The randomised phase II NeoPAL study (NCT02400567) compared neoadjuvant letrozole-palbociclib (LP) to chemo (CT) in 103 patients with early high-risk PAM50-defined luminal BC. Clinical activity was similar in both arms. We report the pre-specified translational analysis. We compared baseline (BL) and surgical tumor samples expression of Ki67, cell cycle proteins and immune cell markers by central IHC, DNAseq, gene expression by the Nanostring nCounter BC360™ panel, and 3'mRNA sequencing (RNA-Seq) with BayesPrism cell type deconvolution. By IHC, BC360 signatures and RNA-Seq, no difference was observed between the BL samples of both arms. Median Ki67 was significantly reduced at surgery in both arms [LP: 27.5% (IQR 20-40) to 1% (IQR 0-5), p<.0001) and was lower in the LP than in the CT arm (median 1% (IQR 0-5) vs 5% (IQR 2-15), p=.0001). Similar reductions were seen in pRb and CCND1 Hscores in each arm. At surgery, the BC360 proliferation signature was reduced in both arms along most of the initially upregulated pathways, while the upregulated BC360 signatures were almost all immune-related (all p<.01). Active immune cell recruitment was confirmed by IHC after both therapies. No DNAseq changes were observed with LP therapy. Deconvolution of bulk RNA-Seq data using a finely annotated single-cell cellular atlas revealed enrichment of cancer cells, immunosuppressive cancer-associated fibroblasts, FOXP3+ CD4+ regulatory T cells and TREM2+ macrophages at BL. In contrast, myoepithelial cells, normal-like fibroblasts, FOLR2+ macrophages and SELL+ CD4+ T cells accumulate after treatment (p values: .046 to 7.2e-07). Strikingly, all these changes were almost identical between the LP and CT arms. Finally, a low ROR score was observed at surgery in 60% and 40% of patients in the LP and CT arms, respectively (p=.064). In these patients, no 3-year breast cancer-specific survival event was observed. This comprehensive analysis strongly suggests that LP has as profound an effect on luminal tumours as chemotherapy, with regard to proliferation decrease, immune attraction and stromal changes associated with tumor response. These results provide rationale for future chemo-sparing studies in high-risk luminal breast cancer.

ER+/Her2- breast cancer (BC) is associated with lower rate of Tumor-infiltrating lymphocytic (TILs), especially CD8+ T cells. We hypothesized that attracting CD8+ T cells on the tumor site could sensitize ER+/Her2- BC to anti-PD(L)1. Post-menopausal patients (pts) with cT2-T4 (>3cm), N0 or N+, M0 BC and Luminal A tumor defined by IHC (grade I-II, ER+ ≥ 60%, Ki67 <20%, and Her2-) have been enrolled to receive a single infusion of tremelimumab (3 mg/kg) with exemestane. After 3 weeks, pts with CD8+ T cells >10% in the tumor were enrolled in the part 2 and treated for 6 months with durvalumab 1500 mg Q4W IV and exemestane. The primary objective was the pathological response (pCR) at surgery in the CD8+ T cells enriched population. Out of the initially 96 pre-screened pts, 61 were included in part 1. Of them, 24 (39.3%) with CD8+ T cell >10% in the tumor after 3 weeks were enrolled in part 2: median age 66 years (61-71), lobular type 7 pts (29.2%), T3 or T2 tumours in 18 (75.0%) and 6 (25.0%) patients, respectively, 16 (66.7%) with N0 disease. Among the 22 pts evaluable for pCR, 1 pt (4.6%; CI 95%: 0.2% - 19.8%) achieved a pCR. The futility criterion was met and the study was stopped. An increase in CD8+T cells by 10.8% (95% CI: 6.8 – 14.7) and 4.8% (95% CI: 0.7 – 8.9) was observed between baseline and week 3 and surgery, respectively. Mean Ki67 level decreased by 6.0% (95% CI: -8.8; -3.3) and 7.0% (95% CI: -10.5; -3.4) between baseline and week 3 and surgery, respectively. TILs increased by 4.7% (95% CI: 0.7 – 8.6) and 3.8% (95% CI: -0.4 – 8.0) between baseline and week 3 and surgery, respectively. During part 1, 38 pts (22%) experienced adverse events (AEs), including 6 (15.8%) grade 3 AEs (colitis and liver enzyme elevation). In part 2, 20 pts (83.3%) developed AEs including 9 (45%) grade 3. Main grade 3 AEs included diarrhea, hypothyroidism, liver enzyme elevation and 1 pneumonitis. Despite an encouraging increase in CD8+ T cells, durvalumab combined with exemestane did not demonstrate significant efficacy, as indicated by the low pCR rate. Ongoing ancillary studies may provide further insights into the immune landscape and potential refinements for future trials.

