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Anemia is common in oncology and negatively impacts quality of life. However, there is lack of knowledge about iron deficiency (ID) epidemiology. The aim of this study was to prospectively assess iron status in patients with locally advanced or metastatic cancer beginning chemotherapy. In this prospective, multicenter cohort study, anemia and ID were evaluated in patients with locally advanced or metastatic solid tumors and lymphoma before starting chemotherapy. Blood samples were collected at inclusion (W0), 6 weeks (W6), and 12 weeks (W12). Prevalence was evaluated in the general population, according to tumor location and was correlated with tumor response. One hundred twenty-nine patients were enrolled between 2013 and 2015; 119 had solid tumors and 10 lymphomas. At W0, there were no significant difference between locations with a prevalence around 50–60% (range 47.2–70.4%) and only a trend for colorectal cancer (70.4%, P = 0.069) due to a higher prevalence of absolute ID (18.5%). Prevalence of ID+ decreased between W0 and W6 and remained stable until W12 due to the proportion of patients with ID and without anemia. However, anemia prevalence increased during W0 and W6 and remained stable to W6 from W12 due to patients with anemia but without ID. A significant correlation between tumor response and ID prevalence was found (P = 0.036). We confirm the high prevalence of ID and anemia in cancer patients. ID status is correlated to tumor response providing a strong rationale for iron monitoring during cancer management.

Background: In ER+ HER2- metastatic breast cancer (MBC) patients, the clinical choice between 1st line hormone therapy (HT, the recommended option) or chemotherapy (CT) is based on the absence of “visceral crisis” or adverse prognostic factors, with no proven/objective criteria. In that context, STIC CTC (NCT01710605) was set up as a strategy trial to test whether circulating tumor cells (CTC) count could help customize the choice between 1st line HT or CT. Methods: For this multicenter phase 3 non-inferiority trial, the main inclusion criteria were: ER+ HER2- MBC with no prior therapy, PS≤2, no contra-indication to HT or CT and informed consent. The a priori treatment choice (HT or CT) and CTC count (CellSearch®) were obtained in all patients prior to randomization. Patients were randomized 1:1 between clinically-driven choice (CTC count not disclosed, HT or CT administered as decided a priori), or a CTC-driven choice (HT if Results: 761 MBC patients were randomized between 02/2012 and 08/2016. Baseline characteristics: 7.8% of patients had a PS=2, 24.1% had a de novo metastatic disease; 63.3% received prior adjuvant HT and 49.9% prior adjuvant CT; 31.3% had ≥3 metastatic sites. A priori treatments (HT or CT) and CTC count (< or ≥5 CTC/7.5ml) were well balanced between the two arms. After randomization, in the clinically-driven arm, N=267 (72.4%) patients received HT and N=102 (27.6%) CT (as decided a priori). In the CTC-driven arm: (1) the a priori choice of HT was confirmed by a low CTC count in N=181 (67.5%) of patients, while N=87 (32.5%) were switched to CT due to a high CTC count; (2) the a priori choice of CT was confirmed by high CTC count in only N=48 (48%) patients, while N=52 (52%) were switched to HT. The primary endpoint was met, PFS being not inferior in the CTC-driven arm (HR=0.98, 90%CI=[0.84–1.13]). Analyses focusing on discordant subgroups showed that for patients with a priori choice of HT but with high CTC count (leading to a switch to CT in the CTC-arm), PFS was significantly longer in the CTC-driven arm than in the standard arm (HR=0.67, 95%CI=[0.49–0.92]; p=0.01), with a non-significant trend toward longer OS (HR=0.68, 95%CI=[0.44–1.07]; p=0.09). Inversely, for patients with a priori choice of CT but with low CTC count (i.e. de-escalation to HT in the CTC arm), PFS was not statistically different between the two arms. Conclusion: This trial demonstrates the clinical utility of CTC count as an objective decision tool when considering 1st line therapy in ER+ HER2- MBC. In most patients, CTC count did confirm the a priori clinical choice; however, trial results show that in discrepant cases, CTC count may be trusted for either escalating (i.e. considering CT in patients if high CTC count) or de-escalating (i.e. considering HT in patients if low CTC count) 1st line therapy. Funding: French National Cancer Institute; Menarini Silicon Biosystems. Citation Format: Bidard F-C, Jacot W, Dureau S, Brain E, Bachelot T, Bourgeois H, Goncalves A, Ladoire S, Naman H, Dalenc F, Gligorov J, Espie M, Levy C, Ferrero J-M, Loirat D, Cottu P, Dieras V, Simondi C, Berger F, Alix-Panabieres C, Pierga J-Y. Clinical utility of circulating tumor cell count as a tool to chose between first line hormone therapy and chemotherapy for ER+ HER2- metastatic breast cancer: Results of the phase III STIC CTC 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 GS3-07.

Background: Palbociclib (Pal) combined with an aromatase inhibitor (AI) is a standard of care as first line therapy in ER+ HER2- metastatic breast cancer (MBC). While ESR1 mutations (ESR1mut) are a characterized mechanism of resistance to AI as single agent, it remains unknown how these mutations, when detected prior to treatment initiation, may affect the efficacy of Pal+AI. In a subsidiary analysis of the first line PADA-1 trial, we report the ESR1mut detection rate at baseline and, in patients with ESR1mut detected at baseline, how ESR1 circulating tumor DNA levels changed after the first cycle of AI-Pal therapy. Methods: PADA-1 (NCT03079011) is a randomized phase III trial testing the clinical utility of real time ESR1mut detection (baseline, at 1 month and then every 2 months) in the blood of patients treated with AI-Pal (first step). Patients with rising ESR1mut in circulating tumor DNA (i.e. increasing or appearing mutations during first line AI-Pal therapy) are randomized in a second step between keeping AI-Pal or switching to Fulvestrant-Pal. Main inclusion criteria are patients with ER+ HER2- MBC, who never received adjuvant AI or completed adjuvant AI for >12 months, with neither prior therapy for MBC nor visceral crisis. ESR1mut are tracked in circulating DNA from up to 4ml of plasma by a ddPCR-based assay targeting E380, L536, Y537 and D538 hotspots (i.e. #90% of known ESR1 activating mutations) with #0.1% sensitivity (Bidard et al, AACR 2018 #3867). Results: From 04/2017 to 05/2018, 803 MBC patients have been included in 80 centers. Among these patients, ESR1mut were detected at baseline, prior to any systemic therapy, in 17 patients (2.1%, 95%CI=[1.3;3.3%]). ESR1mut levels ranged from 6 to 3959 copies/ml of plasma (median: 30 copies/ml); allelic frequency ranged from 0.3% to 47% (median=3.5%). ESR1mut were not associated with any of the tumor pathological characteristics (including PR status, primary TNM stage, number and type of metastatic sites); a non-significant association was observed with primary tumor grade (1.7% vs 4.1% in grade I-II vs III, Fisher: p=0.15). Among patients who received a prior adjuvant endocrine therapy, ESR1mut detection rate was lower in patients treated with tamoxifen (0.9% with any tamoxifen exposure vs 5.7% with no tamoxifen exposure; Yates Chi2: p=0.01) and observed only in patients treated with AI (4.9% with any AI exposure vs 0% with no AI exposure, Yates Chi2: p=0.009). Among the 17 patients with ESR1mut detected at baseline, only 4 patients had residual detectable ESR1mut detected after 1 month of AI-Pal therapy (3 of these 4 had decreased levels of ESR1 mutation). Conclusion: ESR1mut is a rare event in untreated AI-sensitive, ER+ HER2- MBC patients. Such detection is primarily associated with prior use of AI in the adjuvant setting. Interestingly, in most MBC patients with ESR1mut detected at baseline, ESR1mut became undetectable after 1 month of AI-Pal therapy, suggesting that this combination may retain early antitumor efficacy. Funding: Pfizer Citation Format: Bidard F-C, Pistilli B, Dalenc F, De la Motte Rouge T, Sabatier R, Frenel J-S, Ladoire S, Dubot C, Ferrero J-M, Levy C, Lortholary A, Stefani L, Mouret-Reynier M-A, Hardy A-C, Jacquin J-P, Grenier J, Chakiba C, Teixeira L, Soulie P, Everhard S, Lemonnier J, Jeannot E, Bieche I, Berger F, Pierga J-Y, Bachelot T, Delaloge S. Circulating ESR1 mutation detection rate and early decrease under first line aromatase inhibitor and palbociclib in the PADA-1 trial (UCBG-GINECO) [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 PD2-06.

Background:Primary inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer. Survival of IBC patients has been improved by multimodal therapy. However 5-year overall survival (OS) still remains close to 50-60%, due to high risk of disseminated disease. Given the low incidence, prognosis of metastatic cases stages is poorly described. Methods:This study aimed to describe OS of IBC (T4d AJCC TNM classification) with upfront or recurrent metastatic disease compared with non-IBC patients in the ESME database (N=16,702 patients). OS was calculated from the diagnosis of metastasis to the date of death (from any cause), or censored to date of latest news. Secondary objectives included progression-free survival (PFS). Results:From 2008 to 2014, 7,465 patients with diagnosis of MBC and known clinical status of their primary tumor (T) were identified, including 582 IBC (T4d) and 6,883 non-IBC. As expected, metastatic IBC was associated with pejorative features compared to non-IBC, with less hormonal receptors-positive tumors (44% vs 65.6%), more HER2-positive (30% vs 18.6%) or triple-negative (25.9% vs 15.8%) cases (p Compared with non-IBC, synchronous metastatic IBC showed worse median OS and PFS (39.9 months [95%CI 34.2-45.3] vs 48.4 months [95%CI 46.3-50.8], p=0.0035; 10 months [95%CI 8.8-12.7] vs 14.5 months [95%CI 13.6-15.7], p=0.0027, respectively. Similar results were obtained in metachronous metastatic cases (20.01 months [95%CI 17.1-21.2] vs 32.8 months [95%CI 31.5-34.3], p Conclusion:In this large national and multicentric study, IBC is a major and independent factor associated with adverse outcome in metastatic setting. Of note, the independent adverse impact on PFS identified in this study may suggest a lower sensitivity of metastatic IBC to available therapeutics. However, results seem to improve in the last years. Detailed analysis according to phenotype will be available. Citation Format: Monneur A, Bertucci F, Lardy-Cleaud A, Augereau P, Debled M, Levy C, Mouret-Reynier MA, Coudert B, Mailliez A, Bachelot T, Ferrero J-M, Guiu S, Uwer L, Campone M, Cottu P, Jouannaud C, De la Motte Rouge T, Leheurteur M, Petit T, Pistilli B, Dalenc F, Simon G, Robain M, Viens P, Lerebours F, Gonçalves A. Metastatic inflammatory breast cancer: Clinical features and outcomes in the national, multicentric, real-life ESME cohort [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 P5-17-04.

