective analysis between 1980-2008 in 20 838 women with breast cancer – Results in young women (< 40 years old)

Background: The risk for developing breast cancer before the age of 40 is less than 1% and is similar worldwide. Breast cancer in young women is different from that of older women in terms of clinical and pathological characteristics and prognosis. We reviewed the evolution of breast cancer in young women aged Patients and Methods: Women diagnosed with a first breast cancer were prospectively included in the institution database. The analysis population included all women treated and followed between 1980 and 2008 for new breast cancer. The data were grouped into three periods: 1980-1990 (systematic pre-screening), 1991-2003 (first pilot screening experiences) and 2004-2008 (generalized systematic screening) and per age group comparing women Results: From 1980-2008, there were 20838 new breast cancers diagnosed, including 1431 (6.9%) in women Conclusion: Results of the retrospective analysis of a very large cohort of women less than 40 years diagnosed with breast cancer show that woman Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-06-19.

Abstract P2-11-21: Ipsilateral breast tumor recurrence in patients with operable breast cancer who undergo breast-conserving treatment after receiving neoadjuvant chemotherapy: Validation of the MD Anderson prognostic index

BACKGROUND: A prognostic index, the MD Anderson Prognostic Index (MDAPI), has been developed to help refine selection criteria for breast-conserving therapy after neoadjuvant chemotherapy. This score is based on initial nodal status N2/3, residual pathologic tumor size>2cm, a multifocal pattern of residual disease, and lymphovascular space invasion and ranged from 0 to 4. The objective of the current study was to validate the MDAPI for ipsilateral breast tumor recurrence. METHODS: Our study was a single-center retrospective analysis of a large prospectively collected breast cancer database. We identified data from 355 patients who received neoadjuvant chemotherapy and underwent breast-conserving therapy between 2002 and 2010. Predictive factors of ipsilateral breast tumor recurrence and the usefulness of the MDAPI were analyzed. Discrimitaion of models was also calculated. RESULTS: The median follow-up was 65 months, and the 5-year ipsilateral breast tumor recurrence-free survival rate was 90.7%. 5-year IBTR-free survival were 91.3% and 87.4% in MDAPI 0/1 and MDAPI 2+ categories (p = 0.07). (Multivariate analysis demonstrated that MDAPI (p = 0.01), Ki67 (p = 0.0004) and HER2 status (p = 0.0006) were associated significantly with ipsilateral breast tumor recurrence-free survival. Concordance index of the MDAPI was fair (0.6) but adding HER2 and ki67 status in the model improved concordance index : 0.75. CONCLUSIONS: The MDAPI was barely adaptable to the study patients in terms of predicting ipsilateral breast tumor recurrence. Biological factors such as ki67 and HER2 status should be included in the prognostic model. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-11-21.

Abstract P3-06-04: Role of pMAPkinase, pAKT, p27 & IGF-IR as predictive markers of response to trastuzumab in patients with HER2-positive invasive breast cancer treated with neoadjuvant chemotherapy + trastuzumab in the REMAGUS02 trial

