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We assessed long-term associations of Granulocyte-Colony Stimulating Factors (G-CSF) use with patient-reported outcomes (PROs) and hematologic toxicity among chemotherapy-treated, early-stage breast cancer patients in CANTO (NCT01993498). Among 2920 patients longitudinally followed-up until year-4 after diagnosis, 49% used G-CSF. In multivariable-adjusted mixed-models, EORTC QLQ-C30 pain and summary score were not substantially different between groups (overall adjusted mean difference, use vs no-use [95%CI]: +1.27 [-0.33 to +2.87] and −1.01 [-1.98 to −0.04], respectively). PROs were slightly worse at year-4 among patients receiving G-CSF, although differences were of trivial clinical significance. No major differences were observed in leukocyte or platelet count over time., Highlights • Studies on long-term side effects of G-CSF, including on quality of life, are lacking. • We evaluated PROs and hematological values until year-4 after diagnosis among women with early breast cancer receiving G-CSF. • 49% women treated with adjuvant chemotherapy in CANTO (N = 2920) used G-CSF. • Long-term PROs and hematological values were not substantially different in women using G-CSF or not. • There were slightly worse outcomes at year-4 in patients using G-CSF, although of trivial clinical significance.

Genomic tests can guide the decision to administer adjuvant chemotherapy in women with hormone receptor (HR)-positive, Human Epidermal growth Factor 2 (HER2)-negative breast cancer (BC) at intermediate risk of recurrence. We assessed the decision-making and economic impact of the Prosigna test in a real-life setting. Retrospective cohort study of HR + , HER2- BC patients managed from 2016 to 2020, potential candidates for adjuvant chemotherapy, at intermediate risk of recurrence, in whom a Prosigna test was performed according to contemporary guidelines. The additional cost of chemotherapy over one year in terms of direct medical and non-medical costs was estimated in this study to be €9,737 (derived from a previous study, NCT02813317). The cost of the Prosigna test, as defined by the reimbursement system, was €1,849. Among the 809 patients included in this study, 2.3 Prosigna tests had to be performed to avoid adjuvant chemotherapy for one patient. The number of tests that had to be performed to avoid chemotherapy for one patient was higher for patients with grade 3 tumors and pN1mic axillary node involvement and lower for grade 1 tumors or in the absence of axillary node involvement (pN0), but did not vary according to the 10-year overall survival gain predicted by the Predict online test. The cost saving related to withholding of adjuvant chemotherapy for one patient on the basis of the Prosigna test results was €5,485. We present one of the largest cohorts of HR + , HER2- BC patients at intermediate risk of recurrence, in whom a Prosigna test was used to guide the adjuvant therapy decision in a real-life setting, resulting in a 44% decrease in the indication for chemotherapy.

Summary Background Alpelisib, a PI3Kα-selective inhibitor and degrader, plus fulvestrant showed efficacy in hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer in SOLAR-1; limited data are available in the post-cyclin-dependent kinase 4/6 inhibitor setting. BYLieve aimed to assess alpelisib plus endocrine therapy in this setting in three cohorts defined by immediate previous treatment; here, we report results from cohort A. Methods This ongoing, phase 2, multicentre, open-label, non-comparative study enrolled patients with hormone receptor-positive, HER2-negative, advanced breast cancer with tumour PIK3CA mutation, following progression on or after previous therapy, including CDK4/6 inhibitors, from 114 study locations (cancer centres, medical centres, university hospitals, and hospitals) in 18 countries worldwide. Participants aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 2 or less, with no more than two previous anticancer treatments and no more than one previous chemotherapy regimen, were enrolled in three cohorts. In cohort A, patients must have had progression on or after a CDK4/6 inhibitor plus an aromatase inhibitor as the immediate previous treatment. Patients received oral alpelisib 300 mg/day (continuously) plus fulvestrant 500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1. The primary endpoint was the proportion of patients alive without disease progression at 6 months per local assessment using Response Evaluation Criteria in Solid Tumors, version 1.1, in patients with a centrally confirmed PIK3CA mutation. This trial is registered with ClinicalTrials.gov , NCT03056755 . Findings Between Aug 14, 2017, and Dec 17, 2019 (data cutoff), 127 patients with at least 6 months' follow-up were enrolled into cohort A. 121 patients had a centrally confirmed PIK3CA mutation. At data cutoff, median follow-up was 11·7 months (IQR 8·5–15·9). 61 (50·4%; 95% CI 41·2–59·6) of 121 patients were alive without disease progression at 6 months. The most frequent grade 3 or worse adverse events were hyperglycaemia (36 [28%] of 127 patients), rash (12 [9%]), and rash maculopapular (12 [9%]). Serious adverse events occurred in 33 (26%) of 127 patients. No treatment-related deaths were reported. Interpretation BYLieve showed activity of alpelisib plus fulvestrant with manageable toxicity in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer, after progression on a CDK4/6 inhibitor plus an aromatase inhibitor. Funding Novartis Pharmaceuticals.

Background Current international expert guidelines in the 1st line setting for HR+/HER2- ABC recommend endocrine therapy plus a CDK4/6 inhibitor unless there is a visceral crisis. However, due to a lack of sequencing data, recommendations for further treatment lines are not clear-cut. In this context, treatment decisions are often based on response to first line treatment, aggressiveness of the disease and clinical expertise. Evidence-based medicine should inform decisions. This study aims to estimate the weight of beliefs and habits in therapeutic strategy choices. Methods This observational survey « Chemotherapy : beliefs and habits » was conducted among a representative sample of French oncologists with a breast cancer activity in private and public hospitals. The survey was conducted between November 2019 and January 2020. Oncologists were asked about their knowledge, perception and practice regarding the treatment of HR+/HER2- ABC patients. A focus was made on their perception of best available external clinical evidence leading to guidelines. Results 119 physicians answered the survey. They agreed that in absence of visceral crisis the first line treatment of HR+/HER2- metastatic breast cancer should be endocrine therapy plus a CDK4/6 inhibitor (98,3%). First line endocrine therapy was believed to be associated with a higher progression-free survival benefit (79%) and overall survival benefit (75%) compared to chemotherapy. Even in case of primary or secondary endocrine resistance, oncologists remained in favor of using an endocrine-based therapy at first line in 82% and 66% of cases respectively. The visceral crisis concept was presented through clinical cases. In a life-threatening situation, 10% of physicians maintained their choice of 1rst line endocrine therapy plus a CDK4/6 inhibitor. The oncologists were asked to choose the determinants of treatment choices (patient’s preferences, efficacy, safety, quality of life). Oncologists valued patients’ preference and quality of life with increasing treatment lines while clinical efficacy as measured by survival data were less and less guiding in their choice of treatment. Conclusion Evidence-based medicine is the integration of best research evidence with clinical expertise and patient values. It is a useful framework held as a standard in therapeutic strategy. However, beliefs and habits play an important role in the choice of treatment for HR+/HER2- ABC beyond the first treatment line. Clinical trials are needed in this setting to determine the best sequence of treatments. A comprehensive analysis of the survey results will be presented at the meeting. Citation Format: Julien Peron, Sylvie Giacchetti, Ophélie Cassuto, Tullia Deverge, Charlotte Bouyssou, Jean-Marc Ferrero, Elisabeth Luporsi, Florence Lerebours. Impact of oncologists’ beliefs and habits on treatment decisions in hormone receptor positive (HR+)/ HER2 negative advanced breast cancer (ABC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-48.