BACKGROUND:The purpose of this study was to evaluate the prognostic value of the multigene EndoPredict test in prospectively collected data of patients screened for the randomized, double-blind, phase III UNIRAD trial, which evaluated the addition of everolimus to adjuvant endocrine therapy in high-risk, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer. PATIENTS AND METHODS:Patients were classified into low or high risk according to the EPclin score, consisting of a 12-gene molecular score combined with tumor size and nodal status. Association of the EPclin score with disease-free survival (DFS) and distant metastasis-free survival (DMFS) was evaluated using Kaplan-Meier estimates. The independent prognostic added value of EPclin score was tested in a multivariate Cox model after adjusting on tumor characteristics. RESULTS:EndoPredict test results were available for 768 patients: 663 patients classified as EPclin high risk (EPCH) and 105 patients as EPclin low risk (EPCL). Median follow-up was 70 months (range 1-172 months). For the 429 EPCH randomized patients, there was no significant difference in DFS between treatment arms. The 60-month relapse rate for patients in the EPCL and EPCH groups was 0% and 7%, respectively. Hazard ratio (HR) supposing continuous EPclin score was 1.87 [95% confidence interval (CI) 1.4-2.5, P < 0.0001]. This prognostic effect remained significant when assessed in a Cox model adjusting on tumor size, number of positive nodes and tumor grade (HR 1.52, 95% CI 1.09-2.13, P = 0.0141). The 60-month DMFS for patients in the EPCL and EPCH groups was 100% and 94%, respectively (adjusted HR 8.10, 95% CI 1.1-59.1, P < 0.0001). CONCLUSIONS:The results confirm the value of EPclin score as an independent prognostic parameter in node-positive, hormone receptor-positive, HER2-negative early breast cancer patients receiving standard adjuvant treatment. EPclin score can be used to identify patients at higher risk of recurrence who may warrant additional systemic treatments.

Conflicting results have been reported on the impact of HER2-low expression on the efficacy of CDK4/6 inhibitors in hormone receptor-positive (HR+) metastatic breast cancer. No data are yet available in the neoadjuvant setting. We investigated the efficacy of letrozole-palbociclib (LETPAL) combination as neoadjuvant treatment according to HER2 expression in an exploratory analysis of the NeoPAL study (UCBG104, NCT02400567). NeoPAL was a randomised, parallel, non-comparative phase II study which assigned pts with HR+ HER2-, Prosigna®-defined luminal B or A and node-positive, stage II-III breast cancer to LETPAL or chemotherapy. Primary endpoint was residual cancer burden (RCB 0-I rate). Secondary endpoints included clinical response, proliferation-based markers, and safety. HER2 low status was centrally reviewed according to the ASCO/CAP guidelines. 40/53 patients treated in the LETPAL arm were evaluable for this substudy: HER2-low (n=20), HER2-0 (n=20). Luminal B molecular subtype was predominant in both groups (95% and 80% respectively) with a baseline high risk Prosigna® ROR score in 88.9% and 82.6% of patients, respectively. After 4 months of LETPAL, RCB 0-I was observed in one patient of each group and pathological complete response rates were 2.5% and 0% in the HER2-low and HER2-0 subgroups respectively. A 0-I PEPI score was observed in 4 patients in each group. Interestingly, the HER2 status switched (either way) in 7 out of 28 analysable matched samples (25%). LETPAL induced a decrease in the ROR score at surgery in a similar proportion in both groups: 68.4% and 60.0% of tumors switched from high or intermediate risk to low risk in the HER2-low and HER2-zero groups, respectively. All exploratory p values were >0.1. Strikingly similar results were observed in the chemotherapy arm. Neoadjuvant palbociclib activity in combination with letrozole does not seem to be influenced by the tumor's HER2 status (low versus zero).