Older cancer patients are underrepresented in clinical trials. We aimed to evaluate the enrollment of older women aged 70 years old (yo) or over with metastatic breast cancer (MBC) in clinical trials.We used the national Epidemio-Strategy and Medical Economics MBC Data Platform, a French multi-center real-life database. We selected MBC women over 70yo, without central nervous system metastases, with at least one line of systemic treatment, between January 1st, 2008 and December 31st, 2016, and had no other cancer in the 5 years before MBC. The primary objective was to evaluate the proportion of patients enrolled in clinical trials according to their age. Secondary objective was to identify variables associated with enrollment in older ones.5552 women were aged ≥ 70 (median 74yo; IQR 72-77). 14,611 were less than 70. Of the older ones, 239 (4%) were enrolled in a clinical trial during first line of treatment, compared with 1529 (10.5%) for younger ones. Multivariable analysis of variables predicting for enrollment during first line of treatment in older patients were younger age (OR 0.50 [95%CI 0.33-0.76] for the 80-85yo class; OR 0.17 [95%CI 0.06-0.39] for the 85yo and more class), good ECOG Performance Status (PS 0-1) (OR 0.15 [95%CI 0.08-0.27] for the PS 2-4 class), HER2 + disease (OR 1.78 [95%CI 1.27-2.48]), type of treatment (chemotherapy/targeted therapy/immunotherapy OR 5.01 [95%CI 3.13-8.18]), and period (OR 1.65 [95%CI 1.22-2.26] for 2012-2016, compared to 2008-2011).In this large database, few older MBC patients were enrolled in a trial compared with younger ones.

Background Leptomeningeal metastasis (LM) is a rare complication of metastatic breast cancer (MBC), with high morbidity/mortality rates. Our study aimed to describe the largest-to-date real-life population of MBC patients treated with intrathecal (IT) therapy and to evaluate prognostic models. Methods The Epidemiological Strategy and Medical Economics (ESME) MBC database (NCT03275311) includes all consecutive patients who have initiated treatment for MBC since 2008. Overall survival (OS) of patients treated with IT therapy was estimated using the Kaplan–Meier method. Prognostic models were constructed using Cox proportional hazards models. Performance was evaluated using C-index and calibration plots. Results Of the 22 266 patients included in the database between 2008 and 2016, 312 received IT therapy and were selected for our analysis. Compared with non-IT-treated patients, IT-treated patients were younger at MBC relapse (median age: 52 years versus 61 years) and more often had lobular histology (23.4% versus 12.7%) or triple-negative subtype (24.7% versus 13.3%) (all P < 0.001). Median OS was 4.5 months [95% confidence interval (CI) 3.8-5.6] and 1-year survival rate was 25.6%. Significant prognostic factors associated with poorer outcome on multivariable analysis were triple-negative subtype (hazard ratio 1.81, 95% CI 1.32-2.47), treatment line ≥3 (hazard ratio 1.88, 95% CI 1.30-2.73), ≥3 other metastatic sites (hazard ratio 1.33, 95% CI 1.01-1.74) and IT cytarabine or thiotepa versus methotrexate (hazard ratio 1.68, 95% CI 1.28-2.22), while concomitant systemic therapy was associated with better OS (hazard ratio 0.47, 95% CI 0.35-0.62) (all P < 0.001). We validated two previously published prognostic scores, the Curie score and the Breast-graded prognostic assessment, both with C-index of 0.57. Conclusions MBC patients with LM treated with IT therapy have a poor prognosis. We could identify a subgroup of patients with better prognosis, when concomitant systemic therapy and IT methotrexate were used., Highlights • The outcome of BC patients with IT-treated LM is poor, with a median OS of 4.5 months. • Concomitant systemic therapy may improve the outcome in IT-treated patients. • Patients treated with IT methotrexate had better outcome than those treated with IT cytarabine/thiotepa. • The Curie and Breast-graded prognostic assessment scores were prognostic for IT-treated patients.

Background Treatment strategies for metastatic breast cancer (MBC) have made great strides over the past 10 years. Real-world data allow us to evaluate the actual benefit of new treatments. ESME (Epidemio-Strategy-Medico-Economical)-MBC, a nationwide observational cohort (NCT03275311), gathers data of all consecutive MBC patients who initiated their treatment in 18 French Cancer Centres since 2008. Patients and methods We evaluated overall survival (OS) in the whole cohort (N = 20 446) and among subtypes: hormone receptor positive, human epidermal growth factor 2 negative (HR+/HER2−; N = 13 590), HER2+ (N = 3919), and triple-negative breast cancer (TNBC; N = 2937). We performed multivariable analyses including year of MBC diagnosis as one of the covariates, to assess the potential OS improvement over time, and we described exposure to newly released drugs at any time during MBC history by year of diagnosis (YOD). Results The median follow-up of the whole cohort was 65.5 months (95% CI 64.6-66.7). Year of metastatic diagnosis appears as a strong independent prognostic factor for OS [Year 2016 HR 0.89 (95% CI 0.82-0.97); P = 0.009, using 2008 as reference]. This effect is driven by the HER2+ subcohort, where it is dramatic [Year 2016 HR 0.52 (95% CI 0.42-0.66); P < 0.001, using 2008 as reference]. YOD had, however, no sustained impact on OS among patients with TNBC [Year 2016 HR 0.93 (95% CI 0.77-1.11); P = 0.41, using 2008 as reference] nor among those with HR+/HER2– MBC [Year 2016 HR 1.02 (95% CI 0.91-1.13); P = 0.41, using 2008 as reference]. While exposure to newly released anti-HER2 therapies appeared very high (e.g. >70% of patients received pertuzumab from 2016 onwards), use of everolimus or eribulin was recorded in less than one-third of HR+/HER2– and TNBC cohorts, respectively, whatever YOD. Conclusion OS has dramatically improved among HER2+ MBC patients, probably in association with the release of several major HER2-directed therapies, whose penetrance was high. This trend was not observed in the other subtypes, but the impact of CDK4/6 inhibitors cannot yet be assessed., Highlights • OS of HER2+ MBC patients keeps improving over time [Year 2016 HR 0.52 (95% CI 0.42-0.66); P < 0.001, using 2008 as reference]. • This effect seems timely related to the release of drugs demonstrated to improve survival in clinical trials. • OS gains observed in real life among HER2+ MBC patients are at least equivalent to those observed in clinical trials. • YOD had no sustained impact on OS among patients with TNBC and luminal MBC. • The impact of CDK4/6 inhibitors cannot yet be assessed in this cohort.

Background Palbociclib is a CDK4/6 inhibitor with demonstrated efficacy and safety in combination with endocrine therapy in advanced luminal breast cancer (LBC). We evaluated the respective efficacy and safety of chemotherapy and letrozole–palbociclib (LETPAL) combination as neoadjuvant treatment in patients with high-risk LBC. Patients and methods NeoPAL (UCBG10/4, NCT02400567) is a randomised, parallel, non-comparative phase II study. Patients with ER-positive, HER2-negative, Prosigna®-defined luminal B, or luminal A and node-positive, stage II–III breast cancer, not candidate for breast-conserving surgery, were randomly assigned to either letrozole (2.5 mg daily) and palbociclib (125 mg daily, 3 weeks/4) during 19 weeks, or to FEC100 (5FU 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2)×3 21-day courses followed by docetaxel 100 mg/m2×3 21-day courses. Primary end point was residual cancer burden (RCB 0–I rate). Secondary end points included clinical response, proliferation-based markers, and safety. Results Overall, 106 patients were randomised [median Prosigna® ROR Score 71 (22–93)]. RCB 0–I was observed in four and eight patients in LETPAL [7.7% (95% CI 0.4–14.9)] and chemotherapy [15.7% (95% CI 5.7–25.7)] arms, respectively. Pathological complete response rates were 3.8% and 5.9%. Clinical response (75%) and breast-conserving surgery rates (69%) were similar in both arms. Preoperative Endocrine Prognostic Index 0 scores (breast cancer-specific survival) were observed in 17.6% and 8.0% of patients in LETPAL and chemotherapy arms, respectively. Safety profile was as expected, with 2 versus 17 serious adverse events (including 11 grade 4 serious AEs in the chemotherapy arm). Conclusion LETPAL combination was associated with poor pathological response but encouraging clinical and biomarker responses in Prosigna®-defined high-risk LBC. Contemporary chemotherapy regimen was associated with poor pathological and biomarker responses, with a much less favourable safety profile. LETPAL combination might represent an alternative to chemotherapy in early high-risk LBC. Clinical Trial Number NCT02400567.

This abstract was withdrawn by the authors.