Background: Triple negative breast cancer (TNBC) is an heterogeneous disease and encompasses at least 4 subtypes. One of these expresses the androgen receptor (AR). Several prospective trials demonstrated antitumour efficacy with anti-androgen treatment in patients with advanced breast cancer. Darolutamide is an androgen-receptor antagonist with a potent anti-tumour efficacy in metastatic prostate cancer with a favorable safety profile. We conducted a randomized non-comparative phase II trial to study the efficacy and tolerability of darolutamide and capecitabine in AR-positive TNBC (NCT03383679). Material and methods: Patients (Pts) with a metastatic, centrally reviewed, AR-positive (≥ 10% by immunohistochemistry) and TNBC who have received a maximum of one line of chemotherapy for advanced disease were eligible. They were randomised in a 2:1 ratio to receive darolutamide (D arm) 600 mg twice daily or capecitabine (C arm) at 1000 mg/m² twice daily 2 weeks on and 1-week off, until progression or unacceptable toxicity. The primary endpoint was clinical benefit rate (CBR) defined as the proportion of pts presenting a complete response (CR), partial response (PR), or stable disease (SD) at 16 weeks. Main secondary endpoints included objective response rate, overall survival, progression-free survival and safety. An interim statistical analysis was planned when 19 assessable pts will be available in the D arm. According to an optimal 2-stage Simon’s design,if Results: Out of 133 pts screened and centrally analyzed, from 37 centres, 54% (72/133) were AR-positive. 45 pts were randomized (29 in D arm and 16 in C arm) from April 2018 to December 2019. In arm D, median age was 60 years (range 47-88). and 13.8 % received a first line of chemotherapy for metastatic disease. A total of 19 pts were eligible and assessable for the primary endpoint in D arm. 5 CBR were confirmed at 16 weeks (26.3%; 95% CI: 9.2%-51.2 %) including 1 confirmed PR and 4 SD. In arm D, fatigue (23.8%), ASAT increased (23.8%), and blood alkaline phosphatase increased (23.8%) were the most common drug-related adverse events; the majority of them being grade 1 or 2. 6 pts presented with drug-related serious adverse events: one in D arm and 5 in C arm. Conclusions: According to the planned interim analysis, the efficacy objective is met (5 CBR) in D arm. Moreover, darolutamide is well tolerated. Thus, patients are now recruited in the second stage. Keywords: Androgen receptor,triple-negative breast cancer, darolutamide, advanced breast cancer Citation Format: Hervé Bonnefoi, Florence Lerebours, Olivier Tredan, Florence Dalenc, Christelle Levy, Mahasti Saghatchian, Marie Ange Mouret Reynier, Delphine Mollon, Severine Guiu, Laurence Venat Bouvet, Elisabeth Carola, Geraldine Martineau, Marina Pulido, Gaetan MacGrogan, Anthony Goncalves. First efficacy results of a 2-stage Simon’s design randomised phase 2 of darolutamide or capecitabine in patients with triple-negative, androgen receptor positive advanced breast cancer (UCBG06-3) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-05.

Introduction: Mutations in PIK3CA, which encodes the α-isoform of phosphatidylinositol 3-kinase (PI3Kα), occur in ~40% of patients (pts) with HR+, HER2- ABC and can contribute to endocrine resistance. Alpelisib (ALP), a PI3Kα-selective inhibitor and degrader, plus fulvestrant (FUL) demonstrated efficacy in the phase 3 SOLAR-1 trial, which included 20 pts who had prior CDK4/6i in the PIK3CA-mutant cohort. Limited clinical data are available in the post-CDK4/6i setting for PIK3CA-mutated, HR+, HER2- ABC. BYLieve (NCT03056755), an ongoing phase 2, multicenter, open-label, 3-cohort noncomparative study, is the first trial evaluating ALP + endocrine therapy (FUL or letrozole [LET]) in pts with PIK3CA-mutated, HR+, HER2- ABC who progressed on/after prior therapy, including CDK4/6i. In the prior CDK4/6i + aromatase inhibitor (AI) cohort (Cohort A), pts received ALP + FUL. With median follow-up of 11.7 months (mo), the primary endpoint in Cohort A was met—50.4% of pts were alive and without disease progression (PD) at 6 mo per local investigator assessment (n=61; 95% CI, 41.2%-59.6%). Median progression-free survival (mPFS) was 7.3 mo (n=72; 95% CI, 5.6-8.3 mo); AEs were consistent with prior observations. Now, we report on the cohort of pts who received a CDK4/6i + FUL as immediate prior therapy before enrollment (Cohort B). Methods: Daily oral treatment in Cohort B consisted of ALP 300 mg + LET 2.5 mg. Each cohort planned to enroll at least 112 pts with centrally confirmed PIK3CA mutation, based on immediate prior treatment of either a CDK4/6i + AI (Cohort A), a CDK4/6i + FUL (Cohort B), or systemic chemotherapy or endocrine therapy (which may also include prior CDK4/6i + FUL; Cohort C, follow-up ongoing). The primary endpoint, the proportion of pts with centrally confirmed PIK3CA mutation alive without PD at 6 mo per local investigator using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, is assessed for each cohort separately and is met if the lower bound of the 95% CI is >30%. Men and premenopausal women were allowed goserelin 3.6 mg subcutaneously or leuprolide 7.5 mg intramuscularly every 28 days. Results: 126 pts whose immediate prior treatment was CDK4/6i + FUL were enrolled into Cohort B: 115 had centrally confirmed PIK3CA mutations. Median follow-up was 15.0 mo (range, 1-31 mo); 58 (46.0%) had ≥2 lines of prior therapy in the metastatic setting, and 103 (81.7%) pts progressed on prior AI therapy. The primary endpoint was met with 46.1% (95% CI, 36.8%-55.6%) of pts alive without PD at 6 mo. mPFS was 5.7 mo (95% CI, 4.5-7.2 mo). The most frequent all-grade AEs (≥25%) were diarrhea (67.5%), hyperglycemia (63.5%), nausea (54.8%), decreased appetite (44.4%), stomatitis (34.1%), fatigue (31.0%), rash (31.0%), and vomiting (24.6%). Most frequent grade ≥3 AEs included hyperglycemia (25.4%), rash (9.5%), and rash maculopapular (7.9%). Incidence of AEs leading to treatment discontinuation was 14.3% (n=18); most frequent AEs leading to discontinuation were rash (4 pts, 3.2%, including rash maculopapular), fatigue, and diarrhea (3 pts, 2.4% each). Conclusion: Alpelisib in combination with LET following progression on FUL + CDK4/6i and prior AIs was effective in this noncomparative trial. Consistent with the known safety profile of alpelisib, manageable toxicities were observed. These data suggest that alpelisib in combination with LET may be an effective treatment option for pts with PIK3CA-mutated, HR+, HER2- ABC in the post-CDK4/6i setting. Citation Format: Hope S. Rugo, Florence Lerebours, Dejan Juric, Nicholas Turner, Stephen Chia, Pamela Drullinsky, Aleix Prat, Rafael Villanueva Vázquez, Murat Akdere, Christina Arce, Yu-Ming Shen, Eva Ciruelos. Alpelisib + letrozole in patients with PIK3CA-mutated, hormone-receptor positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC) previously treated with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) + fulvestrant: BYLieve study results [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD2-07.

Background Palbociclib is indicated for the treatment of hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC), in combination with endocrine therapy. Emerging real-life data suggest that the efficacy of a palbociclib-based therapy is highly conserved. We report the Institut Curie hospital experience. Patients and methods We retrospectively reviewed all patients with HR + HER2- ABC treated with a palbociclib-based therapy as first or second line for ABC, with an initial prescription from November 2016 to December 2018. Clinical, laboratory and imaging data were retrieved from electronic records. Data lock was December 31st, 2019. Descriptive analyses, univariate and multivariate Cox regression analyses were performed. Results We included 310 consecutive patients. Median age was 61.8 years old. Palbociclib was prescribed in first line in 225 patients (72.6%). Before palbociclib-based therapy initiation, 122 patients (39.3%) were endocrine naive, 96 (31.0%) endocrine sensitive and 92 (29.7%) endocrine resistant. Median follow-up was 20.7 months. Median progression free survival (PFS) was 23.4 months (95%CI: 21.6-NR) in endocrine naive patients, 22.7 months (95%CI: 14.7-NR) in endocrine sensitive, and 13.4 months (95%CI: 10.7–20.8) in endocrine resistant. At 12 months from the initiation of palbociclib, 94.5% of patients were alive. By multivariate analysis, poor prognosis factors for PFS were identified in the endocrine naive/sensitive population: initial ECOG status 2, previous endocrine therapy for ABC, 3 metastatic sites or more. Toxicity profile was similar to previously published data. Conclusion In a non-selected population of patients with HR + HER2- ABC, the efficacy and safety data are strikingly similar to those previously reported., Highlights • Efficacy of palbociclib in advanced breast cancer in real-life is very close to that from the pivotal trials. • Long-term follow-up of patients treated with palbociclib show no cumulative adverse events.