ABSTRACTBackgroundCorrectly classifying early estrogen receptor-positive and HER2-negative (ER+/HER2) breast cancer (EBC) cases allows to propose an adapted adjuvant systemic treatment strategy. We developed a new AI-based tool to assess the risk of distant relapse at 5 years for ER+/HER2-EBC patients from pathological slides.Patients and MethodsThe discovery dataset (GrandTMA) included 1429 ER+/HER2-EBC patients, with long-term follow-up and an available hematoxylin-eosin and saffron (HES) whole slide image (WSI). A Deep Learning (DL) network was trained to predict metastasis free survival (MFS) at five years, based on the HES WSI only (termed RlapsRisk). A combined score was then built using RlapsRisk and well established prognostic factors. A threshold corresponding to a probability of MFS event of 5% at 5 years was applied to dichotomize patients into low or high-risk groups. The external validation, as well as assessment of the additional prognosis value of the DL model beyond standard clinico-pathologic factors were carried out on an independent, prospective cohort (CANTO,NCT01993498) including 889 HES WSI of ER+/HER2-EBC patients.ResultsRlapsRisk was an independent prognostic factor of MFS in multivariable analysis adjusted for established clinico-pathological factors (p<0.005 in GrandTMA and CANTO). Combining RlapsRisk score and the clinico-pathological factors improved the prognostic discrimination as compared to the clinico-pathological factors alone (increment of c-index in the validation set 0.80 versus 0.76, +0.04, p-value < 0.005). After dichotomization, the Combined Model showed a higher cumulative sensitivity on the entire population (0.76 vs 0.61) for an equal dynamic specificity (0.76) in comparison with the clinical score alone.ConclusionsOur deep learning model developed on digitized HES slides provided additional prognostic information as compared to current clinico-pathological factors and has the potential of valuably informing the decision making process in the adjuvant setting when combined with current clinico-pathological factors.

500 Background: Benefit of adjuvant chemotherapy (CT) in addition to endocrine therapy (ET) remains controversial for patients (pts) aged ≥ 70 years with oestrogen receptors-positive (ER+) HER2-negative (HER2-) breast cancer (BC). In a large prospective trial, we first assessed the tumour genomic grade index (GGI) in all pts, and second, randomized pts with a high GGI between CT + ET vs. ET alone. Methods: Eligible pts were women ≥ 70 years with ER+ HER2- primary BC or isolated local relapse, irrespective of other characteristics, for whom adjuvant systemic treatment was considered. G8 score, Charlson comorbidity index (CCI) and 4-year mortality Lee score were collected at baseline. GGI was centrally performed by RT-PCR on FFPE samples. Pts with low GGI were not recommended to receive CT and were followed in an observational cohort. Pts with high (+ equivocal) GGI were randomized 1:1 to CT + ET vs. ET alone, using G8, pN and centre for stratification. Investigators chose between 3 CT regimens: 4 cycles of doxorubicin/cyclophosphamide, non-pegylated liposomal doxorubicin/cyclophosphamide or docetaxel/cyclophosphamide, given q3w with G-CSF. Standard ET consisted of 5 years of aromatase inhibitor, tamoxifen or a sequence based on tolerance. Based on CALGB 49907 results, the primary objective was to demonstrate an overall survival (OS) benefit for CT (4-year assumptions 87.5 vs 80%, HR=0.60) in the intent to treat (ITT) population. With 171 events, the trial had 90% power to demonstrate a difference with a bilateral test α=0.05. Secondary objectives included BC specific survival (BCSS), invasive disease-free survival (iDFS), event-free survival (EFS), competing events, cost-effectiveness and Q-TWiST analysis, geriatric dimensions, willingness and quality of life. Results: Between 04/2012 and 05/2016, 1,969 pts from 61 French and 12 Belgian centres were enrolled. Of them, 1,089 (55%) were randomized between CT + ET and ET alone. Median follow-up was 5.8 years at the data cut-off (17/12/2021) with 180 OS events observed. Median age was 75 (70-92), G8 score, CCI and Lee score being >14, ≤ 2, and ≤ 8 in 60%, 62% and 84% of pts, respectively. Tumours were ≥ pT2, pN+, isolated local relapses, with histological grade III, in 56%, 46%, 11% and 39% of cases, respectively. No significant OS difference was observed between arms (HR 0.85 [0.64-1.13], p=0.2538); 4-year OS was 90.5% in the CT + ET arm and 89.7% in the ET alone arm. The forest plot could not identify any subgroup deriving significant benefit from CT. ITT and per protocol analysis of secondary objectives (BCSS, iDFS, EFS) showed similar results. Conclusions: In this large phase III trial, we did not find a statistically significant OS benefit with the addition of CT to ET after surgery for ER+ HER2- BC with a high GGI. Analysis of the other outcome measures will be presented. Clinical trial information: NCT0156405.