Background: In 2014, UNICANCER (composed of 18 French Comprehensive Cancer Centers) launched the Epidemiological Strategy and Medical Economics (ESME) program to investigate real-world data in solid tumors. Real-world data give the opportunity to assess for the activity of specific drugs outside clinical trials. Eribulin is approved for pre-treated metastatic breast cancer (MBC). Marketing authorization has been granted in France in July 2012. However few data are available regarding its efficacy in real life. We evaluated eribulin use as second and third line of chemotherapy in MBC patients from the ESME database. Methods: Data from all newly diagnosed MBC patients having initiated at least one treatment between Jan. 2008 and Dec. 2014 are included in the ESME database. Data were collected retrospectively using a clinical trial-like methodology. Primary endpoint was overall survival (OS), defined from the starting date of second or third line chemotherapy (eribulin versus other chemotherapy). Progression-free survival (PFS) was calculated as a secondary endpoint. Results: Of 16,703 MBC patients included in the ESME database, 7,412 received at least 2 lines of chemotherapy: eribulin/other chemotherapy, total 1,966/5,446, second line 363/5,446, third line 654/2,669. Depending on second or third line chemotherapy use classification, median age was 59 years (range 20-97) and 58 year (range 21 – 94), triple negative tumors accounted for 20% and 19% of cases, and median follow-up reached 26 months and 22 months respectively. Table reports median OS and PFS, according to lines and type of chemotherapy. OS eribulin (months)OS other chemotherapy (months)pPFS Eribulin (months)PFS other chemotherapy (months)pSecond line12.4 (11.3-15.1)11.8 (11.3-12.3)0.4654.1 (3.7-4.9)4.1 (4.0-4.3)0.9225Third line10.3 (9.3-11.5)7.7 (7.3-8.0) Supportive analyses (using a propensity score for adjustment and as a matching factor for nested case–control analyses) and sensitivity analyses will be available for full presentation at the meeting. Conclusion: In this large-scale real-life setting, MBC patients treated with third line eribulin showed an improved OS and PFS compared with those receiving another chemotherapy. The difference was not statistically significant for second line treatment. Citation Format: Jacot W, Heudel P-E, Fraisse J, Gourgou S, Guiu S, Dalenc F, Pistilli B, Campone M, Levy C, Debled M, Leheurteur M, Chaix M, Lefeuvre C, Goncalves A, Uwer L, Ferrero J-M, Eymard J-C, Petit T, Mouret-Reynier M-A, Courtinard C, Cottu P, Robain M, Mailliez A. Real-life activity of eribulin among metastatic breast cancer patients in the multicenter national observational ESME program [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 P6-14-02.

Background Anti-HER2 therapies are associated with a risk of cardiac toxicity, particularly as part of anthracycline-based regimens. BERENICE (NCT02132949), a nonrandomized, Phase 2 cardiac safety study showed neoadjuvant treatment with pertuzumab (P) + trastuzumab (H) and 2 common anthracycline–taxane-based regimens had a safety profile consistent with prior studies of P+H, and was associated with high pathologic complete response rates. Here we report safety data from the P+H adjuvant treatment period (AP). Methods Patients (pts) with centrally confirmed, localized HER2-positive breast cancer and normal cardiac function received 4 q2w dose-dense doxorubicin and cyclophosphamide cycles (60/600mg/m2) then 12 qw paclitaxel injections (80mg/m2; Cohort A), or 4 q3w fluorouracil/epirubicin/cyclophosphamide cycles (500/100/600 mg/m2) then 4 q3w docetaxel cycles (75mg/m2, up to 100mg/m2;Cohort B). In both cohorts, 4 q3w cycles of P (loading:840mg; maintenance:420mg) + H (loading:8mg/kg; maintenance:6mg/kg) were started with taxane therapy and continued in the adjuvant setting (for up to 13 cycles to complete 1 year of treatment). Surgery was scheduled after 8 cycles of preoperative therapy. Primary endpoints were incidence of New York Heart Association (NYHA) Class III/IV heart failure and incidence of left ventricular ejection fraction (LVEF) declines (≥10%-points from baseline to Results In total, 397 pts received ≥1 dose of study medication and were included in the overall treatment period (OTP) safety analysis. Of these, 371 (Cohort A:181; Cohort B:190) pts entered the AP and were included in the AP safety analysis. Mean (SD) number of AP treatment cycles of P and H were 12.3 (2.0) in Cohort A and 12.3 (2.2) in Cohort B. In the AP, incidence of heart failure was minimal (0.5%) and confirmed LVEF decline incidence was low (Table 1). Table 1: Cardiac AE Cohort ACohort B OTP n=199AP n=181OTP n=198OTP n=190NYHA Class III/IV heart failure Events, n4011Pts with event, n (%)3(1.5)01(0.5)1(0.5)LVEF decline Events, n36223429Pts with LVEF decline, n (%)21(10.6)14(7.7)22(11.1)20(10.5)Pts with confirmed LVEF decline, n (%)7(3.5)5(2.8)7(3.5)6(3.2) General adverse events (AEs) are shown in Table 2; 26 (14.4%) pts in Cohort A and 45 (23.7%) in Cohort B had diarrhea AEs (mostly grade 1). Table 2: General AE Cohort ACohort BPts, n (%)OTP n=199AP n=181OTP n=198AP n=190Any AE198(99.5)171(94.5)198(100.0)171(90.0)Grade ≥3 AE109(54.8)23(12.7)126(63.6)40(21.1)Serious AE54(27.1)15(8.3)61(30.8)17(8.9)AE leading to P or H discontinuation19(9.5)9(5.0)14(7.1)11(5.8) Conclusion P+H in the adjuvant setting, following P+H with anthracycline-based regimens in the neoadjuvant setting, are associated with low incidence of cardiac AEs. Cardiac safety results for P+H in the AP and OTP of BERENICE were consistent with results from prior studies evaluating adjuvant treatment with single-agent H, suggesting the addition of P to H in the adjuvant setting does not increase cardiac toxicity. Citation Format: Dang C, Ewer MS, Delaloge S, Ferrero J-M, Verrill M, Colomer R, Vieira C, de la Cruz Merino L, Lucas J, Werner TL, Douthwaite H, Bradley D, Waldron-Lynch M, Eng-Wong J, Swain SM. Safety of adjuvant treatment with pertuzumab plus trastuzumab after neoadjuvant anthracycline-based chemotherapy in patients with HER2-positive localized breast cancer: Updated results from the BERENICE study [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 P5-20-04.

Background Primary inflammatory breast cancer (IBC) is a rare and aggressive entity whose prognosis has been improved by multimodal therapy. However, 5-year overall survival (OS) remains poor. Given its low incidence, the prognosis of IBC at metastatic stage is poorly described. Materials and methods This study aimed to compare OS calculated from the diagnosis of metastatic disease between IBC patients and non-IBC patients in the Epidemiological Strategy and Medical Economics database (N = 16 702 patients). Secondary objectives included progression-free survival (PFS) after first-line metastatic treatment, identification of prognostic factors for OS and PFS, and evolution of survival during the study period. Results From 2008 to 2014, 7465 patients with metastatic breast cancer and known clinical status of their primary tumor (T) were identified (582 IBC and 6883 non-IBC). Compared with metastatic non-IBC, metastatic IBC was associated with less hormone receptor-positive (44% versus 65.6%), more human epidermal growth factor receptor 2-positive (30% versus 18.6%), and more triple-negative (25.9% versus 15.8%) cases, more frequent de novo M1 stage (53.3% versus 27.7%; P < 0.001), and shorter median disease-free interval (2.02 years versus 4.9 years; P < 0.001). With a median follow-up of 50.2 months, median OS was 28.4 months [95% confidence interval (CI) 24.1-33.8 months] versus 37.2 months (95% CI 36.1-38.5 months) in metastatic IBC and non-IBC cases, respectively (P < 0.0001, log-rank test). By multivariate analysis, OS was significantly shorter in the metastatic IBC group compared with the metastatic non-IBC group [hazard ratio = 1.27 (95% CI 1.1-1.4); P = 0.0001]. Survival of metastatic IBC patients improved over the study period: median OS was 24 months (95% CI 20-31.9 months), 29 months (95% CI 21.7-39.9 months), and 36 months (95% CI 27.9-not estimable months) if diagnosis of metastatic disease was carried out until 2010, between 2011 and 2012, and from 2013, respectively (P = 0.003). Conclusion IBC is independently associated with adverse outcome when compared with non-IBC in the metastatic setting., Highlights • IBC is a rare and aggressive form of breast cancer with poor prognosis. • OS was compared between IBC and non-IBC patients in a national French cohort of metastatic breast cancer. • IBC was correlated with more pejorative histologic characteristics. • Outcomes (OS and PFS) were significantly and independently worse in IBC than in non-IBC metastatic breast cancer.