Objective Cognitive complaints are more frequent in women with breast cancer (BC) than in healthy controls and can be present before any treatment. Findings regarding contributive factors remain inconsistent. This study aimed to identify different groups of patients with cognitive complaints at BC diagnosis and to determine whether these different groups were associated with demographic, medical, or psychological characteristics. Methods Cognitive complaints were assessed in a subset of 264 women from the French multicenter prospective CANTO cohort, at baseline before any treatment. Clustering analyzes were performed using the six-cognitive dimension Costa's scoring of the FACT-Cog V3. Univariable analyses were used to study how cognitive function (standardized neuropsychological tests, ICCTF), anxiety, depression, fatigue, and quality of life (HADS, FA12, QLQ-C30) were associated with specific cognitive complaints groups. Results Results included 263 women (54±11 years), newly diagnosed with BC (69% stages I-III). Four distinct groups emerged, ranged from "no complaints" (22.8%), "low complaints" (55.1), "mixed complaints" (14.5%), to "consistent complaints" (7.6%). No significant differences were found in terms of demographic and medical factors between the four groups. However, the groups with higher proportions of patients with complaints were found to have more impairment in executive function, higher scores of anxiety, depressive symptoms, and fatigue, and lower quality of life, than the groups with lower proportions of cognitive complaints. Conclusion Using complete cognitive assessment prior to BC treatment, we identified four distinct cognitive complaints groups with specific characteristics. This work provides valuable clinical basis to further investigations for a better understanding of cognitive complaints and their associates.

Background: Twenty to 30% of patients with breast cancer have cognitive impairment after surgery and before adjuvant treatment, but very few studies have focused on cognition before any treatment. This study used a subgroup of women with newly diagnosed breast cancer from the French cancer and toxicities (CANTO) cohort to describe cognition before any treatment in comparison with a group of healthy controls (HC). Methods: Cognitive assessment was performed before any breast cancer treatment (surgery or neoadjuvant treatment) on women with newly diagnosed invasive stage I–III breast cancer and HCs. Objective cognitive performance, cognitive complaints, anxiety, depression, and fatigue were assessed. Objective cognitive impairment was defined according to International Cognition and Cancer Task Force recommendations. Results: Of the 264 included patients with breast cancer (54 ± 11 years) and 132 age-matched HCs (53 ± 9 years), overall objective cognitive impairment was observed in 28% of patients with breast cancer and 8% of HCs (P < 0.001). Cognitive complaints were reported by 24% of patients versus 12% of HCs (P < 0.01). Patients reported significantly more anxiety and emotional and cognitive fatigue than HCs (P < 0.01). After adjustment, significantly more patients with breast cancer had overall objective cognitive impairment than HCs [OR = 3.01; 95% confidence interval (CI): 1.31–6.88] without significant difference between groups for cognitive complaints (OR = 1.38; 95% CI: 0.65–2.92). Cognitive complaints were positively associated with fatigue (OR = 1.03; 95% CI: 1.02–1.05). Conclusions: In this prospective study, compared with HCs, patients with localized breast cancer had more objective cognitive impairment before any treatment. Cognitive complaints were mostly related to fatigue. Impact: Baseline assessment before treatment is important to assess the impact of each cancer treatment on cognition.

Prosigna® tests are performed in Institut Curie to guide adjuvant chemotherapy decision in early estrogen receptor (ER) positive, Human Epidermal growth factor Receptor (HER2) negative breast cancer (BC) patients, with an intermediate risk of recurrence. The objective of this study was to check the absence of an early warning signal for therapeutic decisions guided by the use of genomic tests in terms of the occurrence of events during the follow-up. Methods: Follow-up analysis were made on 2 populations: Real-life population: ER positive, HER2 negative BC patients who had a Prosigna® test in clinical routine, were prospectively registered and their data collected. Prosigna® test was indicated for patients with an intermediate risk of recurrence defined by our regional guidelines (1): grade 1 T1cN1, grade 1 T2N0-1, grade 2 T1cN0 with pejorative prognosis parameters (Ki67>20% or lympho-vascular emboli), grade 2 T2N0, grade 3 T1cN0. Decision impact (DI) study (2): a prospective multicenter study evaluating the decision impact of Prosigna® tests on adjuvant chemotherapy treatment. All consecutive T1-T2 NO-N1(mic) ER positive, HER2 negative BC patients were included. Survival was estimated by Kaplan-Meier methods and compared between patients who received or not chemotherapy based on the tests results with a Log-rank test (chemotherapy was administered for patients with a 10-years distant recurrence probability >=10%). Results are given in % with 95% intervalley confidence. Results: 647 patients were included (124 from DI study and 523 from clinical routine). Median age was 59 years-old (28-83). The median size of the tumor was 17 mm, (3-75), with a majority of grade 2 tumors (n=473, 73%) and 14% of lymph node involvement (n=90). Prosigna® tests results showed: 54% of luminal A.; respectively 30% (n=195), 40% (n=257) and 30% (n=195) of high, intermediate and low risk categories. The median 10-years distant recurrence probability was 10% (2-45%). The median follow-up of the patients was 18 months (0-52). We did not observe death in our study population, and we registered 10 recurrences (4 distant-DMFS- and 6 locoregional-LDFS). Disease free survival (DFS) at respectively 12 and 24 months were 99.8% (98.9-100) and 98.6% (96.5-99.4). Locoregional DFS at 12 and 24 months were 99.8% (98.9-100) and 99.2% (97.4-99.8) and distant DFS at 12 and 24 months were 100% and 99.4% (97.5-99.8). We did not observe survival differences between patients treated by chemotherapy and hormone therapy (CT) and patients treated by hormone therapy alone (No CT). DFS were respectively for CT and no CT groups 99.6% (97.4-99.9) and 99.5% (96.8-99.9, p=0.8) at 12 months, and 98.9% (95.1-99.7) and 99% (96-99.7, p=0.8) at 24 months. Distant and locoregional DFS were also not different between CT and No CT groups. Discussion: The first results of this study, mainly composed of clinical routine patients, are totally reassuring. We did not identify early warning signal in terms of survival with the use of Prosigna® test to guide adjuvant chemotherapy decisions in early BC patients at intermediate risk of recurrence. Moreover, our results are in accordance with the TAILORx (3) and MINDACT (4) randomized prospective studies survivals. References: 1. https://www.gustaveroussy.fr/sites/default/files/referentiel-cancer-du-sein-gustaveroussy-curie-2016-2017.pdf 2. Hequet D, et al. PLoS One. 2017 Oct 18;12(10):e0185753 3. Sparano JA, et al. N Engl J Med. 2018 Jul 12;379(2):111-121 4. Cardoso F, et al; N Engl J Med. 2016 Aug 25;375(8):717-29 Citation Format: Delphine Hequet, Louise Maumy, Celine Callens, David Gentien, Ivan Bieche, Paul Cottu, Jean-Marc Guinebretiere, Anne Vincent-Salomon, Florence Lerebours, Roman Rouzier. Outcomes results of Prosigna® test in early breast cancer patients: Experience of Institut Curie, France [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-08-21.