Everolimus (EVE) in combination with hormone therapy (HT) has been shown to improve progression free survival for advanced HR+/HER2- breast cancer (BC). The double blind randomized UNIRAD trial aimed to investigate the benefit of adjuvant EVE in combination with standard adjuvant HT versus HT alone for women with high-risk HR+/HER2- early BC. Women with high-risk HR+/HER2- early BC (≥4 N+ or 1-3 N+ and EPclin score ≥ 3.3) who had completed initial treatment and started adjuvant HT for ≤ 3 years were randomly allocated (1:1) to placebo (P-HT) or EVE (E-HT) for 2 years. HT treatment was investigator's choice. The primary endpoint was disease-free survival (DFS) from randomization. Secondary endpoints included metastasis free survival (MFS), overall survival (OS) and toxicity. UNIRAD is registered with ClinicalTrials.gov (NCT01805271). 1278 patients (pts) were randomized between June 2013 and March 2020 in 72 centers/3 countries; 641 in the P-HT arm, and 637 in the E-HT arm. The present final analysis was conducted after decision of stopping the study for futility at the first pre-planned interim analysis in March 2020. Median duration of HT before randomization was 15 months (IQR: 4.9-29.9). 700 (55%) and 544 pts (44%) received aromatase inhibitor and tamoxifen, respectively. After a median follow up of 35.7 months (range: 0.7-85), 147 events were recorded. Median 3 years DFS was 88% in both arms (HR=0.95; 95%CI: 0.69-1.32). MFS (HR=0.88; 95%CI: 0.62-1.25) and OS (HR=1.09, 95CI: 0.62-1.92) did neither differ. 187 pts (30%) vs 101 pts (16%) presented at least one grade 3-4 adverse event in the E-HT and P-HT arms, respectively. There was 1 toxic death in the E-HT arm. Dose reduction and early treatment discontinuation due to AEs respectively occurred in 34% and 35% of pts in the E-HT arm, vs 12% and 10% in the P-HT arm (p<0.001). Median duration of EVE exposition was 9.2 months (IQR=2.1-23.4). Everolimus given in combination with adjuvant HT for high risk early BC did not improve 3-year DFS compared with HT alone. Follow-up will continue to evaluate long-term outcomes.

The organisers regret that the abstract publication number was omitted from the title of the original publication of this abstract. The title with the abstract publication number is as follows: VP1-2021: Efficacy of everolimus in patients with HR+/HER2- high risk early stage breast cancer The organisers would like to apologise for any inconvenience caused. Efficacy of everolimus in patients with HR+/HER2- high risk early stage breast cancerAnnals of OncologyVol. 32Issue 4PreviewEverolimus (EVE) in combination with hormone therapy (HT) has been shown to improve progression free survival for advanced HR+/HER2- breast cancer (BC). The double blind randomized UNIRAD trial aimed to investigate the benefit of adjuvant EVE in combination with standard adjuvant HT versus HT alone for women with high-risk HR+/HER2- early BC. Full-Text PDF Open Archive