Background A genomic-driven therapeutic strategy in metastatic breast cancer (MBC) was recently demonstrated as feasible in the clinical practice, but its actual impact on patient outcome remains elusive. SAFIR02 study is an ongoing national multicentric phase II randomized trial evaluating targeted therapies matching specific genomic alterations (GA) administered as maintenance after objective response and/or stable disease obtained with chemotherapy in HER2-negative MBC patients. This analysis reports on feasibility of the procedure and the rate of identified actionable targets. Methods Eligible MBC patients (PS=0/1, first- or second-line of chemotherapy, HER2-negative/hormone receptor (HR)-negative or endocrine resistant HR-positive; measurable per RECIST 1.1; accessible to tumor biopsy; no bone metastases-only disease, no major organ dysfunction) were subjected to tumor biopsy for genomic analysis (CGH arrays, Affymetrix Cytoscan; NGS, Ion Torrent PGM, AmpliSeq, panel of around 50 genes). Actionable GA were identified and corresponding targeted therapies were proposed by a multidisciplinary tumor board (MTB). Patients received cytotoxic-based treatment at physician's choice and those with stable or responding disease after 6 to 8 cycles (or at least 4 if stopped for toxicity reason) and targetable GA, were offered randomization between targeted therapy or chemotherapy maintenance until progression or intolerance (main study). Since January 2016, an amendment was made to propose to patients without targetable alteration a randomization between anti-PD-L1 (MEDI4736) or standard chemotherapy maintenance (substudy). Results Between March 2014 and May 2016, 457 patients have been enrolled at 21 centers. Genomic analyses could not be obtained in 107 cases (23%) due to either biopsy failure (n= 40; 9%) or low cellularity (n=67; 14%). Of the 307 patients reviewed by the MTB, 197 (64%) had an actionable GA, including PIK3CA-PIK3CB-PIK3R1 (n=51), FGF4 or FGFR1/2 (n= 42), BRCA1/2 (n=15), AKT1/2/3 (n=13), BRAF/KRAS/NRAS (n=13), HER2/3 (n=10), NF1-FRS2 (n=10), MTOR-RPTOR-TSC2 (n=8), PTEN (n=7), STK11 (n=7), IGF1R (n=7), EGFR (n=5). Therapeutic proposals by MTB included AZD5363 (n=71), AZD4547 (n=42), AZD2014 (n=23), selumetinib (n=23), olaparib (n=16), AZD8931 (n=15), vandetanib (n=5), bicalutamide (n=2). In an exploratory analysis involving 157 patients, the rate of targeted therapy proposal by MTB markedly differed between triple-negative patients (TNBC; 24 of 48, 50%) and HER2-negative/HR-positive patients (92 of 109, 84%; p=6.14. 10-6, Chi-2 test). At the time of the analysis, 85 patients have been randomized (main study, 68; substudy, 17). Causes of randomization failure (n=108) included disease progression (n=45) or death (n=25), non-eligibility criteria (n=27), patient/physician's decision (n=11). Conclusion A large number of patients had identified targetable GA. Of note, the rate of targeted therapeutic proposal was significantly lower in TNBC than in HER2-negative/HR-positive patients. Rapidly progressing disease may impede ultimate randomization. Citation Format: Gonçalves A, Bachelot T, Lusque A, Arnedos M, Campone M, Bièche I, Lacroix L, Pierron G, Dalenc F, Filleron T, Sablin M-P, Jimenez M, Ferrero J-M, Lefeuvre-Plesse C, Bonnefoi H, Attignon V, Soubeyran I, Jezequel P, Commo F, André F. High-throughput genome analysis and therapeutic decision for patients with HER2-negative metastatic breast cancer: First feasibility and molecular results of the randomized phase II study SAFIR02 BREAST (UCBG-0105/1304) [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 PD1-08.

Background : The addition of anti-proliferative agents such new inhibitors of CDK4/6 to hormonotherapy have significantly improved the efficacy in patients with metastatic breast cancer (MBC). Oral vinorelbine provided the opportunity to give new schedules of chemotherapy with favourable tolerability and prolonged exposure. The present trial was designed to evaluate the clinical effects of the addition of oral vinorelbine to aromatase inhibitors in first line treatment for MBC. Methods : In this phase III, randomized, prospective, open trial named VICTORIANE (NCT02730091), postmenopausal women with HR+/HER2– with MBC are randomized (1:1) between letrozole or anastrozole once a day (Arm A) versus oral vinorelbine 50 mg three times a every week with letrozole or anastrozole (Arm B). Continuous daily schedule (days 1-28 of each 28 days cycle) is planned until disease progression or discontinuation for other reasons. A minimisation algorithm was used stratifying treatment allocation according to the existence of visceral metastases, prior adjuvant hormonal treatment and centers. The study is conducted in compliance with the principles of good clinical practice and the declaration of Helsinki. Key inclusion criteria include, histologicaly proven HER2-negative and Estrogen Receptor-positive breast cancer, metastatic setting, no prior systemic anti-cancer therapy for MBC, recurrence after prior hormonal therapy in the adjuvant setting is allowed if disease free interval is greater than 24 months from the completion of treatment, normal liver, bone marrow and renal functions, Performans status greater than 2. Non inclusion criteria include symptomatic visceral disease, or disease burden precluding endocrine therapy, and prior therapy with vinorelbine. The primary endpoints is progression-free survival (PFS; local assessment, RECIST v1.1) and secondaries endpoints are overall survival, health-related quality of life, overall response rate and safety. Analysis of the primary endpoint will be performed with a stratified log-rank test (95% confidence interval). A 30 percent reduction in the risk of events (Hazard Ratio (HR) = 0.70) was assumed under H1 in the arm B. This reduction was estimated based on an absolute gain of 3.857 months in terms of median PFS, from 9 months (arm A) to 12.857 months (arm B). Global recruitment of the planned 340 pts is ongoing and should be completed in march 2018. Final results will be expected in 2019. Citation Format: Villanueva CB, Barthelemy P, Ferrero JM, Jacquin JP, Bonnetain F, Mansi L, Pivot X. VICTORIANE: A randomized phase 3 study assessing the addition of oral vinorelbine to aromatase inhibitors for the treatment of patients with metastatic breast cancer [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 OT1-04-07.

Background: Neoadjuvant pertuzumab (P)+trastuzumab (H)+standard chemotherapy (CT) significantly increases pathologic complete response (pCR) rates v H+CT. However, anti-HER2 therapy following anthracyclines can cause heart failure, and data are limited or lacking on combining P+H after epirubicin or doxorubicin. We report cardiac and overall safety as well as total pCR (tpCR) rates with widely used but understudied anthracycline-containing regimens. Methods: BERENICE (NCT02132949), a non-randomized, open-label, phase II study, enrolled patients (pts) with centrally confirmed HER2-positive, locally advanced, inflammatory, or early-stage, unilateral, and invasive breast cancer, Eastern Cooperative Oncology Group performance status ≤1, and baseline left ventricular ejection fraction (LVEF) ≥55%. In the neoadjuvant period, Cohort A pts received four q2w dose-dense doxorubicin+cyclophosphamide cycles (60 mg/m2/600 mg/m2 with granulocyte-colony stimulating factor support as needed) followed by 12 qw paclitaxel doses (80 mg/m2) + four q3w P+H cycles (P 840 mg, then 420 mg; H 8mg/kg, then 6 mg/kg). Cohort B received four q3w fluorouracil/epirubicin/cyclophosphamide cycles (500 mg/m2/100 mg/m2/600 mg/m2) followed by four q3w docetaxel cycles (75 mg/m2 escalated to 100 mg/m2) + four q3w P+H cycles. Surgery was performed after cycle 8 for both cohorts. The primary objective was to evaluate cardiac safety during the neoadjuvant period, assessed by incidence of 1) New York Heart Association (NYHA) Class III/IV heart failure and 2) significant LVEF declines (≥10% from baseline with a value of Results: Four hundred one pts were enrolled between Jul 2014–Aug 2015. Clinical cutoff was Mar 3, 2016. Demographics and baseline characteristics were generally balanced between cohorts; 64.3% v 61.7% of pts had centrally confirmed hormone receptor (HR)-positive disease and 95.0% v 93.0% had T1–T3 primary tumors. Three pts in Cohort A and none in Cohort B experienced NYHA Class III/IV heart failure during neoadjuvant treatment (table). Thirteen pts in Cohort A v four in Cohort B had significant LVEF declines (table). One Cohort B pt's LVEF decline was prior to anti-HER2 treatment. AE and serious AE (SAE) rates were well balanced between cohorts. The most common AEs were nausea, diarrhea, and alopecia. The most common SAE was febrile neutropenia. tpCR rates were similar between cohorts (table). Neoadjuvant periodCohort ACohort BSafety: Pts, n (%)N=199N=198NYHA Class III/IV heart failure3 (1.5%)0Significant LVEF decline13 (6.5%)4 (2.0%)tpCR (ypT0/Tis ypN0): Pts, n/N (%) Intention-to-treat123/199 (61.8%)122/201 (60.7%)HR-positive66/128 (51.6%)71/124 (57.3%)HR-negative53/65 (81.5%)51/75 (68.0%) Conclusion: Cardiac and general safety of the two anthracycline-containing regimens in BERENICE were as expected and were consistent with the known P+H+CT profiles. Both regimens were active, and tpCR rates were high. Citation Format: Swain SM, Ewer MS, Viale G, Delaloge S, Ferrero JM, Verrill M, Colomer R, Vieira C, Werner TL, Douthwaite H, Bradley D, Waldron-Lynch M, Eng-Wong J, Dang C. Primary analysis of BERENICE: A phase II cardiac safety study of pertuzumab, trastuzumab, and neoadjuvant anthracycline-based chemotherapy in patients with locally advanced, inflammatory, or early-stage, unilateral, and invasive HER2-positive breast cancer [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 P4-21-41.