Background: The incidence of breast cancer (BC) increases with age. However, there appears to be a trend that elderly patients with BC receive less than the standard treatment compared to younger ones and this leads to poorer outcomes. The aim of this work was to assess whether chemotherapy has a differential impact on the health related quality of life (HRQOL) of elderly patients with BC, compared to younger ones. Methods: CANTO (NCT 01993498) is a multicenter prospective observational study (26 centers in France) whose main objective is to study the chronic toxicities of anticancer treatments in 12,000 women with localized stages I to III BC. HRQOL was assessed at baseline and at the end of acute treatments (surgery +/- radiotherapy +/- chemotherapy) using the EORTC-QLQ-C30 questionnaire and its BC specific module, the EORTC-QLQ-BR23. HRQOL at the end of acute treatments of patients aged 70 and over treated by chemotherapy was compared to that of the youngest ones. Multivariable mixed linear model was used to assess the determinants of HRQOL for the dimensions with minimal clinically important differences; defined as a mean difference of at least 5 points in HRQOL scores; between younger and older patients. Results: 3079 patients were included in the CANTO cohort from March 2012 to December 2014 and treated by chemotherapy. The mean age at diagnosis was 53 years and 7.3% of this population was ≥70 years old. Older and younger patients treated by chemotherapy were similar for the disease stage at diagnosis (p=0.7869), the tumor histology (p=0.07), the SBR grade (p=0.2350) and the HER2 status (p=0.4268). However, elderly patients treated by chemotherapy were more likely to be overweight (p Citation Format: Sandrine Dabakuyo Yonli, Oumar Billa, Olivia Dialla, Florence Joly, Sarah Dauchy, Charles Cecile, Cedric Lemogne, Patrick Soulie, Marie-Ange Mouret-Reynier, Carole Tarpin, Mario Campone, Sophie Guillermet, Jean-Marc Ferrero, Sylvie Giacchetti, Florence Lerebours, Suzette Delaloge, Anne-Laure Martin, Sibille Everhard, Charles Coutant, Fabrice Andre, Patrick Arveux. Impact of chemotherapy on the health related quality of life among elderly patients with localized breast cancer: Findings from the prospective CANTO cohort [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-11-07.

The Prosigna® test has been performed in Institut Curie, France, since 2016 in clinical routine with a financial support of the health ministry dedicated to innovative procedures. The genomic platform at the Institut Curie performs the Prosigna® test for patients cared for at the Curie Hospital and in other institutions. Our main objective was to evaluate the impact of Prosigna® tests on adjuvant chemotherapy decisions. The second objective was to assess the costs associated with implementation of the test for patient management. Methods: Early breast cancer patients with estrogen receptor positive and human epidermal growth factor receptor 2-negative tumors, who had a Prosigna® test in clinical routine, were prospectively registered and observed. The Prosigna® test was indicated for a population candidate for a chemotherapy, with an intermediate risk of recurrence defined by our regional guidelines (1): grade 1 T1cN1, grade 1 T2N0-1, grade 2 T1cN0 with risk factors (Ki67>20% or lympho-vascular emboli), grade 2 T2N0, grade 3 T1cN0. The French Health Authority (FHA) has also recently defined the population who are candidates for genomic testing: T1c/T2 and N0/N1(mic) and grade 2 without risk factors (age Results: Prosigna® test was performed for 831 patients in clinical practice from 2016 and 2019 at Institut Curie. Due to missing data, analyses have been performed on 735 patients. Median age was 57 years-old (28-80), and median size 18 mm (3-80). We observed a majority of grade 2 tumors (n=572, 78%), and 21% of lymph node involvement. Median Ki67 was 20 (0-100). Prosigna® tests classified respectively 234 (32%), 295 (40%) and 206 (28%) in high, intermediate and low risk categories. In the all real-life population (n=735), chemotherapy was avoided for 308 (42%) patients after Prosigna® test results, and in 192 (44%) cases in the population defined by the FHA (n=433). From a financial point of view, both the real-life data and the population defined by FHA demonstrated cost savings,1 739 614€ (n=735 patients). and 1 068 671€(n=433), respectively. Conclusion: This large real-life study showed a 40% decrease in adjuvant chemotherapy recommendations after introduction of the Prosigna® test in a population of chemotherapy candidates. Moreover, this therapeutic de-escalation demonstrated an overall cost savings for the health system despite the added cost of the test. References: 1. https://www.gustaveroussy.fr/sites/default/files/referentiel-cancer-du-sein-gustaveroussy-curie-2016-2017.pdf 2. Baffert S, et al. The patient-breast cancer care pathway: how could it be optimized? BMC Cancer. 2015 May 12;15:394 3. Héquet D, et al. Direct medical and non-medical costs of a one-year care pathway for early operable breast cancer: results of a French multicenter prospective study. Plosone 2019, accepted, in press. Citation Format: Delphine Hequet, Guillaume Harrissart, Celine Callens, David Gentien, Ivan Bieche, Paul Cottu, Jean-Marc Guinebretiere, Anne Vincent-Salomon, Florence Lerebours, Roman Rouzier. Prosigna® test in clinical routine: Impact on adjuvant chemotherapy decision and medico-economic considerations in France [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-14-10.

PURPOSE: A major question when treating HR+/HER2- metastatic breast cancer (MBC) is whether early introduction of chemotherapy (CT) increases endocrine resistance. We aimed to describe progression-free survival (PFS) under first endocrine therapy (ET) depending on whether given before or after CT in a large nationwide cohort, in the pre-CDK era. METHODS: The real-life retrospective ESME database includes all patients with MBC whose first-line treatment was initiated between 2008 and 2014 in one of the 18 French Comprehensive Cancer Centres. Our primary objective was to compare PFS from start of first ET in patients with HR+/HER2- MBC who received ET or CT first. RESULTS: We identified 6293 patients who received at least one ET line during their first two therapeutic lines for MBC. As first-line therapy, 3832 (60.9%) received ET alone (ET1 1st group), whilst 2461 (39.1%) received CT, including 2024 patients (32.2%) with maintenance ET after CT (ET1 after CT group). Median PFS under first ET was 12.4 months (95% CI 11.9-13.1) in ET 1st group vs. 12.6 months in ET1 after CT group (95% CI 12.1-13.4), HR 0.96 (95% CI 0.90-1.01, P = 0.1277). CONCLUSIONS: PFS under first ET appears identical whether prescribed before or after chemotherapy. These data suggest chemotherapy does not promote endocrine resistance.

International audience; Return to work (RTW) after breast cancer is associated with improved quality of life. The link between household characteristics and RTW remains largely unknown. The aim of this study was to examine the effect of the family situation on women’s RTW two years after breast cancer. We used data of a French prospective cohort of women diagnosed with stage I-III, primary breast cancer (CANTO, NCT01993498). Among women employed at diagnosis and under 57 years old, we assessed the association between household characteristics (living with a partner, marital status, number and age of economically dependent children, support by the partner) and RTW. Logistic regression models were adjusted for age, household income, stage, comorbidities, treatments and their side effects. Analyzes stratified by age and household income were performed to assess the association between household characteristics and RTW in specific subgroups. Among the 3004 patients included, women living with a partner returned less to work (OR = 0.63 [0.47–0.86]) and decreased their working time after RTW. Among the 2305 women living with a partner, being married was associated with decreased RTW among women aged over 50 (OR = 0.57 [0.34–0.95]). Having three or more children (vs. none) was associated with lower RTW among women with low household income (OR = 0.28 [0.10–0.80]). Household characteristics should be considered in addition to clinical information to identify vulnerable women, reduce the social consequence of cancer and improve their quality of life.

PurposeFemale breast cancer (BC) patients exposed to gonadotoxic chemotherapy are at risk of future infertility. There is evidence of disparities in the discussion of fertility preservation for these patients. The aim of the study was to identify factors influencing the discussion of fertility preservation (FP).Material and MethodsWe analyzed consecutive BC patients treated by chemotherapy at Institut Curie from 2011-2017 and aged 18-43 years at BC diagnosis. The discussion of FP was classified in a binary manner (discussion/no discussion), based on mentions present in the patient’s electronic health record (EHR) before the initiation of chemotherapy. The associations between FP discussion and the characteristics of patients/tumors and healthcare practitioners were investigated by logistic regression analysis.ResultsThe median age of the 1357 patients included in the cohort was 38.7 years, and median tumor size was 30.3 mm. The distribution of BC subtypes was as follows: 702 luminal BCs (58%), 241 triple-negative breast cancers (TNBCs) (20%), 193 HER2+/HR+ (16%) and 81 HER2+/HR- (6%). All patients received chemotherapy in a neoadjuvant (n=611, 45%) or adjuvant (n= 744, 55%) setting. A discussion of FP was mentioned for 447 patients (33%). Earlier age at diagnosis (discussion: 34.4 years versus no discussion: 40.5 years), nulliparity (discussion: 62% versus no discussion: 38%), and year of BC diagnosis were the patient characteristics significantly associated with the mention of FP discussion. Surgeons and female physicians were the most likely to mention FP during the consultation before the initiation of chemotherapy (discussion: 22% and 21%, respectively). The likelihood of FP discussion increased significantly over time, from 15% in 2011 to 45% in 2017. After multivariate analysis, FP discussion was significantly associated with younger age, number of children before BC diagnosis, physicians’ gender and physicians’ specialty.ConclusionFP discussion rates are low and are influenced by patient and physician characteristics. There is therefore room for improvement in the promotion and systematization of FP discussion.