Background: Predicting a benefit from trastuzumab in patients with HER2+ breast cancer remains an important goal. Possible mechanisms of resistance include altered receptor antibody interaction, Akt and MAPK pathways, and loss of p27. The objective of this study was to determine the correlation between pMAPkinase (pMAPK), pAKT, p27, IGF-IR protein expression and the benefit of trastuzumab for patients randomized to chemotherapy (CT) alone and CT with trastuzumab. Patients and methods: From May 2004 to October 2007, 120 patients with stage II and III HER2+ breast carcinomas were enrolled in a phase II trial of neoadjuvant chemotherapy (CT) with epirubicin-cyclophosphamide (4 courses) followed by docetaxel ± trastuzumab (T) (4 courses). A complete pathological response (pCR) was defined by the absence of residual invasive carcinoma in the breast and axillary lymph nodes. A tissue microarray was constructed from paraffin-embedded tumor samples collected prior to neoadjuvant chemotherapy. Patients9 tumours were scored HER2 3+ immunohistochemically (IHC) or 2+ IHC with HER2 amplification by FISH. Immunohistochemical analysis of pMAPK, pAKT, p27 and IGF-IR was performed on tumor tissue microarrays before CT. The H-score (intensity × %) was evaluated. Specimens were classified as exhibiting high or low expression based on a median value as the cut-off point for each marker. A logistic regression model, including the marker and its interaction with treatment, was used to analyse the markers predictive of a treatment effect on the pCR. The independent predictive value was analysed in a multivariate logistic regression adjusting on the lymph node and ER status. Results: 117/120 (97.5%) patients had sufficient tumor for the analysis. The pCR rate was 19% in the CT arm and 25% in the CT+T arm. The median H-score was: pMAPK = 28, pAKT= 25, p27= 50 and IGF-IR = 15. No significant difference was observed in the pCR rate between the two arms according to pAKT, p27, IGF-IR expression. The pCR rate was higher in CT+T compared to CT alone in patients with high pMAPK expression (OR = 4.7 (0.9–24.2); interaction p = 0.03). No difference was observed in the pCR rate in patients with low pMAPK expression (OR = 0.5 (0.1–1.8). Conclusions: In HER2-positive breast cancers, pMAPK expression evaluated by IHC was significantly associated with a pathological response in the arm with neoadjuvant trastuzumab. High pMAPK expression could be a predictive marker of response to trastuzumab in a CT +T regimen. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-04.

Abstract P1-14-18: Overall survival results of a multicenter randomized phase II study in locally advanced breast cancer patients treated with or without celecoxib for HER2 negative tumor (Remagus 02 trial)

Background: Cox 2 is frequently over expressed in breast cancers. Celecoxib is a COX-2 inhibitor with anti angiogenic and pro-apoptotic activities. There are few data of anti-COX2 treatment in breast cancers. and no data on the impact of neoadjuvant anti COX 2 agent on survival. Patients and methods/: From May 2004 to October 2007, 340 stage II-III breast cancer patients were included in a phase II randomized trial and received 4 cycles (c) of epirubicin (75 mg/m2)–cyclophosphamide (750 mg/m2) q 3 w followed by 4 (c) of docetaxel (100 mg/m2) q 3 w. Pts with HER2 negative tumors (220 pts) were randomized to receive or not neoadjuvant celecoxib (200 mg bid) combined with docetaxel. All pts with hormone receptors positive tumor received hormonal treatment according to menopausal status (Pierga et al BCRT 2010). We report here overall survival (OS) and disease free survival (DFS) data and prognostic factors analyses at 5 years. Results/: At a median follow up of 49 months, the median DFS and OS are not reached for the whole population and none of them is significantly different between pts who received celecoxib or who did not (p = respectively 0.62 and 0.36). Celecoxib had no impact either on clinical and pathological complete response rate (pCR). DFS is significantly higher in patients who achieved pCR as compared to those who did not (p = 0.017; RR = 0.21 [0.051–0.88], whereas OS is borderline significant [p = 0.07; RR = 0.19 (0.026–1.4)]. Patients with triple negative (TN) tumors (78 pts) achieved worst DFS (p = 0.02) and OS (p Conclusion/: Celecoxib had no influence on pCR, DFS or OS. Despite higher pCR rate triple negative breast cancer patients9 subgroup remains with the poorest outcome. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-14-18.

Les lésions de métaplasies cylindriques atypiques diagnostiquées sur biopsie mammaire

Among pre-invasive breast diseases, the lesion of flat epithelial atypia has a level of risk that remains unclear. The clinical significance of these lesions and how to behave during their diagnostic biopsy (monitoring vs. surgery) are still uncertain, because few studies (including monitoring) are available and because of the polymorphic spectrum of lesions and their many denominations across the studies in the literature. This article aims to update our knowledge and provide elements for the management of these lesions diagnosed on breast biopsy.