1070 Background: In PADA-1 (NCT03079011), a phase III trial testing the clinical utility of ESR1mut detection, ER+ HER2- advanced breast patients (ABC pts) received Aromatase Inhibitor (AI) and Palbociclib (Pal) +/- LHRH agonist as first line therapy. PADA-1 was open to “AI-sensitive” pts, including those with de novo stage IV disease or metastatic relapse after adjuvant endocrine therapy but also pts with metastatic relapses during adjuvant tamoxifen (TAM). In this subsidiary analysis, we report the efficacy of AI+PAL as first line therapy in patients relapsing on adjuvant TAM. Methods: Main inclusion criteria in PADA-1 are: pre- or post-menopausal pts with ER+ HER2- ABC, who did not receive any prior therapy for ABC and who had no adjuvant AI or completed adjuvant AI for > 12 months or who had disease recurrence while on adjuvant TAM. Results: From 04/2017 to 01/2019, 1017 ABC pts have been included in PADA-1, of which 115 (11.3%) had a metastatic relapse while on adjuvant TAM (TAM only (N = 112) or TAM+GnRH agonist (N = 3)). Median age at inclusion was 46 years (range 25-81), and 58 (50.4%) patients had visceral disease. The median PFS under AI+PAL was 20.4 months (95%CI16.1;27.8) in patients relapsing during adjuvant TAM. In contrast, median PFS in patients with de novo metastatic disease and metastatic relapses after the completion of adjuvant endocrine therapy were 30.6 months (95%CI26.7;Not reached) and 27.8 months (95%CI24.1;30.)], respectively. A subgroup analysis among patients relapsing on adjuvant TAM showed that those relapsing during the first two years of adjuvant TAM had a shorter PFS (11.4 months 95%CI[8.7;20.7]) than those relapsing after 2 years of adjuvant TAM (23.8 months 95%CI[20.2;Not reached]). Conclusions: To our knowledge, these are the first data on first line AI+CDK4/6 inhibitor in patients relapsing on adjuvant TAM. While PFS on AI + PAL appears primarily driven by endocrine resistance status, our data show that AI+PAL is a valuable option also in patients relapsing during adjuvant TAM. Clinical trial information: NCT03079011 .

The double blind randomized UNIRAD trial (NCT01805271) showed that adding Everolimus (EVE) to adjuvant endocrine therapy (ET) for high-risk early breast cancer (BC) does not improve 3-year disease-free survival (iDFS) compared with ET alone. We report the subgroup analysis focusing on the pre-specified stratification factors.

Background: Use of OCAM varies widely among cancer pts, ranging 20– 80%. Efficacy of OCAM for cancer-related symptoms including fatigue is controversial, while some interactions with standard anticancer therapy were reported. We aimed to describe factors associated with use of OCAM, particularly its relationship with self-reported fatigue in BC pts.

Among MBC patients with germline breast cancer predisposing mutations, more than 60% have an ER+/HER2- subtype. For these patients, the best therapeutic strategy within the use of endocrine therapy (ET) + CDK4-6 inhibitors, chemotherapy and eventually PARP inhibitors is still to determine. PADA-1 (NCT03079011) is a randomized phase III trial testing the clinical utility of real time ESR1mut detection in the blood of patients treated with AI+P as first line metastatic treatment. In a subsidiary analysis of this trial, we report on the characteristics and outcome of known germline BRCA (1/2) or PALB2 mutation carriers included in the trial. From 2017/03 to 2019/01, 1017 MBC patients have been included in 83 centers. BRCA1-2/PALB2 status was distributed as follows: mutated in any of the 3 genes (N=20; 2 %; Group A), wild type or variants of uncertain significance (N=125; 12.3%; Group B), non-tested (N=872; 85.7%; Group C). BRCA2 mutation was predominant (n=16) while BRCA1 (n=3) and PALB2 (n=1) were rare. Patients with BRCA1-2/PALB2 (group A) had a median age of 47.1y and were mostly premenopausal (70%). Adjuvant chemotherapy and ET was delivered in 65% and 55% of BRCA1-2/PALB2 mutated patients. With a median follow-up of 21.2m (95% CI [0;34]), median PFS with AI+ P was 14.3m (95%IC [10.4-NR]) in mutation carriers (group A) versus 26.7m (95%IC [24.1-29.4]) in groups B + C (p=0.056). The cumulative incidence of ESR1 mutation emergence during the course of first line was significantly higher in BRCA1-2 PALB2 mutation carriers (Fine & Gray method p=0.03). In this exploratory analysis, BRCA1-2 PALB2 mutation carriers with HR+/HER2- MBC seem might derive less benefit of AI+P than non-mutated patients. Emergence of ESR1 mutation is a frequent biological event in this subset of patients.