Background: The COVID-19 pandemic rapidly spread in Europe and France Cancer patients were identified at higher risk of infection and evolution to severe forms, especially those undergoing active treatment Academic and experts’ recommendations proposed to protect cancer units and prioritize cancer treatment In the same time, French authorities implemented a national lockdown from march 16, 2020 Most anti-cancer institutions have modified their organization, trying to combine cancer units COVID-free sanctuarization, continuity in priority care and precautionary principle The impact of COVID-19 outbreak on global cancer care has not been formally evaluated Methods: Data of oncological practice at the Antoine Lacassagne Center (mild-COVID-19 incidence rate area) were recorded (per week) for 3 periods, based on the timing of french lockdown: before (Jan-1 to Mar-15), during (Mar-16 to May-10) and after the end of lockdown (May-11 to Jul-12) We collected the number of chemotherapy and radiotherapy sessions, surgery procedures (senology and gynecology), blood products transfusions, on-site / telemedicine visits and inclusions in clinical trials Results: Preliminary results compare period 1 (Jan-1 to Mar-15) to interim period 2 (Mar-16 to Apr-19, available data at the time of submission) Variation of practice is detailed in the table Activities were negatively impacted by the lockdown, mostly reconstructive surgery (-90%), on-site oncology visits (-73%) and clinical research (-69%) In parallel, telemedicine visits were multiplied by 100 [Formula presented] Conclusions: The evaluation of practice variation for cancer care is essential to understand the real impact of COVID-19 outbreak on global cancer management, so as to get prepared to further epidemic waves (for ex implementation of telehealth innovations) or long-term consequences on cancer outcome Legal entity responsible for the study: The authors Funding: Has not received any funding Disclosure: D Borchiellini: Advisory/Consultancy, Research grant/Funding (institution): Astellas;Astra Zeneca;MSD;Novartis;Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: BMS;Janssen;Pfizer;Roche;Research grant/Funding (institution): Calithera;Exelixis;Infinity;Merck KGaA;Advisory/Consultancy: Ipsen;Sanofi J-M Hannoun-Levi: Advisory/Consultancy: Eckert & Ziegler BEBIG E Francois: Honoraria (self): Amgen;MSD;Novartis;Honoraria (self), Travel/Accommodation/Expenses: Servier;Advisory/Consultancy, Travel/Accommodation/Expenses: Roche All other authors have declared no conflicts of interest

Background: Due to better molecular classification and new treatment options, epidemiology and prognosis of mBC is rapidly changing. Clinical data extracted from randomized studies are only relevant to specific subpopulations and retrospective studies are prone to selection bias. SToRM is a prospective clinical trial that aims to create a cohort of 1500 mBC patients, with the ultimate goal of identifying germ line polymorphisms associated with prognosis of breast cancer (BC) and response to treatment in the metastatic phase. Material and methods: Any newly (within 1 year) diagnosed mBC patients were eligible. Whole blood samples were drawn and germline DNA extracted for genetic analysis. Extensive epidemiologic data, disease history from primary diagnosis to metastatic spread, pathological characteristics and ER, PR and HER2 status were collected. Patients are prospectively followed until death. Genotyping using the HumanCoreExome chipset from Illumina is currently underway and will be completed in early summer 2015. Results: 1502 patients were included from March 2012 to May 2014 from 71 French institutions. Median age at metastatic relapse was 60 years (range 26-93). Median time from primary diagnosis to metastatic relapse was 30 months (range 0-473) with 24% of patients already metastatic at initial diagnosis. 78% of patients were ER+, 18% were HER2+ and only 16% were triple negative. Molecular subtype classification derived from pathological data following St Gallen consensus recommendations is presented below: n (%)Luminal A like261 (22.2%)Luminal B like HER2 negative476 (40.5%)Luminal B like HER2 positive134 (11.4%)HER2 positive non Luminal (ER-)111 (9.5%)Triple negative193 (16.4%)Missing data327 64% of the patients had received previous adjuvant treatment, among which 81% received adjuvant chemotherapy and 9% trastuzumab. At metastatic relapse, loco-regional progression, liver, lung and bone metastasis were documented in 301 (20%), 494 (33%), 410 (27%) and 1017 (68%) patients respectively. 313 patients (21%) had bone only metastatic disease. First line treatment included: chemotherapy (71%), endocrine therapy (50%) and anti-HER2 treatments (17%). Survival data will be presented at the meeting. Conclusion: Despite a theoretically better prognosis and widespread use of adjuvant hormonal treatment, ER+/HER2- breast cancer still account for more than 60% of mBC. The proportion of patients with HER2+ disease (18%) and triple negative disease (16%) is consistent with percentages observed in early BC populations. In comparison with a cohort of "cured", localized cancer, such as the SIGNAL/PHARE study, GWAS analysis will allow for the identification of genetic polymorphisms correlated with treatment resistance. Fundamentally, such variants will provide insight into the molecular mechanisms responsible for host-genetic influence on BC progression. From a clinical perspective, genetic variants that predispose to metastatic disease can serve as stratification variables in future clinical trials, particularly as the development of new treatment options for resistant BC is needed. Citation Format: Bachelot T, Lavergne E, Romieu G, Rios M, Heudel P-E, Roemer-Becuwe C, Jouannaud C, Tredan O, Chaigneau L, Arnedos M, Orfeuvre H, Petit T, Quenel-Tueux N, Jacquin J-P, Ferrero J-M, Moullet I, Abadie-Lacourtoisie S, Penault-Llorca F, Blanc E, Cox D. SToRM: A prospective clinical trial of 1502 metastatic breast cancer (mBC) patients with detail of clinical presentation, molecular subtype, treatment modalities, prognosis and GWAS genotyping. [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 P1-08-06.

Background: Breast cancer (BC) during pregnancy (BCP) is a rare situation that requires collaboration between oncologists, surgeons and obstetricians. The main objectives of this study were to compare the overall survival (OS) and disease free survival (DFS) of a multicenter cohort of pregnant patients (pts) with those of matched control pts. Methods: Patients from 27 centers and diagnosed between 2000 and 2006 with histological confirmed M0 invasive BC were included in this retrospective study. For the cohort of BCP, pts whose pregnancy was interrupted were not eligible. Controls were matched to BCP pts on 5 criteria: clinical T (of TNM), hormonal receptor (HR) status, HER2 status, administration of neo-adjuvant chemotherapy and pathological nodal status in the absence of neo-adjuvant chemotherapy. Survival times were estimated from the date of diagnosis using Kaplan-Meier method. OS was calculated until death from every cause, DFS was calculated until relapse or death from every cause; patients alive were censored at the date of last news. Results: 100 BCP pts were identified. Their clinical and pathological characteristics were described on a previous presentation (SABCS 2013 P6-06-07). Matched controls could not be found for 12 BCP pts. 88 BCP pts were matched with 204 controls. The only differences between the 2 populations in terms of characteristics or treatment were more radical mastectomy (p=0.036) and fewer taxane administrations in the BCP group (p=0.06). The median duration of follow-up was 8.2 years for cases and 7.7 years for controls. There were no differences between BCP pts and controls in 5-year OS: 83.4%, IC 95% (73.5-89.8) vs 83.8%, IC 95% (77.9-88.3) nor 7-year OS: 76.5% (65.5-84.4) vs 78.1% (71.5-83.3) (p=0.52). The 5-year DFS was 58.6% IC 95% (47.3-68.3) vs 67.2% IC 95% (60.2-73.2) (p= 0.16). However, 5-year DFS was lower in HR+ BCP pts subgroup than in HR+ control group (56.7% IC 95% (40.7-69.8) vs 70.9% IC 95% (61.4-78.5) (p=0.023). Conclusion: This multicenter French large study confirmed that there are no differences on OS and DFS between pregnant and no pregnant pts, though this might not be true for HR subgroup. Citation Format: Vanlemmens L, Ploquin A, Delaloge S, Rouzier R, Lesur A, Frenel J-S, Loustalot C, Bachelot T, Provansal M, Ferrero J-M, Coussy F, Debled M, Kerbrat P, Vinceneux A, Djelila A, Baron M, Jebert S, Decoupigny E, Tresch E, Bonneterre J. 5-year overall survival of early breast cancer during pregnancy: A multicenter French case control study. [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 P1-07-02.

Introduction Les inhibiteurs de CDK4/6 associes a une hormonotherapie ont montre leur efficacite chez les patientes atteintes d’un cancer du sein metastatique (CSM), hormono-sensible (RH + ) et sans amplification du recepteur 2 du facteur de croissance epidermique humain (HER2-) dans plusieurs essais therapeutiques de phase 3. Ces essais ont identifie des facteurs pronostiques (FP) independants de la survie sans progression (SSP) tels que la presence de metastases hepatiques (MH) au diagnostic, statut du recepteur a la progesterone (RP), le grade tumoral (G), le « performance status » (PS) au diagnostic et la presence de metastases osseuses exclusives (MO). Le but de ce travail est de decrire ces FP au sein de cette population cible en pratique courante. Methodes La Plateforme Epidemiologie Strategie Medico-Economique (ESME) CSM ( NCT03275311 ) est alimentee par un recueil retrospectif et multicentrique de donnees (18 CLCCs) a partir des donnees du Dossier Patient Informatise. La population eligible etait les patientes diagnostiquees et ayant initie une premiere ligne pour un CSM RH+/HER2 entre le 01/01/2008 et le 31/12/2015. Ont ete exclus de l’analyse, les patientes presentant un autre cancer synchrone, des metastases cerebrales, un cancer du sein inflammatoire et celles ayant recu une hormonotherapie de type antiestrogene en traitement du primitif. Un modele de Cox etait utilise pour l’analyse des facteurs pronostiques. Resultats Au total, 9852 cas ont ete inclus dans l’analyse. Le suivi median de cette population etait de 50,6 mois (IC95 %, 49,4–51,6). La survie sans progression mediane etait de 12,2 mois (IC :95 % 11,9–12,6). Le modele de Cox multivarie montre que la presence de MH, l’absence d’expression de RP et un haut G tumoral sont des FP du CSM (HR = 1,65, 95 %IC = [1,56–1,74] ; HR = 0,83, 95 %IC = [0,79 ; 0,88] ; HR = 1,45, 95 %IC = [1,35–1,57] respectivement). Le PS n’a pas ete decrit etant donne le nombre important de donnees manquantes. Conclusion La presente description de la prise en charge en pratique courante de 9852 patientes avec un CSM de type RH+/HER2-, diagnostiquees entre 2008 et 2015 et presentant des FP defavorables (MH, RP-, haut G tumoral) retrouve des resultats similaires a ceux des essais cliniques pour cette population, demontrant leur eligibilite a un traitement par inhibiteurs des cyclines CDK4/6 et soulignant l’importance de cette famille de molecule dans le traitement du CSM HR+/HER2- en 1ere ou 2e ligne.

