Triple-negative breast cancer (TNBC) is a heterogeneous group of aggressive breast cancers for which no targeted treatment is available. Robust tools for TNBC classification are required, to improve the prediction of prognosis and to develop novel therapeutic interventions. We analyzed 3,247 primary human breast cancer samples from 21 publicly available datasets, using a five-step method: (1) selection of TNBC samples by bimodal filtering on ER-HER2 and PR, (2) normalization of the selected TNBC samples, (3) selection of the most variant genes, (4) identification of gene clusters and biological gene selection within gene clusters on the basis of String© database connections and gene-expression correlations, (5) summarization of each gene cluster in a metagene. We then assessed the ability of these metagenes to predict prognosis, on an external public dataset (METABRIC). Our analysis of gene expression (GE) in 557 TNBCs from 21 public datasets identified a six-metagene signature (167 genes) in which the metagenes were enriched in different gene ontologies. The gene clusters were named as follows: Immunity1, Immunity2, Proliferation/DNA damage, AR-like, Matrix/Invasion1 and Matrix2 clusters respectively. This signature was particularly robust for the identification of TNBC subtypes across many datasets (n D 1,125 samples), despite technology differences (Affymetrix© A, Plus2 and Illumina©). Weak Immunity two metagene expression was associated with a poor prognosis (disease-specific survival; HR D 2.68 [1.59-4.52], p D 0.0002). The six-metagene signature (167 genes) was validated over 1,125 TNBC samples. The Immunity two metagene had strong prognostic value. These findings open up interesting possibilities for the development of new therapeutic interventions.
Introduction: Adverse effects of chemotherapy on fertility are a critical concern for young breast cancer (BC) patients. Fertility preservation (FP) is currently offered to BC patients, though literature data concerning reproductive outcomes are scarce. Also, very few data are available on whether these procedures are associated with delay to treatment, or whether they impact oncologic outcomes. The objective of our study is to evaluate: (i) efficacy of FP procedures in terms of stored material and pregnancy rates, (ii) safety regarding time from BC diagnosis to chemotherapy, and oncologic outcomes in a large real-life cohort of BC patients. Methods: We retrospectively analyzed medical charts of all consecutive patients aged between 18 and 43 diagnosed with invasive BC between 01/01/2011 and 30/09/2017 and treated with chemotherapy at Institut Curie (Paris and Saint Cloud). Baseline factors (antral follicle count (AFC), AMH), details on fertility preservation procedures, and results (number of frozen oocytes and embryos) were retrieved in 3 academic hospitals (Jean Verdier, Antoine Béclère and Cochin). All medical charts were reviewed in March 2018 to assess time from diagnosis to surgery / chemotherapy, pregnancy outcomes, recurrence and survival. We compared time from first consultation to start of chemotherapy (time diagnosis-to-CT) in case of neoadjuvant chemotherapy (NAC between patients who had or who did not have PF. Results: On 1.390 patients identified, 622 had NAC, 768 had adjuvant CT. Median age at diagnosis was 38.8 y.o. 136 were BRCA mutated. - 264 patients (19%) underwent a FP procedure: In Vitro Maturation (IVM) (58%, n=154); ovarian stimulation protocol (STIM) (31%, n=82); others (10%, n=28). The mean number of oocytes preserved was 5 [0-36] and was not different between IMV and STIM. - Delays from diagnosis to CT were not different in patients who had FP than those who did not, neither in patients with NAC (no FP: 24.1 days VS FP: 22.8, p=0.24) nor in patients with adjuvant CT (no FP: 70.6 days VS FP : 66.8, p=0.11). - 39 patients had at least one pregnancy: 28 spontaneous, 6 without information, and 5 from oocyte/embryo donation. The pregnancy rate was higher in patients in FP group (n=16 ; 6%) than in no FP group (n=23 ; 2%). 3 reused material : 2 without pregnancy and one had a miscarriage. - About oncologic outcomes, 90 patients underwent relapse (6,4%), and this rate was not significantly different in the 2 groups (n=12, 4,5% VS n=78, 6.9%). - Patients with BRCA mutation (BRCAm) had lower AMH (2.9 VS 4.1 ng/mL ; p = 0,03) and antral follicle count (17.6 VS 24 ; p = 0.01). However, there was no difference on the stored material, and pregnancy rate was higher than in patients with no mutation or unkwnown status (7.6 VS 2.6% ; p = 0,01). Conclusion: Pregnancy rate was higher in patients with FP, however majority of pregnancies was spontaneous, and no live birth was observed after material reuse. FP procedures were not associated with delay to treatment. Though bias cannot be excluded, preliminary data do not show an adverse impact of FP on oncologic outcome. Further follow-up is needed. Citation Format: Hamy-Petit A-S, Toussaint A, Sautter C, Coussy F, Donnadieu A, Rouzier R, Saule C, Frank S, Bensen A, Grynberg M, Scarabin-Carre V, Santulli P, Balezeau T, Guerin J, Reyrat E, Jamain C, Hours A, Lecourt A, Reyal F. Fertility preservation in young breast cancer patients: Real life data on 1390 patients treated in the Institut Curie [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-16-02.