Abstract Background The role of chemotherapy in early luminal breast cancer remains challenged. The NEOPAL trial (NCT 02400567; Cottu et al, ESMO 2017 LBA09) compared sequential chemotherapy (CT) and letrozole-palbociclib (LP) as neoadjuvant treatment in PAM50 defined high-risk luminal breast cancer patients, showing that LP might be as efficient as CT with regard to breast conserving surgery and pathological response. We report here extended exploratory pathological results, focusing on tumor infiltrating lymphocytes (TILs), proliferative response and preoperative endocrine prognostic index (PEPI) scores. Material and Methods Tumor blocks from baseline biopsy and surgical specimens were available for centralized review from the 106 randomized patients (53 in each arm). TILs quantification, KI67 staining and counting, and ER quantification were performed according to standard methods. Residual proliferative cancer burden (RPCB) and PEPI scores were computed according to published algorithms. Wilcoxon rank sum test and Mann Whitney test were used to compare paired and unpaired data. The chi-square and Fisher exact tests were used for categorical variables. Results Overall, median TILs count did not differ between LP and CT patients, both at baseline (p=0.37) and at the end of treatment (p=0.42). Median TILs count climbed from 5% (0-60) to 10% (1-60) in the LP arm (p=0.0026) and from 2% (0-30) to 10% (0-60) in the CT arm (p=0.0023). Median Ki67 dropped sharply in both arms, from 30% (1-80) to 1% (0-30) in the LP arm (p=1.10e-8) and from 30% (2-80) to 5% (0-30) in the CT arm (p=3.10e-9). Decrease in the Ki67 geometric mean was as sharp. Of note, while baseline Ki67 was similar in both arms (p=0.315), decrease in the LP arm was significantly more profound than in the CT arm (p=0.00075). Pathological response according to RPCB were as follows, in the LP and CT arm, respectively: class 0: 9.6%/10.2%; class I: 84.6%/73.5%; class II: 5.8%/16.3%. The relapse free survival PEPI scores were as follow in the LP and CT arm, respectively: class I: 13.5%/16.3%; class II: 59.6%/46.9%; class III: 28.9%/36.8% (p=0.504). Breast cancer specific survival PEPI scores were as follow in the LP and CT arm, respectively: class I: 18.9%/8.2%; class II: 54.7%/40.8%; class III: 26.4%/51%. These results were significantly better in the LP arm (p=0.027). There was no correlation between final TILs quantification and the RPCB or PEPI scores. Conclusions In this prospective multicenter study with centralized pathological review, neoadjuvant letrozole-palbociclib combination generates impressive proliferative and endocrine specific response features. It compared well with chemotherapy. The LP combination also significantly increased lymphocytic infiltration. Its clinical significance and utility remain to be elucidated, but it potentially adds new prognostic and theranostic information. Citation Format: Vincent-Salomon A, Mathieu M-C, Bataillon G, Arnould L, Verrièle V, Ghnassia J-P, Haudebourg J, Penault-Llorca F, Lefebvre C, Maran-Gonzalez A, Guinebretière J-M, Duprez R, Berghian A, Blanc-Fournier C, Calès V, Galant C, Delrée P, Lemonnier J, Delaloge S, Cottu PH. TILs variations, proliferative response and PEPI scores in patients with luminal breast cancer receiving neoadjuvant letrozole-palbociclib or chemotherapy: An extended analysis of the NEOPAL trial [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 P4-15-02.

Breast cancer is associated with a high 5-year survival rate and more than half women are still of working age at diagnosis. Many studies evaluated the clinical determinants of return to work (RTW) but few investigated RTW in relation to family factors. Our objective was to study the role of household characteristics in non-RTW two years after breast cancerdiagnosis. We used data of a French prospective cohort of women diagnosed with stage I-III, primary breast cancer (CANTO, NCT01993498). Patients had to be under 57 and have a job at diagnosis. We performed logistic regressions to model non-RTW two years after diagnosis in relation to household characteristics at diagnosis (marital status, children, support from partner), adjusting for tumor characteristics, health status at baseline and one year after diagnosis, and household income at diagnosis. In a second step, we conducted analyses stratified for household income at diagnosis. In total, 1874 women were eligible. Being in a relationship did not impact non-RTW (OR = 1.43 [95% CI 0.95-2.16]). Among the 1566 women in a relationship, being married was associated with elevated odds of non-RTW(OR = 1.37 [0.96-1.94]). Having children(OR = 1.17 [0.81-1.69]) or receiving support from their partner (OR = 1.17 [0.77-1.78]) was not associated with non-RTW. However, the situation differed in low-income households(<2500€) among whom being married was associated with more elevated odds of non-RTW(OR = 1.94 [0.97-3.88]). No clear association was observed between having children (OR = 1.85 [0.85-4.03]) and non-RTW, but living with at least two children (OR = 2.76 [1.14-6.70]) and receiving support from their partner (OR = 2.28 [1.01-5.17]) was associated with increased odds of non-RTW. The family environment is associated with non-RTW among the poorest women but not the others. Among the poorest women, the family environment is associated with non-RTW. Among all women, the family environment is not associated with non-RTW.