Background Outcome of HER2-positive metastatic breast cancer (MBC) patients has improved since the use of trastuzumab. However, most HER2-positive MBC patients will progress within 1 year of trastuzumab-based therapy. Only limited data are available concerning long-term responders. Methods The primary objective of this study was to compare overall survival (OS) of HER2+ MBC patients with long-term response to first-line trastuzumab with overall survival of those with non-long-term response, based on two institutional databases: the French Epidemiological Strategy and Medical Economics program and the Breast Database. Long-term responders (LTR) were defined as patients with non-progressive disease for ≥ 2 years on first-line trastuzumab. Secondary objectives included progression-free survival (PFS), and predictive factors for LTR status. Results From 2004 to 2014, 422 HER2-positive MBC patients received first-line trastuzumab. With a median follow-up of 48 months, median OS and PFS were 63 months (CI95%, 50-71), and 18 months (CI95%, 15-21) respectively. In 111 patients (26.3%) classified as LTR, median OS was 110 months (CI95%, 95-not reached) versus 56 months in non-LTR patients (CI95%, 47-68). In multivariate logistic regressions, the following factors were independently associated with LTR status: number of metastatic sites (≤ 2 versus > 2, p = 0.01); endocrine therapy for metastatic disease (p = 0.001) and taxane-based first-line chemotherapy (p = 0.003). Conclusion Several features are associated with long-term response to trastuzumab: few metastatic sites, taxane-based chemotherapy and maintenance endocrine therapy in HR+ patients. Further studies are needed to identify patients in whom trastuzumab can be stopped after several years of sustained response.

Introduction Li-Fraumeni syndrome (LFS) resulting from monoallelic germline TP53 gene mutation is a rare hereditary cancer predisposition. Breast cancer (BC) is the most common cancer among women with TP53 germline mutation with a risk ranging from 49% to 85% by the age of 60 years old. Most of these cancers are early onset. Few patients' cases have been reported so far in the literature. Our aim was to describe the medical history of a cohort of LFS women diagnosed with BC recruited from a single institution. The characteristics combined were genetic alteration diagnosis, tumor characteristics, treatment, outcome, and LFS associated cancers. Methods We retrospectively identified breast cancer patients with TP53 germline mutation from the Institut Curie (Paris, France) database and described their cancer characteristics and medical history. Results From 1989 to 2015, 25 patients affected with BC (31 tumors) and TP53 germline mutation carrier were identified, with a median follow up of 6.5 years. Median age at BC diagnosis was 30.5 years. All patients were women. 33% had a previously identified TP53 mutation in their family. 70% of them had BC as their first cancer event. 60% of the patients presented with another LFS associated cancer or non-related cancers: osteosarcoma (22%), glioblastoma (18%), pulmonary carcinoma (13%), gastric linitis plastica (9%), malignant hemopathy (9%), soft tissue sarcoma (9%), adrenocortical carcinoma (4%), ovarian cystadenocarcinoma (4%), renal tumor (4%), choroid plexus carcinoma (4%). 92% of the breast tumors were ductal carcinoma (28% DCIS and 64% IDC), 7% were sarcoma (1 phyllodesarcoma, 1 pleiomorphic liposarcoma); there were no lobular carcinoma. Among the IDC, 50% were HER2 positive, 72% were hormone-receptor positive. Most patients had a mastectomy (64%), and most of them received radiation (55%). However, when TP53 mutation had been identified prior to the treatment, none of the patients received radiotherapy (5 patients). Most patients received chemotherapy (70%) (37% in neoadjuvant setting, 33% in adjuvant setting, 25% for metastatic setting). 40% of the patients received hormone therapy (37% as adjuvant treatment, 7% for metastatic disease) Most of the patients did not relapse from BC (75%). Overall, only 17% of the patients had metastatic BC. To date, 12 patients of our series have died (48%), 6 patients (24%) from other LFS-associated cancers and 4 patients from BC (16%). Conclusion To the best of our knowledge, this descriptive series is the largest study of tumor characteristics and medical history of LFS-women with BC, the most frequent cancer among women with TP53 germline mutation. It confirms the higher HER2 overexpression rate observed in LFS-patients BC, as suggested in the literature and showed a high rate of DCIS at initial presentation. Most of the patients developed other LFS-associated cancers. In depth molecular analysis of these BC will be performed in order to gain insight into their biological specificities and to adapt the therapeutic management of this poor prognosis syndrome. Citation Format: Tran M, Loirat D, Colas C, Bozec L, Laurence V, Lerebours F, Cabel L, Bidard F-C, Stoppa-Lyonnet D, Vincent-Salomon A, Gauthier-Villars M, Lavigne M, De Pauw A. Breast cancer characteristics and outcomes in patients with TP53 germline mutation [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 P1-09-07.

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.

Background: Randomized trials, although not all, suggest exercise therapy improves treatment completion rates / relative dose intensity in patients with early-stage breast cancer receiving adjuvant chemotherapy (CT). In addition, preclinical studies show that exercise therapy adds to the antitumor activity of standard CT in murine models of breast cancer. We evaluated the association between exercise and pathologic complete response (pCR) rate (i.e., ypT0ypN0) in patients receiving neoadjuvant CT for operable breast cancer. Methods: Using a prospective design, patients with stage I-III breast cancer receiving anthracycline-taxane (± trastuzumab) neoadjuvant CT participating in a multicenter, national cohort study in France (CANTO, NCT01993498) completed questionnaire assessing self-reported exercise behavior (GPAQ 16). Multivariate logistic models were performed to determine the relationship between pre-CT exercise exposure (total MET-h/wk categorized into the proportion of patients meeting WHO exercise guidelines, the equivalent of ≥10 MET-h/wk), pCR rates, CT± trastuzumab dose reductions, delays, treatment completion or interruptions for the overall cohort and on the basis of clinical subtype. Results: Between March, 2012 to December, 2014, a total of 989 patients participating in CANTO received neoadjuvant CT and completed GPAQ 16. Here we present interim analyses on 608 patients. Fifty-four percent of patients engaged on of ≥10 MET-h/wk prior to CT administration. In multivariable analysis for the overall cohort, exercise exposure was not associated with higher pCR (p=0.69). The pCR rate was 27.7% for patients reporting Conclusion: On the basis of interim analyses, higher pretreatment exercise exposure is not associated with higher clinical response or treatment tolerability in breast cancer patients receiving uniform conventional neoadjuvant CT. Full results will be presented at the meeting. Citation Format: Baker JL, Di Meglio A, El Mouhebb M, Iyengar NM, Michiels S, Cottu P, Lerebours F, Coutant C, Lesur A, Tredan O, Soulie P, Vanlemmens L, Jouannaud C, Levy C, Everhard S, Martin A-L, Arveux P, Fabrice A, Vaz Luis I, Jones LW. Association between exercise, pathological complete response, and treatment tolerability in patients receiving neoadjuvant chemotherapy for operable breast cancer: Results from the CANTO 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 P1-15-03.