Background Breast cancer diagnosed during pregnancy (BCP) is rare, but the prevalence is expected to rise. Long-term follow-up data regarding this clinically challenging condition are scarce. The main objective of this multicentre case-control French study was to compare the survival between pregnant patients and matched controls. Methods Patients from 27 centres diagnosed between 2000 and 2009 with histologically proven invasive breast cancer occurring during pregnancy were retrospectively included. Controls were matched to BCP patients on age, clinical T stage, hormone receptor, HER2, administration of neo-adjuvant chemotherapy and pathological node involvement in the absence of neo-adjuvant chemotherapy. Five-year overall survival (OS), disease-free survival (DFS) and metastasis-free survival (MFS) rates were estimated using the Kaplan–Meier method. Results One hundred and eleven BCP patients and 253 controls were included. Median age was 33 and 35 years, respectively. Both populations were managed similarly, except for less frequent sentinel node dissection (p = 0.026) and taxane administration (p = 0.03) among BCP patients. Median follow-up was 7.5 years. Survival rates were similar between both BCP and control patients: 5-year OS rates were 83.1% (95% CI: 74.5–89.0) vs 85.5% (95% CI: 80.4–89.4), respectively, p = 0.31; 5-year DFS rates 60.0% (95% CI: 50.1–68.6) vs 68.5% (95% CI: 62.3–73.9), respectively, p = 0.12 and 5-year MFS rates 71.0% (95% CI: 61.3–78.6) and 74.5% (95% CI: 68.6–79.5), respectively, p = 0.21. Conclusion Our study showed that the survival outcomes of patients diagnosed with BCP were not significantly different as compared to those of matched non-pregnant controls. A proper management of women diagnosed with BCP is crucial.

Background Anti-HER2 therapies are associated with a risk of increased cardiac toxicity, particularly when part of anthracycline-containing regimens. We report cardiac safety of pertuzumab, trastuzumab, and chemotherapy in the neoadjuvant treatment of HER2-positive early breast cancer. Patients and methods BERENICE (NCT02132949) is a nonrandomized, phase II, open-label, multicenter, multinational study in patients with normal cardiac function. In the neoadjuvant period, cohort A patients received four cycles of dose-dense doxorubicin and cyclophosphamide, then 12 doses of standard paclitaxel plus four standard trastuzumab and pertuzumab cycles. Cohort B patients received four standard fluorouracil/epirubicin/cyclophosphamide cycles, then four docetaxel cycles with four standard trastuzumab and pertuzumab cycles. The primary end point was cardiac safety during neoadjuvant treatment, assessed by the incidence of New York Heart Association class III/IV heart failure and of left ventricular ejection fraction declines (≥10 percentage-points from baseline and to a value of

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.

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 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.

Aim: The aim of this study was to determine the rate of breast -onserving surgery (BCS) after neoadjuvant chemotherapy (nCT) in patients initially thought suitable for mastectomy as the only conceivable surgical option. Methods: This retrospective study was conducted in the Cancer Center Antoine Lacassagne in Nice (France). Between 2007 and 2012, 168 patients received nCT. We selected among those only the ones who received nCT (n = 119) in order to facilitate a conservative treatment's surgery (a radical treatment was the single option that could be initially proposed to these patients). Patients presenting with metastatic, inflammatory or multifocal tumors or the ones that could already be eligible for a conservative treatment without any nCT were excluded. Results: Among the 119 patients included, 118 presented an invasive ductal carcinoma, a SBR grade 3 in 54.8% and triple negative breast tumor in 34.4%. The mean tumor size before nCT measured by MRI was 41.6 mm (15-110) and 25.3 mm (0-90) after nCT. Eighty-six of patients (72.3%) underwent a BCS. For 33.6% of these patients, an oncoplastic technique was used. Only 4.3% of the selected patients had to undergo an additional surgery due to insufficient surgical margins during the initial surgery. The median follow-up was 41.1 month (CI95%: 35.2-48.3). Five-years overall survival (OS) and disease-free survival (DFS) were 76% (CI95%: 65-89), 71% (CI95%: 61-82), respectively. The factors significantly affecting the eligibility to BCS were as follows: the MRI tumor's initial size with 34 mm (range: 15-100) for BCS versus 55 mm (range: 23-110) for mastectomy (p Conclusions: nCT for patients with “chemosensitive” breast tumor leads to a significant “mastectomy to BCS” conversion's rate. The type of surgery does not seem to affect the patient's OS and DFS. Oncoplastic procedures allow expandion of patient eligibility for BCS after nCT. Disclosure: All authors have declared no conflicts of interest.

Background Inflammatory breast cancer (IBC) is a rare and aggressive disease requiring a multimodal treatment. We evaluated the benefit of adding docetaxel–5-fluorouracil (D-5FU) regimen after preoperative dose-intense (DI) epirubicin–cyclophosphamide (EC) and locoregional treatment in IBC patients. Patients and methods PEGASE 07 was a national randomized phase III open-label study involving 14 hospitals in France. Women with nonmetastatic IBC were eligible and randomly assigned to receive either four cycles of DI EC (E 150 mg/m2 and C 4000 mg/m2 every 3 weeks with repeated hematopoietic stem cell support), then mastectomy with axillary lymph node dissection, and radiotherapy (arm A) or the same treatment followed by four cycles of D-5FU (D 85 mg/m2, day 1 and 5FU 750 mg/m2/day continuous infusion, days 1–5 every 3 weeks) administered postradiotherapy (arm B). Patients with hormone receptor-positive tumors received hormonal therapy. Disease-free survival (DFS) was the primary end point. Secondary end points included tolerance, pathological complete response (pCR) rate, and overall survival (OS). Results Between January 2001 and May 2005, 174 patients were enrolled and treated (87 in each arm). Median follow-up was similar in both arms: 59.6 months [95% confidence interval (CI) 58.4–60.3] in arm A and 60.5 months (95% CI 58.3–61.4) in arm B. The estimated 5-year DFS rates were not different: 55% (95% CI 43.9–64.7) in arm A and 55.5% (95% CI 44.3–65.3) in arm B [hazard ratio (HR) = 0.94 (0.61–1.48); P = 0.81]. Identical results were observed for 5-year OS: 70.2% (95% CI 59.1–78.8) in arm A and 70% (95% CI 58.8–78.7) in arm B [HR = 0.93 (0.55–1.60); P = 0.814]. Following DI EC induction, in-breast and global (breast plus nodes) pCR were 28.9% and 20.1%, respectively. Estrogen receptor and pCR status were independently associated with survival. Conclusion The addition of D-5FU after preoperative DI EC and standard local therapy did not improve DFS in IBC. Clinical trial number ClinicalTrials.gov identifier: NCT02324088.

International audience; Background: We present a pooled analysis of predictive and prognostic values of circulating tumour cells (CTC) and circulating endothelial cells (CEC) in two prospective trials of patients with inflammatory breast cancer (IBC) treated with neoadjuvant chemotherapy combined with neoadjuvant and adjuvant bevacizumab. Patients and methods: Nonmetastatic T4d patients were enrolled in two phase II multicentre trials, evaluating bevacizumab in combination with sequential neoadjuvant chemotherapy of four cycles of FEC followed by four cycles of docetaxel in HER2-negative tumour (BEVERLY-1) or docetaxel and trastuzumab in HER2-positive tumour (BEVERLY-2). CTC and CEC were detected in 7.5 and 4 ml of blood, respectively, with the CellSearch System. Results: From October 2008 to September 2010, 152 patients were included and 137 were evaluable for CTC and CEC. At baseline, 55 patients had detectable CTC (39%). After four cycles of chemotherapy, a dramatic drop in CTC to a rate of 9% was observed (P < 0.01). Pathological complete response (pCR) rate was 40%. No correlation was found between CTC or CEC levels and pCR rate. Median follow-up was 43 months. CTC detection (1 CTC/7.5 ml) at baseline was associated with shorter 3-year disease-free survival (39% versus 70% for patients without CTC, P < 0.01, HR 2.80) and shorter 3-year overall survival (OS) (P < 0.01). In multivariate analysis, independent prognostic parameters for shorter survival were absence of hormonal receptors , no pCR and CTC detection at baseline. CEC level at baseline or variations during treatment had no prognostic value. Conclusion: In this pooled analysis of two prospective trials in nonmetastatic IBC, detection rate of CTC was 39% with a strong and independent prognostic value for survival. Combination of pCR after neoadjuvant treatment with no CTC detection at baseline isolated a subgroup of IBC with excellent OS (94% 3-year OS), suggesting that CTC count could be part of IBC stratification in prospective trials.

Background EndoTAG-1, composed of paclitaxel embedded in liposomal membranes targeting tumor endothelial cells, was evaluated for safety and efficacy in advanced triple-negative breast cancer (TNBC). Patients and methods One hundred and forty patients were treated with weekly EndoTAG-1 (22 mg/m2) plus paclitaxel (70 mg/m2), twice weekly EndoTAG-1 (2× 44 mg/m2), or weekly paclitaxel (90 mg/m2) for greater than or equal to four cycles (3-week treatment + 1-week rest) or until progression/toxicity. Primary end point was progression-free survival (PFS) rate evaluated centrally after four cycles of therapy (week 16). The study was not powered for intergroup comparisons. Results The PFS rate at week 16 was 59.1% [one-sided 95% CI: 45.6, ∞] on combination treatment, 34.2% [21.6, ∞] on EndoTAG-1, and 48.0% [30.5, ∞] on paclitaxel. Median PFS reached 4.2, 3.4, and 3.7 months, respectively. After complete treatment (week 41 analysis), median overall survival (OS) was 13.0, 11.9, and 13.1 months for the modified Intention-to-Treat (ITT) population and 15.1, 12.5, and 8.9 months for the per-protocol population, respectively. The clinical benefit rate was 53%, 31%, and 36% for the treatment groups. Safety analysis revealed known toxicities of the drugs with slight increases of grade 3/4 neutropenia on combination therapy. Conclusion Treatment of advanced TNBC with a combination of EndoTAG-1 and standard paclitaxel [Taxol® (Bristol-Myers Squibb GmbH), or equivalent generic formulation] was well tolerated and showed antitumor efficacy. The positive trend needs to be confirmed in a randomized phase III trial. Study registration European Clinical Trials Database: EudraCT number 2006-002221-23. ClinicalTrials.gov identifier: NCT00448305.