Purpose : Lymphovascular invasion (LVI) is a poor prognosis factor in breast cancer (BC), but data on its value in the neoadjuvant setting is scarce. This study evaluates the relationships between post-NAC LVI and prognosis in BC. Methods: We identified 1197 patients with primary BC receiving NAC +/- trastuzumab between 2002 and 2011. Information on LVI in post-NAC surgical specimen was retrieved from review of medical charts. Univariate and multivariate analyses were performed to assess the association of clinical, pathological factors with disease free survival (DFS) and overall survival (OS) was assessed using a cox proportional hazard model. Results: On 1197 tumors, 528 were luminal (44.1%), 375 were triple negative breast cancer (TNBC) (31.3%) and 294 were HER2-positive (24.6%). On post-NAC surgical specimens, LVI was present in 302 (25.2%), absent in 531 (44.4%), and was not mentionned in 364 cases (30.4%). The presence of post-NAC LVI was associated with an impaired DFS (HR=2.17, 95 CI [1.65 - 2.86], p<0.001) and the magnitude of this impact varied by BC subtype (p-value for interaction=0.02), (luminal BC: HR=1.75, p=0.006; TNBC : HR=2.77, p<0.001 ; HER2-positive BC : HR=5.12, p<0.001). Table 1 Univariate analysis and multivariate analysis on DFS (whole population) Univariate Multivariate VariableClassHRClpHRCIpAge< 451 0.35 45-550.82[0.62 - 1.08] >550.87[0.64 - 1.19] Menopausal statuspremenopausal1.04[0.81 - 1.34]0.75 postmenopausal1 BMI class19-251 < 191.24[0.75 - 2.05]0.41 > 251.36[1.06 - 1.75]0.01 Tumor sizeT1-T21 T31.77[1.38 - 2.27]<0.011.77[ 1.32 - 2.38 ]<0.001Clinical nodal statusN01 N1-N2-N31.35[1.05 - 1.72]0.021.43[ 1.07 - 1.91 ]0.016HistologyDuctal1 Other1.24[0.87 - 1.78]0.24 GradeGrade I-II1 III1.24[0.87 - 1.78]0.07 Ki 67<201 >201.54[1.06 - 2.22]0.02 Mitotic index≤221 >221.18[0.9 - 1.53]0.23 DCIS componentno1 yes1.33[0.88 - 2.01]0.18 Pre-NAC LVIno1 yes1.35[0.88 - 2.01]0.09 ER statusnegative1 positive0.72[0.56 - 0.91]<0.01 PR statusnegative1 positive0.66[0.51 - 0.85]<0.01 HER2 statusnegative1 positive0.84[0.62 - 1.14]0.26 BC subtypeluminal1 TNBC1.53[1.17 - 2]<0.012.67[ 1.93 - 3.69 ]<0.001 HER20.99[0.72 - 1.38]0.971.25[ 0.82 - 1.88 ]0.299Post NAC parametersPost-NAC LVI (breast)no1 yes2.17[1.65 - 2.86]<0.012.3[ 1.72 - 3.08 ]<0.001pCRNo pCR1 pCR0,4[0.27 - 0.59]<0.01 Pathological nodal involvement0 1-31.48[1.11 - 1.97]<0.01 ≥4 N+3.13[2.34 - 4.19]<0.01 RCB class01 10.97[0.36 - 2.64]0.96 22.88[1.69 - 4.89]<0.01 35.21[3.01 - 9.02]<0.01 ER: oestrogene receptor PR: progesteron receptor RCB: residual cancer burden Post-NAC LVI was an independent predictor of poor DFS, that overwhelmed the prognostic impact of pathological complete response in all 3 BC subtypes. Post-NAC LVI was also an independent predictor of poor OS in the whole cohort and in all BC subtypes. Table 1 resumes univariate and multivariate analysis on DFS in whole population. Conclusion: Post-NAC LVI is a strong independent prognostic factor associated with poor DFS and OS, that (i) should be systematically mentioned in pathological reports following NAC and (ii) could be used to select high risk patients candidates to second line trials in the post-neoadjuvant window. Citation Format: Hamy-Petit A-S, Lam G-T, Laas E, Darrigues L, Balezeau T, Guerin J, Livartowski A, Sadacca B, Pierga J-Y, Vincent-Salomon A, Bidard F-C, Lerebours F, Brain E, Becette V, Rouzier R, Lae M, Reyal F. Lymphovascular invasion in breast carcinoma following neodjuvant chemotherapy is a strong prognosis factor [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-03-04.
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<0.001) as compared to ER+/PgR- (DFS: HR=2.07 [1.27-3.39]; OS: HR=2.53 [1.3-4.92]) and ER-/PR-; DFS: HR=1.56 [0.98-2.46]; OS: HR: 3.34 [1.87 – 5.97]. In the ER-/PR- group, DFS reached a "plateau" after three years follow-up, while the annual risk of relapse remained constant in the ER+/PR- subgroup. 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, Guinebretière 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.
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