Purpose: High levels of tumor-infiltrating lymphocytes (TILs) before neoadjuvant chemotherapy (NAC) are associated with higher pathological complete response (pCR) rates, and better survival in TNBC and HER2-positive breast cancers (BCs). We investigated the value of changes in TIL levels and final TIL levels after treatment, by evaluating lymphocyte infiltration before and after NAC in a real-life BC cohort. Patients and methods: We assessed stromal TIL levels in 716 pre- and post-treatment matched paired specimens, according to the guidelines of the international TIL working group. Results: Pre-NAC TIL levels were higher in tumors for which pCR was achieved than in cases of residual disease (33.9% versus 20.3%, p=0.001), in luminal tumors and TNBCs, but not in HER2-positive BCs, (pInteraction =0.001). The association between pre-NAC TIL levels and pCR was non-linear in TNBCs (p=0.005). Mean TIL levels decreased during NAC (pre-NAC TILs: 24.1% versus post-NAC TILs: 13.0%, p Conclusion: The associations of pre, post-NAC TIL levels with response to treatment and DFS differ between BC subtypes and may deviate from linearity. The characterization of immune subpopulations may improve our understanding of the complex interactions between pre- or post-NAC setting, BC subtype, response to treatment and prognosis. Citation Format: Hamy A-S, Bonsang-Kitzis H, De Croze D, Laas E, Darrigues L, Topciu L, Menet E, Vincent-Salomon A, Lerebours F, Pierga J-Y, Brain E, Feron J-G, Benchimol G, Lam G-T, Laé M, Reyal F. Interaction between molecular subtype and stromal immune infiltration dynamics in breast cancer patients treated with neoadjuvant chemotherapy [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 P3-11-01.

As the first monoclonal antibody against vascular endothelial growth factor (VEGF), bevacizumab (BEV) is a definitely controversial antiangiogenic therapy in breast cancer. The initial excitement over improvements in progression-free survival (PFS) with BEV was tempered by an absence of overall survival (OS) benefit and serious adverse effects. Missing targeted population urged us to identify the predictive biomarkers for BEV efficacy. In this review we focus on the research in breast cancer and provide recent investigations on clinical, radiological, molecular and gene profiling markers of BEV efficacy, including the new results from randomized phase III clinical trials evaluating the efficacy of BEV in combination with comprehensive biomarker analyses. Current evidences indicate some predictive values for genetic variants, molecular imaging, VEGF pathway factors or associated factors in peripheral blood and gene profiling. The current challenge is to validate those potential biomarkers and implement them into clinical practice.

Purpose Among metastatic breast cancer (MBC) patients, those with a triple-negative breast cancer phenotype (mTNBC) have the worst prognosis, but the benefit of chemotherapy beyond second line on outcome remains uncertain. The purpose of this study was to identify predictive factors of outcome after third- or fourth-line chemotherapy. Methods The ESME-MBC database is a French prospective real-life cohort with homogeneous data collection, including patients who initiated first-line treatment for MBC (2008–2016) in 18 cancer centers. After selection of mTNBC cases, we searched for independent predictive factors (Cox proportional-hazards regression models) for overall survival (OS) on third- and fourth-line chemotherapy (OS3, OS4). We built prognostic nomograms based on the main prognostic factors identified. Results Of the 22,266 MBC cases in the ESME cohort, 2903 were mTNBC, 1074 (37%) and 598 (20%) of which had received at least 3 or 4 lines of chemotherapy. PFS after first- and second-line chemotherapy (PFS1, PFS2) and number of metastatic sites ≥3 at baseline were identified by multivariate analysis as prognostic factors for both OS3 (HR = 0.76 95%CI[0.66–0.88], HR = 0.55 95%CI[0.46–0.65], HR = 1.36 95%CI[1.14–1.62], respectively), and OS4 (HR = 0.76 95%CI[0.63–0.91], HR = 0.56 95%CI[0.45–0.7], HR = 1.37 95%CI[1.07–1.74]), respectively. In addition, metastasis-free interval was identified as a prognostic factor for OS3 (p = 0.01), while PFS3 influenced OS4 (HR = 0.75 95%CI[0.57–0.98]). Nomograms predicting OS3 and OS4 achieved a C-index of 0.62 and 0.61, respectively. Conclusion The duration of each previous PFS is a major prognostic factor for OS in mTNBC patients receiving third- or fourth-line chemotherapy. The clinical utility of nomograms including this information was not demonstrated., Highlights • After 3rd- or 4th-line therapy, PFS remained linear in the majority of women with metastatic triple-negative breast cancer. • The duration of each previous PFS had an impact on the OS associated with subsequent lines. • PFS2 was more strongly predictive of outcome than PFS1 for third-line therapy. • PFS2 and PFS3 had an impact on outcome irrespective of PFS1 for fourth-line therapy. • The clinical utility of nomograms including duration of each previous PFS to predict OS was not sufficient.

Simple Summary Over the last ten years, neoadjuvant endocrine therapy (NET) has been increasingly investigated and has gained recognition. NET should not only be used to allow surgery or to improve breast-conserving surgery rates in patients not eligible for NCT, but also as a research tool for the search for endocrine sensitivity biomarkers and targeted therapies, and for prognostic information in ER+/HER2-. Abstract Endocrine therapy is the mainstay of treatment in HR+/HER2- breast cancers, which represent about 70% of all breast cancers. Neoadjuvant therapy has been developed since the 1990s to address several issues, including breast-conserving surgery (BCS) and improvement of survival rates. For a long time, neoadjuvant endocrine therapy (NET) was confined to frail patients in order to improve surgery outcome. Since the 2000s, NET now plays a central role as a research tool for predictive endocrine sensitivity biomarkers and targeted therapies. One of the major issues in early HR+/HER2- breast cancer is to identify patients in whom chemotherapy can be safely withheld. In vivo assessment of response to NET might be the best treatment strategy to address this issue.

Background: Fatigue is a multidimensional symptom. It is recognised as one of the most burdensome and long-lasting adverse effects of cancer and cancer treatment. We aimed to characterise long-term fatigue trajectories among breast cancer survivors. Methods: We performed a detailed longitudinal analysis of fatigue using a large ongoing national prospective clinical study (CANcer TOxicity, NCT01993498) of patients with stage I–III breast cancer treated from 2012–2015. Fatigue was assessed at diagnosis (baseline), year-one, -two, and -four post-diagnosis. Baseline clinical, socio-demographic, behavioural, tumour- and treatment-related characteristics were available. Trajectories of fatigue and risk factors of trajectory-group membership were identified by iterative estimates of group-based trajectory models and multivariable logistic regression. Findings: Three trajectory-groups were identified for severe global fatigue (N=4173). Twenty-one per cent of patients were in the "High" risk group, having a risk estimate of severe global fatigue of 94·8% [95% confidence interval (CI) 86·6–100·0] at diagnosis and 64·8% [95% CI 59·2–70·1] at year four; 19% of patients clustered in the "Deteriorating" group with a risk estimate of severe global fatigue of 13·8% [95% CI 6·7%–20·9%] at diagnosis and 64·5% [95% CI 57·3–71·8] at year four; and 60% were in the “Low” risk group with a risk estimate of 3·6% [95% CI 2·5–4·7] at diagnosis and 9·6% [95% CI 7·5–11·7] at year four). The distinct dimensions of fatigue clustered in different trajectory groups than those identified by severe global fatigue, being differentially impacted by socio-demographic, clinical, and treatment-related factors. Interpretation: Our findings highlight the multidimensional nature of cancer-related fatigue and the complexity of its risk factors. This study helps to identify patients with increased risk of severe fatigue and to inform personalised interventions to ameliorate this problem. Funding: Susan G. Komen, French Foundation for Cancer Research, Foundation Gustave Roussy, and French Government (Agence Nationale de la recherche [ANR]). Declaration of Interest: None to declare. Ethical Approval: All study participants provided informed consent, and the national regulatory and ethics committee approved the study (ID-RCB:2011-A01095-36,11-039).

Inflammatory breast cancer (IBC) is a highly aggressive entity with a poor outcome and relative resistance to treatment. Despite progresses achieved during the last decades, the survival remains significantly lower than non-IBC. Recent clinical trials assessing PD-1/PD-L1 inhibitors showed promising results in non-IBC. Pembrolizumab, an anti-PD-1 monoclonal antibody, revolutionized the treatment of different cancers. Several recent studies suggested a potential interest of targeting the immune system in IBC by revealing a more frequent PD-L1 expression and an enriched immune microenvironment when compared with non-IBC. Here, we describe the rationale and design of PELICAN-IPC 2015-016/Oncodistinct-003 trial, an open-label, randomized, non-comparative, phase II study assessing efficacy, and safety of pembrolizumab in combination with anthracycline-containing neoadjuvant chemotherapy in HER2-negative IBC. The trial is ongoing. The primary endpoint is the pCR rate (ypT0/Tis, ypN0) in overall population and the co-primary endpoint is safety profile during a run-in phase. Key secondary objectives include tolerability, invasive disease-free, event-free and overall survivals, as well as collection of tumor and blood samples for translational research.Clinical Trial Registrationhttps://clinicaltrials.gov/ (NCT03515798).