Background Long term information on the risk/benefit ratio of currently available therapies remains crucial for treatment decisions. In the PACS04 phase III trial, patients (pts) with node-positive (N+) breast cancer (BC) were double-randomized to concomitant taxane-anthracycline versus standard FEC, as well as 1-year trastuzumab versus nill in the HER2+ subpopulation. Methods 3009 pts (20% HER2+, 12% triple negative (TNBC) BC) were randomly assigned to receive 6 cycles of fluorouracil 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 (FEC) or epirubicin 75mg/m2 and docetaxel 75 mg/m2 (ED). Pts with HER2+ tumors were randomized to either trastuzumab (TRA) for one year, or observation (OBS). The primary endpoint was disease-free survival (DFS). Results After a median 115-month follow-up, DFS was not different in the ED compared to the FEC arm (70% vs 68% respectively, HR = 0.88 [95% CI: 0.77-1.01]; p = 0.064), nor was OS: 80% with FEC and 81% with ED (HR = 0.97 [95% CI: 0.81-1.16]; p = 0.729). Subgroup analysis suggested better DFS with ED in non-TNBC pts [HR = 0.82 (0.71-9.96) p = 0.02]. In the 528 pts with HER2+ BC, there was trend for a higher DFS in the TRA arm (68%; [95% CI: 61-74]) versus the OBS arm (60%; [95% CI: 54-66]); HR = 0.77 [95% CI:0.57-1.03]; p = 0.079 (intent to treat population). In the per protocol population, DFS, but not OS, was significantly higher in the TRA arm (HR: 0.69 [95%CI: 0.51-0.94]; p = 0.0156). ED led to more neurological and hematological toxicities (31% vs 11% febrile neutropenia) and led to 5 versus 1 treatment-related deaths. During follow-up, 75 pts developed a second non-breast primary cancer (43 with FEC and 32 with ED); 12 were hematologic malignancies (7 with FEC and 5 with ED). Long term cardiac deaths were rare (3 with FEC and 1 with ED). Conclusions This study did not show superiority of the concomitant anthracycline-taxane arm, which was more toxic in high-risk N+ BC pts. Long-term results of the HER2+ subpopulation are in line with the other adjuvant TRA trials but less striking probably due to lack of power. Long term cardiac toxicity and second primary cancer rate are similar to what has been reported by others. Clinical trial identification NCT00054587. Legal entity responsible for the study UNICANCER. 101 rue Tolbiac, 75013 Paris, France. Funding Roche, Ligue Nationale Contre le Cancer. Disclosure All authors have declared no conflicts of interest.

Background : The quality of life of couples which one of the members is affected by a cancerous pathology at a relatively young age is important to evaluate in global care. No questionnaire specifically addresses some thematic proper to young women (ex education, desire for a child(s), couple relationship), problems which are yet important for young women suffering from breast cancer. Besides, no questionnaire evaluates the partner's quality of life in this particular context, even if he is frequently the first source of support for the woman (Vanlemmens et al., 2012). Objectives : The main objective was to create a particular and specific tool for measuring the impact of breast cancer on the quality of life of young women (< 45 years of age) with non-metastatic disease and the quality of life of their partners. This work presents the psychometric validation of two questionnaires for patient and partner consisted of items comparable to the semantic level. Methods: We followed the different steps to construct a quality of life tool. After preliminary non-directive interviews and identification of relevant items, we administered the questionnaires on a wide sample of 546 young breast cancer patients and 497 partners. Psychometric testing assessed the hypothesized scale structure based on an examination of item-scale correlation, scale reliability by testing for internal consistency using Cronbach's alpha coefficient, construct validity with inter-scale correlations. Results : Items analyses indicate a good internal consistency of both questionnaires (superior to .75). This questionnaire includes 37 items. The factorial structure highlights 8 factors : 1) management of children and of everyday life, 2) negative affectivity and apprehension about future, 3) feeling of couple cohesion, 4) financial difficulties, 5) body image and sexual life, 6) deterioration with close relations, 7) sharing and support of close relations, and 8) management of the professional life..This structure explains respectively 56% for the patients and 58% for the partners of the total variance. As expected, convergent validity showed strong correlations with Kalicou scales and quality of life measures (QLQC-30 and QLQBR-23). Conclusions: Overall psychometric results for the 2 Kalicou questionnaires confirmed them as valid questionnaires for breast cancer patients and partners. This study will allow the clinicians to have a measurement tool for subjective real-life experience of young breast cancer women and their partner. These questionnaires will also allow comparisons according to the stage and study the interactions of couple. This tool should help to identify modifications of the subjective quality of life. The objective is to improve the medical, psychological and social care for patients and their partner, with a systemic, dynamic approach. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-09-07.

Background: Weekly paclitaxel and capecitabine intermittent regimen is a safe and effective combination in first line treatment of MBC including triple negative cancer (Lortholary et al, Breast Cancer Res Treat 2012). In TNMBC, the combination of A with first line Ta or Xel has been shown to improve response rate (RR) and progression-free survival (PFS) (Miller K et al., N Engl J Med 2007, Robert J et al., J Clin Oncol 2011). This phase II study is to evaluate the efficacy and safety of A-TaXel combination in TNMBC. Methods: Patients (pts) with measurable TNMBC were treated in first line until progression with q28 cycles of Ta (80 mg/m2 D1, 8, 15) + Xel (800 mg/m2 bid D1-5, 8-12, 15-19) + A (10 mg/kg D1, 14). Primary end point was best overall RR; secondary were safety, PFS, response duration and overall survival (OS). Results: From 04/2010 to 03/2012, 64 pts were accrued including 2 ineligible pts. Patients characteristics were: median age (56.7 yrs), ECOG PS 0 (55%), histological grade III (61%), previous adjuvant chemotherapy (74%), visceral disease (65%), > 1 metastatic sites (74%). Patients received a median of 6 cycles (1-6), mean 5.1. Grade 3-4 neutropenia, anemia and thrombopenia were 23%, 4% and 16% respectively with febrile neutropenia in 5% of pts. G-CSF support was observed in 7% of cycles. Most frequent non hematologic toxicities were alopecia (gr2 40%), hand-foot syndrome (gr2 27%, gr3 13%), nail toxicity (gr2 40%), hypertension (gr3 35%), neuropathy (gr2 26%, gr3 6%), mucositis (gr2 16%, gr3-4 9%), fatigue (gr3 18%, gr4 2%), nausea (gr2 15%, gr3 2%) and thrombosis (gr2 3%, gr3-4 5%). Treatment interruption due to toxicity was 22%, DPD deficiency in one patient, hospitalization 23%. RR was 77%, CR 19%, PR 58%, stable disease 14% and progressive disease 9%. Median response duration was 5.6 months. Median PFS was 7.9 months (6.7-9) and OS 19.2 months (17.3-21.1). Conclusion: A-TaXel is an effective regimen with high RR and manageable toxicity. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-13-07.

Background: A subset of patients with HER2-positive metastatic (mBC) or locally advanced breast cancer (aBC) respond to 1st line trastuzumab-based regimen and have no disease progression for several years. These long-term responders were evaluated in daily practice in the LORHA study. Patients and disease characteristics were presented earlier (ESMO 2012). Material and Methods: Lorha is an ambispective, multicenter, non-interventional study conducted in 57 centers in France. Eligible patients were women aged more than 18 years with HER2-positive mBC or aBC treated with 1st line trastuzumab and progression-free for at least 3 years after starting trastuzumab. The primary objective was to describe clinical and tumor characteristics. Secondary objectives included Progression Free Survival (PFS), Overall Survival (OS), treatment administration and safety. Patients were followed-up for 12 months. Final results are presented here. Results: Overall 160 patients were enrolled; 128 were eligible for efficacy analysis and 154 for safety analysis. Median age was 61 years [34-95]. Tumor characteristics were: invasive ductal carcinoma for 112 patients (88%), positive hormonal receptors in 72 patients (58%). At initial diagnosis, 91 patients (71%) had stage I - II tumors and 37 patients (29%) had de novo mBC or aBC. The main metastatic localizations were bone, liver, lymph nodes and lung in 54 (43%), 44 (35%), 25 (20%) and 24 (19%) patients, respectively. Median 1st line trastuzumab treatment duration was 4.5 years [0.8 - 12.1]. Trastuzumab 1st line was associated with a taxane-based chemotherapy in 104/128 patients (81%). Median PFS was 6.4 years [5.7; - Not reached] and median overall survival was not reached. At 1-year follow-up, 23 deaths (15% of patients) were reported, mainly due to disease progression (21 patients - 91%). No toxic death related to trastuzumab was observed. Grade 3-4 adverse events reported prospectively occurred in 14 patients (10%) and included two patients (1.2%) with grade 3-4 cardiac events related to trastuzumab (congestive cardiac failure and left ventricular dysfunction), both events resolved, one with sequelae. Conclusions: Final results of the LORHA study show that long responding patients receiving first-line trastuzumab-based treatment for aBC or mBC in daily practice, can reach a median PFS of more than 6 years, combined with an acceptable safety profile. Median overall survival is still not reached. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-08.