Abstract Background In this study we aimed to examine the independent effect of baseline QoL and persistent CRT among pts with early BC. Methods We included data stage I-III BC pts treated with chemotherapy who were included in the CANTO prospective cohort study (NCT-01993498) from 03/2012 to 12/2014. The primary outcome was CRT defined as the presence at 3-6 months after the end of treatment, of any of the following toxicities (NCI-CTC-AE): infection, venous or arterial thrombosis, neurological G2-4, digestive G3-4 or pulmonary toxicities G3-4). Treatment deliver including chemotherapy dose reductions were also examined. The independent variable of this study was baseline Qol defined by the EORTC QLQ-C30 subscales of general global health status (GHS) ( Results Among 3079 BC pts included in this analysis, 33% received neoadjuvant and 77% adjuvant treatment. Median age at diagnosis was 53 years, median BMI= 25 kg/m2, 94% of patients had a PS = 0 and 83% stage I-II disease. Pts reported on average a good GHS = 68 (±19) and PF = 90 (±14). GHS and PF were higher in women with better performance status PS = 0 vs 1+, (68 vs 60 p  Conclusions Global and physical QoL before BC treatments are independently associated with CRT. QoL should be assessed before any treatment to identify patients at risk CRT. Clinical trial identification NCT01993498. Legal entity responsible for the study UNICANCER/Villejuif, France, 94805 Principal Investigator: Fabrice Andre Gustave Roussy – Villejuif. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Abstract Background: Increased levels of CTC and a persistent elevated level after just one cycle of chemotherapy are very strong and independent markers of worse progression-free survival (PFS) and overall survival (OS) in patients (pts) with metastatic breast cancer (MBC) (Bidard et al, Lancet Oncol 2014). ctDNA can be used to detect mutation associated with resistance to treatment. It has also been shown that dynamic changes in ctDNA levels closely reflect changes in tumor burden. We prospectively monitored CTC and ctDNA early variations during first line chemotherapy for MBC. Patients & methods: The French cohort COMET is a prospective study including first line HER2 negative patients (pts) receiving weekly paclitaxel and bevacizumab according to EMA approved combination. The aim of this cohort is to evaluate clinical, biological and radiological parameters associated with pts outcome (CTC, serum markers, ctDNA, pharmacogenomic polymorphisms, metabolomic parameters, visceral fat, serum estradiol level and quality of life). We present here the first planned analysis on pts evaluated for CTC (CellSearch) and ctDNA using targeted sequencing (Roche SeqCap technology) of a panel of 46 genes and 8 promoters, using unique molecular identifiers to increase ctDNA detection sensitivity. Blood samples were obtained at baseline (BL) and before the second cycle of chemotherapy (C2). Results: From 09/2012 to 5/2014, 218 pts were included in this substudy. Median age was 55 years and 22% of pts had triple negative BC. At BL, 70% of pts had ≥1 detectable CTC per 7.5 ml of blood (median 4 CTC, range 1- 30,000) and 37% at C2. With a threshold of ≥5 CTC, 47% of pts were positive at BL and 22% at C2. For ctDNA, out of the first 141 pts analyzed, 105 had at least one somatic mutation detected in plasma (74%). The average number of mutations per pt was 2.7 and most commonly mutated genes were TP53 and PIK3CA. ESR1 was found mutated in 9% of all cases and restricted to the ER+ subgroup. Median Allelic Frequency was 10% (range 0.6-83%). Only 33% of pts had detectable ctDNA at C2. At BL, CTC and ctDNA levels were correlated (r=0.46, p<0.0001). Despite no complete overlap, 11% of pts had no CTC nor ctDNA detected. Median follow-up was 53 months and median OS was 32 months. Increased level of CTC and ctDNA were significantly associated with decreased PFS and OS. At C2, ≥5 CTC or still detectable ctDNA were strong markers of reduced OS: HR 4.6 (CI95 3.1-7) and HR 3.2 (CI95 1.8 – 5.5), respectively (both p< 0.0001). At multivariate analysis for PFS, detectable ctDNA at C2 and triple negative status were the only significant prognostic factors. None of serum marker level at BL or their early variations had prognostic value. Conclusion: This is the largest prospective cohort assessing the respective prognostic values of early CTC and ctDNA changes in homogenously treated first line MBC patients. Analysis of mutations profile variations and comparison with primary tumor and metastasis biopsies are ongoing and may reveal early mechanisms of resistance. Citation Format: Pierga J-Y, Silveira A, Lorgis V, Tanguy M-L, Tredan O, Dubot C, Jacot W, Goncalves A, Debled M, Levy C, Ferrero J-M, Jouannaud C, Luporsi E, Mouret-Reynier M-A, Dalenc F, Lemonnier J, Berger F, Proudon C, Bidard F-C. Circulating tumor DNA (ctDNA) and circulating tumor cells (CTC) predictive value in HER2 negative metastatic breast cancer patients treated with first line weekly paclitaxel and bevacizumab: Results of a prospective cohort from the French Breast Cancer InterGroup Unicancer (UCBG): COMET study [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 PD2-03.