Purpose Previous cohort studies have reported plasma TK1 activity (pTKa) as a potential prognostic biomarker in estrogen receptor-positive (ER+) HER2-negative (HER2−) metastatic breast cancer (MBC). In this prospective study, we report here the prognostic impact of pTKa in ER+/HER2− MBC patients treated with endocrine therapy and CDK4/6 inhibitor. Experimental design Patients were included into the prospective, ethics committee-approved ALCINA study (NCT02866149). Eligibility criteria were patients with ER+/HER2− MBC treated at Institut Curie with endocrine therapy and palbociclib. Plasma samples were obtained at baseline and after 4 weeks of treatment. pTKa was quantified by the DiviTum® assay (Biovica, Sweden). Results From May 2016 to August 2018, 103 patients treated with endocrine therapy and palbociclib were included. Patients had received a median of two prior systemic therapies for MBC (range 0–14). Median follow-up was 13.8 months (range 6–31), with median PFS and OS of 9.6 months (95%CI [7.0–11.3]) and 28 months (95%CI [23–not reached]), respectively. Median baseline pTKa was 292 Du/L (range 20–27,312 Du/L, IQR [89–853]). After adjusting for other prognostic factors, baseline pTKa remained an independent prognostic factor for both PFS (HR = 1.3 95%CI [1.1–1.4], p = 0.0005) and OS (HR = 1.3 95%CI [1.2–1.6], p p Conclusion This study demonstrates the clinical validity of pTKa as a new circulating prognostic marker in ER+/HER2− MBC patients treated with endocrine therapy and palbociclib.

PURPOSE Nonadherence to long-term treatments is often under-recognized by physicians and there is no gold standard for its assessment. In breast cancer, nonadherence to tamoxifen therapy after surgery constitutes a major obstacle to optimal outcomes. We sought to evaluate the rate of biochemical nonadherence to adjuvant tamoxifen using serum assessment and to examine its effects on short-term, distant disease-free survival (DDFS). PATIENTS AND METHODS We studied 1,177 premenopausal women enrolled in a large prospective study (CANTO/NCT01993498). Definition of biochemical nonadherence was based on a tamoxifen serum level < 60 ng/mL, assessed 1 year after prescription. Self-reported nonadherence to tamoxifen therapy was collected at the same time through semistructured interviews. Survival analyses were conducted using an inverse probability weighted Cox proportional hazards model, using a propensity score based on age, staging, surgery, chemotherapy, and center size. RESULTS Serum assessment of tamoxifen identified 16.0% of patients (n = 188) below the set adherence threshold. Patient-reported rate of nonadherence was lower (12.3%). Of 188 patients who did not adhere to the tamoxifen prescription, 55% self-reported adherence to tamoxifen. After a median follow-up of 24.2 months since tamoxifen serum assessment, patients who were biochemically nonadherent had significantly shorter DDFS (for distant recurrence or death, adjusted hazard ratio, 2.31; 95% CI, 1.05 to 5.06; P = .036), with 89.5% of patients alive without distant recurrence at 3 years in the nonadherent cohort versus 95.4% in the adherent cohort. CONCLUSION Therapeutic drug monitoring may be a useful method to promptly identify patients who do not take adjuvant tamoxifen as prescribed and are at risk for poorer outcomes. Targeted interventions facilitating patient adherence are needed and have the potential to improve short-term breast cancer outcomes.

Tobacco use is associated with an increase in breast cancer (BC) mortality. Pathologic complete response (pCR) rate to neoadjuvant chemotherapy (NAC) is influenced by tumor-infiltrating lymphocyte (TIL) levels and is associated with a better long-term survival outcome. The aim of our study is to evaluate the impact of smoking status on TIL levels, response to NAC and prognosis for BC patients. We retrospectively evaluated pre- and post-NAC stromal and intra tumoral TIL levels and pCR rates on a cohort of T1-T3NxM0 BC patients treated with NAC between 2002 and 2012 at Institut Curie. Smoking status (current, ever, never smokers) was collected in clinical records. We analyzed the association between smoking status, TIL levels, pCR rates and survival outcomes among the whole population, and according to BC subtype. Nine hundred and fifty-six BC patients with available smoking status information were included in our analysis (current smokers, n = 179 (18.7%), ever smokers, n = 154 (16.1%) and never smokers, n = 623 (65.2%)). Median pre-NAC TIL levels, pCR rates, or median post-NAC TIL levels were not significantly different according to smoking status, neither in the whole population, nor in any BC subtype group. With a median follow-up of 101.4 months, relapse-free survival (RFS) and overall survival (OS) were not significantly different by smoking status. We did not find any significant effect of tobacco use on pre- and post-NAC TILs nor response to NAC. Though our data seem reassuring, BC treatment should still be considered as a window of opportunity to offer BC patients accurate smoking cessation interventions.

IntroductionThe Residual Cancer Burden (RCB) quantifies residual disease after neoadjuvant chemotherapy (NAC). Its predictive value has not been validated on large cohorts with long-term follow up. The objective of this work is to independently evaluate the prognostic value of the RCB index depending on BC subtypes (Luminal, HER2-positive and triple negative (TNBCs)).MethodsWe retrospectively evaluated the RCB index on surgical specimens from a cohort of T1-T3NxM0 BC patients treated with NAC between 2002 and 2012. We analyzed the association between RCB index and relapse-free survival (RFS), overall survival (OS) among the global population, after stratification by BC subtypes.Results717 patients were included (luminal BC (n = 222, 31%), TNBC (n = 319, 44.5%), HER2-positive (n = 176, 24.5%)). After a median follow-up of 99.9 months, RCB index was significantly associated with RFS. The RCB-0 patients displayed similar prognosis when compared to the RCB-I group, while patients from the RCB-II and RCB-III classes were at increased risk of relapse (RCB-II versus RCB-0: HR=3.25 CI [2.1-5.1] pversus RCB-0: HR=5.6 CI [3.5-8.9] pHER2-positive cancers; but not for luminal cancers (Pinteraction = 0.07). The prognosis of RCB-III patients was poor (8-years RFS: 52.7%, 95% CI [44.8 – 62.0]) particularly in the TNBC subgroup, where the median RFS was 12.7 months.ConclusionRCB index is a reliable prognostic score. RCB accurately identifies patients at a high risk of recurrence (RCB-III) with TNBC or HER2-positive BC who must be offered second-line adjuvant therapies.

PURPOSE Adverse effects of breast cancer treatment can negatively affect survivors’ work ability. Previous reports lacked detailed clinical data or health-related patient-reported outcomes (PROs) and did not prospectively assess the combined impact of treatment and related sequelae on employment. METHODS We used a French prospective clinical cohort of patients with stage I-III breast cancer including 1,874 women who were working and ≥ 5 years younger than legal retirement age (≤ 57 years) at breast cancer diagnosis. Our outcome was nonreturn to work (non-RTW) 2 years after diagnosis. Independent variables included treatment characteristics as well as toxicities (Common Toxicity Criteria Adverse Events [CTCAE] v4) and PROs (European Organization for Research and Treatment of Cancer [EORTC] Quality of life Questionnaires, Breast cancer module [QLQ-BR23] and Fatigue module [QLQ-FA12], Hospital Anxiety and Depression Scale) collected 1 year after diagnosis. Logistic regression models assessed correlates of non-RTW, adjusting for age, stage, comorbidities, and socioeconomic covariates. RESULTS Two years after diagnosis, 21% of patients had not returned to work. Odds of non-RTW were significantly increased among patients treated with combinations of chemotherapy and trastuzumab (odds ratio [OR] v chemotherapy-hormonotherapy: for chemotherapy-trastuzumab, 2.01; 95% CI, 1.18 to 3.44; for chemotherapy-trastuzumab-hormonotherapy, 1.62; 95% CI, 1.10 to 2.41). Other significant associations with non-RTW included grade ≥ 3 CTCAE toxicities (OR v no, 1.59; 95% CI, 1.15 to 2.18), arm morbidity (OR v no, 1.59; 95% CI, 1.19 to 2.13), anxiety (OR v no, 1.47; 95% CI, 1.02 to 2.11), and depression (OR v no, 2.29; 95% CI, 1.34 to 3.91). CONCLUSION Receipt of systemic therapy combinations including trastuzumab was associated with increased odds of non-RTW. Likelihood of unemployment was also higher among patients who reported severe physical and psychological symptoms. This comprehensive study identifies potentially vulnerable patients and warrants supportive interventional strategies to facilitate their RTW.