Background: Health Authorities point out that DPD deficiency confers a significant risk of major toxicity for patients receiving capecitabine. Identification of at-risk patients is thus of major concern. This multicentric prospective study of the French GPCO group (Groupe de Pharmacologie Clinique Oncologique, Unicancer) evaluated the sensitivity, specificity and predictive values of DPD phenotyping and genotyping to predict severe cap-related toxixity in metastatic breast cancer patients. Methods: 303 patients were included between February 2009 and February 2011 (15 institutions). Eighty-eight% received capecitabine as monotherapy, 28% were treated as first line (mean dose at 1st cycle 1957 mg/m2/d). Pre-treatment uracil (U, physiological DPD substrate) plasma concentration was measured in 286 patients (HPLC assay). DPD genotyping (IVS14+1G>A, 2846A>T, 1679T>G, 464T>A) was performed on 281 patients. Severe toxicity (G3-4 CTCAE v3 criteria) was measured over cycles 1-2. Results: Grade 3-4 toxicity (diarrhea, vomiting, hematoxicity, hand-foot syndrome) has been observed in 19.6% of patients (one toxic death). A marked trend for higher U concentrations has been noted in patients developing severe toxicity vs those who didn't (median 12.7 ng/ml (Q1-Q3 9-17) vs median 10.2 ng/ml (range 8-13), respectively, p = 0.014). However, ROC curve has showed that this difference was too small for use as a reliable toxicity predictor. The patient with toxic death had an elevated U concentration at 17 ng/ml. Among the 7 patients with a DPD mutation (3 pts IVS14+1, 3 pts 2846A>T, one 1679T>G, all heterozygous), 5 developed severe toxicity (including the toxic death, 2846A>T), one did not, and the last one was not documented. Relative risk for developing severe toxicity was 4.60 in mutated patients vs wild-type patients (95%CI 2.95-7.16, p = 0.001); positive and negative predictive values were 83.3% and 81.9%, respectively; specificity was 99.5% and sensitivity was 9.8%. Conclusions: Breast cancer patients harbouring a DPD variant allele are at risk to develop severe, up to lethal, capecitabine-related toxicity. Pre-treatment U measurement remains to be more firmly established as a reliable predictor of capecitabine toxicity. These observations are of major interest for breast cancer patients candidate for capecitabine therapy. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-15-04.

Background: Bevacizumab (Bev) and trastuzumab (H) are proven treatments of advanced or HER2-positive metastatic breast cancer; however, few data exist for these drugs in inflammatory breast cancer (IBC). The aim of our study was to assess efficacy and safety of neoadjuvant Bev combined with H and chemotherapy (CT) in patients (pts) with primary HER2 positive IBC. The primary endpoint of the study, pathological complete response (pCR) rate by central review according to Sataloff classification, has been previously reported (pCR = 63.5%) together with circulating tumor cells (CTC) and circulating endothelial cells (CEC) detection rates and changes during treatment (Pierga et al, Lancet Oncol 2012). In the present abstract we are reporting the 3 year follow up analysis results. Methods: In this phase 2, multicentre, open-label, single-arm, non-comparative trial, we enrolled women with histologically confirmed HER2-positive non-metastatic IBC. The primary endpoint was to determine the rate of pCR; secondary endpoints included disease-free survival (DFS), overall survival (OS), safety (CTCAE v3) and potential predictive markers. Pts received 4 cycles of FEC100 + BEV 15 mg/kg, d1 q21d, followed by 4 cycles of docetaxel 100 mg/m2 + BEV 15 mg/kg + H 8→6 mg/kg q21d. Pts underwent surgery 4–6 weeks after the last dose, followed by radiotherapy (RT). H was continued during surgery and RT and as adjuvant therapy. BEV was re-introduced as adjuvant therapy for 10 cycles, giving a total of 18 cycles each of BEV and H. CTC and CEC were detected by the CellSearch system. Results: We enrolled 52 pts in 21 centers; 42 (81%) of 52 pts received all eight cycles of neoadjuvant therapy, 49 pts (94%) underwent surgery; 48 pts (92%) received adjuvant treatment and 44 pts (85%) were followed during 3 years (there were 8 withdrawals from study treatment period). Grade ≥3 adverse events (AEs) in >5% of pts were: neutropenia (44% of pts); febrile neutropenia (29%); alopecia and leukopenia (10%), hand-foot syndrome and febrile bone marrow aplasia (8%), increased γ-glutamyltransferase (8%), anemia, hypertension and mucositis (each 6%). There were 9 pts with grade ≥3 AE of special interest for BEV: hypertension in 3 pt; proteinuria in 2 pts; postoperative wound complication, infected lymphocele, incision site abscess and impaired healing in 1 pt each and cardiac failure in 1 pt. Ten pts developed a cardiac failure (Grade ≥1), which was mostly Grade 2 and resolved in all cases. There was no treatment-related death. Median follow-up was 36 months. 3-year DFS rate was 67.8% [52.8- 79.0] and OS rate was 89.8% [77.2- 95.6]. pCR was significantly associated with DFS: 3 year DFS rate was 78% [95% CI:58- 89] in pts with pCR vs 53% [95% CI:29- 72] in pts without pCR (p = 0.0445). CTC positivity (≥1CTC/7.5ml) at baseline (35% of pts) was also strongly associated with lower DFS rate (3 year DFS: 43% [95% IC: 20- 64] vs 81% [95% IC: 62- 91], p Conclusion: Neoadjuvant BEV, H, and CT is highly active in IBC (3-y DFS 67.8%) with an acceptable safety profile. CTC positivity (≥1CTC/7.5ml) at baseline and pCR at the end of neoadjuvant treatment are two prognostic factors for DFS in non-metastatic IBC. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-12-06.

Background Inflammatory breast cancer (IBC) is a rare but aggressive form of locally advanced breast cancer, the optimal systemic treatment of which is still discussed. Beverly 2 trial was a phase II study evaluating the efficacy and safety of a preoperative regimen associating bevacizumab, trastuzumab, and chemotherapy in 52 patients with non-metastatic HER2-positive IBC, reporting a promising rate of pathological complete response (pCR, 63.5%, 95% CI 49.4–77.5; Pierga et al, Lancet Oncol, 2012). During the study, serum samples were collected at baseline and subjected to proteomic-based approaches to identify circulating biomarkers predictive of treatment response. Methods Baseline serum samples from responsive (pCR, according to Sataloff classification, n = 12) and non-responsive (no pCR, n = 11) patients were subjected to isobaric Tag for Relative and Absolute Quantification (iTRAQ)-based proteomics. Samples were pooled according to pCR and hormone receptor (HR) status, to constitute 4 independent mixes (pCR/HR-positive, pCR/HR-negative, nopCR/HR-positive, nopCR/HR-negative). Each of them underwent immuno-depletion of highly abundant proteins, concentration, reduction, alkylation and tryptic digestion. Then, each mix was fractionated and subjected to iTRAQ identification and quantitation using nano-liquid chromatography (LC) and electrospray ionisation (ESI)-orbitrap tandem mass spectrometry (MS/MS) (LTQ-orbitrap, Thermofisher). Differentially expressed proteins were analysed using IPA (IngenuitySystems) to highlight biological functions and signalling pathways that were most significantly enriched. Results iTRAQ-based measurements identified and quantified a total of 302 serum proteins. Among them, 48 proteins displayed a significant (fold-change > 1.5 and p-value < 0.05) differential expression between pCR and noPCR pts (18 proteins down-regultated and 30 proteins up-regulated in pCR patients), some of them previously described to be involved in breast cancer biology and/or angiogenesis, including : Alpha-1-acid glycoprotein 1, von Willebrand factor, Galectin-3-binding protein, serum amyloid A-1, Apolipoprotein E, Pigment epithelium-derived factor, Corticosteroid-binding globulin (down-regulated proteins in pCR patients); serum amyloid P-component, angiotensinogen, plasma serine protease inhibitor, carbonic anhydrase 1, mannose-binding protein C, hyaluronan-binding protein 2, peroxiredoxin-2, properdin, ADAMTS13, tetranectin, biotinidase, lumican (up-regulated proteins in pCR patients). Proteins with differential expression during treatment were involved in various biological processes, including cell-to-cell signaling and interaction, lipid metabolism, small molecule biochemistry, molecular transport, cellular function and maintenance as well as various canonical pathways such as acute phase response signalling, LXR/RXR activation and coagulation system. Conclusion iTRAQ-based quantitative proteomics identify serum proteins that could predict the therapeutic response to pre-operative trastuzumab plus bevacizumab-based chemotherapy in HER2-positive IBC. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-12-08.

Background: Decrease of circulating tumor cells (CTC) during treatment is an independent prognostic factor in metastatic breast cancer (MBC). We specifically evaluated the impact of CTC on brain metastasis outcome. Methods: HER2-positive MBC with brain metastasis not previously treated with whole-brain radiotherapy received firstline combination of lapatinib and capecitabine in a phase II study. CTC were detected at baseline and day 21 (CellSearch). Results: Median follow-up of the 44 analyzed patients was 21.2 months. The central nervous system objective response (CNS-OR) rate was 66%. At baseline, 20 of 41 assessable patients for CTC (49%) had ≥1 CTC (range 1–301, median 3) and 9 (22%) had ≥5 CTC. At day 21, 7 of 38 patients (18%) had ≥ 1C TC (P = 0.006, versus baseline), and CTC had disappeared in 11 patients. CNS-OR rate was significantly higher in patients with no CTC at day 21 [25 of 31 (80%) versus 2 of 7 (29%), P= 0.01]. The 1-year overall survival rate was 83.9% in patients with no CTC at day 21 versus 42.9% in patients with ≥ 1C TC (P= 0.02). Conclusions: This is the first report showing a correlation between CNS metastasis response, outcome and early CTC clearance under targeted treatment of HER2+ MBC. Clinical Trials number: NCT00967031.