Background In ER+ HER2- metastatic breast cancer (MBC), resistance to estrogen deprivation by Aromatase Inhibitors (AI) can stem from activating ESR1 mutations (ESR1mut) or from other less characterized, mutually exclusive mechanisms. In this study, we report on factors associated with the onset of ESR1mut during therapy (vs other mechanisms of resistance). Methods PADA-1 (NCT03079011) is a phase III trial testing the clinical utility of real time ESR1mut detection (on cell-free DNA, every 2 months) in ER+ HER2- MBC pts treated first line with AI and palbociclib. Main inclusion criteria are pts with no overt resistance to adjuvant AI and no prior therapy for MBC. This analysis compared pts who experienced a progressive disease with no ESR1mut detected (ESR1wt-PD) with those with a rising ESR1mut detected during therapy. Results 1017 MBC pts were included in PADA-1 from 04/2017 to 01/2019 and are being followed-up. As of 01/31/2019, 242 pts presented either with an ESR1wt-PD (n = 139, 57.4%) or a detectable ESR1mut (n = 103, 42.6% (either prior to PD or at time of PD) at any time during AI-palbociclib therapy. During the first 6 months on treatment, ESR1mut (n = 17, 18.7%) was less frequent than ESR1wt-PD (n = 74, 81.3%); after 6 months, the opposite was true (ESR1mut: n = 80, 53.0% vs ESR1wt-PD n = 71, 47.0%); this change was highly significant (Chi2 test, p Conclusions ctDNA analysis in PADA-1 suggests that ESR1mut are rarely involved in primary resistance to AI-palbociclib therapy (i.e. PD within 6 months) but may represent the most prevalent mechanism of acquired resistance. The observed association between ESR1mut and metastatic sites might underlie the reported higher efficacy of selective estrogen receptor degraders (such as fulvestrant) in pts with bone metastases. Clinical trial identification NCT: 03079011; EudraCT: 2016-004360-18. Legal entity responsible for the study UNICANCER. Funding Pfizer. Disclosure F. Bidard: Advisory / Consultancy, lectures fees: Pfizer; Advisory / Consultancy, lectures fees: AstraZeneca. B. Pistilli: Honoraria (self): AstraZeneca; Honoraria (self): MSD; Honoraria (self), Advisory / Consultancy: Pfizer; Advisory / Consultancy: Puma; Advisory / Consultancy: Merus. T. de La Motte Rouge: Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Eisai; Advisory / Consultancy: MSD. R. Sabatier: Licensing / Royalties: Novartis; Research grant / Funding (self), Travel / Accommodation / Expenses, Licensing / Royalties: AstraZeneca; Licensing / Royalties: Tesaro; Research grant / Funding (institution): EISAI; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer. F. Clatot: Research grant / Funding (institution): AstraZeneca; Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS. T. Bachelot: Honoraria (self), Non-remunerated activity/ies: Roche; Honoraria (self), Research grant / Funding (institution), Non-remunerated activity/ies: Novartis; Honoraria (self), Research grant / Funding (institution), Non-remunerated activity/ies: AstraZeneca; Honoraria (self), Research grant / Funding (institution), Non-remunerated activity/ies: Pfizer. S. Delaloge: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Lilly; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Puma; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche. All other authors have declared no conflicts of interest.