Background Neoadjuvant endocrine therapy (NET) has shown efficacy in terms of clinical response and surgical outcome in postmenopausal patients with estrogen receptor-positive / HER2-negative breast cancer (ER+/HER2- BC) but monitoring of tumor response is challenging. The aim of the present study was to investigate the value of an early metabolic response compared to morphological and pathological responses in this population. Methods This was an ancillary study of CARMINA 02, a phase II clinical trial evaluating side-by-side the efficacy of 4 to 6 months of anastrozole or fulvestrant. Positron Emission Tomography/Computed Tomography using 2-deoxy-2-[18F]fluoro-D-glucose (FDG-PET/CT) scans were performed at baseline (M0), early after 1 month of treatment (M1) and pre-operatively in 11 patients (74.2 yo ± 3.6). Patients were classified as early “metabolic responders” (mR) when the decrease of SUVmax was higher than 40%, and “metabolic non-responders” (mNR) otherwise. Early metabolic response was compared to morphological response (palpation, US and MRI), variation of Ki-67 index, pathological response according to the Sataloff classification and also to Preoperative Endocrine Prognostic Index (PEPI) score. It was also correlated with overall survival (OS) and recurrence-free survival (RFS). Results Tumor size measured on US and on MRI was smaller in mR than mNR, with the highest statistically significant difference at M1 (p = 0.01 and 7.1 × 10− 5, respectively). No statistically significant difference in the variation of tumor size between M0 and M1 assessed on US or MRI was observed between mR and mNR. mR had a better clinical response: no progressive disease in mR vs 2 in mNR and 2 partial response in mR vs 1 partial response in mNR. One patient with a pre-operative complete metabolic response had the best pathological response. Pathological response did not show any statistically significant difference between mR and mNR. mR had better OS and RFS (Kaplan-Meier p = 0.08 and 0.06, respectively). All cancer-related events occurred in mNR: 3 patients died, 2 of them from progressive disease. Conclusions FDG-PET/CT imaging could become a “surrogate marker” to monitor tumor response, especially as NET is a valuable treatment option in postmenopausal women with ER+/HER2- BC.

International audience; Breast cancer is the most frequently diagnosed cancer in women and the first cause of cancer death in France. Among the different subtypes of breast cancer, the predominant form is characterized by positive hormone receptors (more than 70% of breast cancers). Hormone therapy thus plays a key role in the strategy of management of these cancers both in adjuvant and metastatic situations. The two types of adjuvant hormone therapy used are selective estrogen receptor modulators and aromatase inhibitors. Fulvestrant, an anti-estrogen, is used alone or in combination with other molecules in metastatic situations. Hot flashes are one of the symptoms most frequently reported by patients under hormone therapy. Hormone replacement therapy, which is currently the most effective treatment for hot flashes, is contraindicated in patients with a personal history of breast cancer. Various therapeutic classes of drugs have been tested in this indication but without real efficacy in the various studies carried out to date, and moreover associated with non-negligible side effects. The recent discovery of the implication of the kisspeptin system located at the hypothalamic level in the mechanism of genesis of hot flashes opens the way to possible new symptomatic treatments for hot flashes. Neurokinin 3 receptor antagonists have shown encouraging preliminary results in postmenopausal cancer-free patients and could be considered in patients in hormonal therapy for breast cancer. Broader additional studies are needed to confirm these initial results.

Background Few data are available on survival and predictive factors in early breast cancer (BC) patients treated with neoadjuvant endocrine therapy (NET). Methods This is a pooled analysis of two multicentre, randomised non-comparative phase 2 clinical trials evaluating neoadjuvant anastrozole and fulvestrant efficacy for postmenopausal HR+/HER2- breast cancer patients: HORGEN (NCT00871858) and CARMINA02 (NCT00629616) studies. Results In total, 236 patients were included in CARMINA02 and HORGEN trials. Modified intention-to-treat analysis was available for 217 patients. Median follow-up was 65.2 months. Relapse-free survival (RFS) and overall survival (OS) at 5 years were 83.7% (95% CI: 77.9–88) and 92.7% (95% CI: 88.2–95.6), respectively, with no difference between treatment arms. On univariate analysis, tumour staging (T2 vs T3–4; p = 0.0001), Ki-67 at surgery (≤10% vs >10%; p = 0.0093), pathological tumour size (pT1–2 vs pT3–4; p = 0.0012) and node status (pN negative vs positive; p = 0.007), adjuvant chemotherapy (p = 0.0167) and PEPI score (PEPI group I + II vs III; p = 0.0004) were associated with RFS. No events were observed in patients with pathological response according to the Sataloff classification. Multivariate analysis showed that preoperative endocrine prognostic index (PEPI) group III was associated with significantly worse RFS (p = 0.0069, hazard ratio = 3.33 (95% CI: 1.39–7.98)). Conclusions Postmenopausal HR+/HER2- breast cancer patients receiving NET generally have a favourable outcome. The PEPI score identifies a subset of patients of poorer prognosis who are candidates for further additional treatment.

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.

Background There is no large prospective trial assessing mid-term adverse effects of adjuvant chemotherapy. In order to address this question, we developed CANTO (CANcer TOxicities - NCT01993498 - http://etudecanto.org/), a prospective trial dedicated to the quantification of side effects after treatment for patients with early breast cancer and to develop predictors of such toxicities. The aim of this presentation is to assess chemotherapy (CT) practice and to report toxicities that persist 3-6 months after CT. Methods CANTO is a prospective study enrolling newly diagnosed invasive cT0-cT3, cN0-3, M0 breast cancer patients (pts) of 26 French comprehensive cancer centers. The study has included 10 500 patients at the time of submission. Pts are assessed at diagnosis, 3-6, 12, 36, 48 and 60 months after treatment completion. CANTO collects >100 items related to toxicities. In the current study, we focus on the first set of data available from the trial (1st database lock, n=6090). We here assess CT practice and toxicities at 3 months. Results Information about (neo)adjuvant CT (NACT/ACT) is available in 5805 pts (96%). Median age at diagnosis was 57y (22-93). Pts had HR+/HER2-, HER2+ or triple negative (TN) tumors in 74%, 15% and 11% of cases. Ki67 was assessed in 70%, and genomic tests in 1% of pts, respectively. Overall, 3074 pts (53%) received CT, either adjuvant (ACT: 76%) or neoadjuvant (NACT: 24%). ACT/NACT pts (84%) received a sequential anthracyclines–taxanes based 6 courses CT schedule. CT was administered in 44.7%, 87.2% and 92.3% of HR+/HER2+/TN tumors, respectively. ACT was administered in 73.2% of pT2+ pts (vs 36.0% in pT0-1 – p We focus here on clinically most relevant patient reported symptoms at 3 m (any grade). side effects at 3m no CT (%)CT (%)p valuePain76.682.1 Pain complaint was recorded in 3596 pts (97.2% of pts with available data), with a median value of 4 on the VAS (range 1-10). In ACT/NACT pts, muscle and joint pain were predominant. Neurological symptoms were seen in 3024 pts (59%), the most frequent pertaining to cognitive disorder (attention trouble, CT: 61.2% vs noCT: 56% - p=.06) and peripheral neuropathy (overall 31%). Paresthesias and sensory neuropathy were much more frequent in CT vs noCT pts: respectively 37.3% vs 20.3% and 25.7% vs 12.8% (both p Conclusions In this real life, prospective cohort, CT is frequently prescribed and appears in good compliance with current guidelines. Overall, symptoms burden at treatment completion is strikingly high, and much higher in pts receiving CT. A special attention should be given to pain and neurological symptoms. Dedicated questionnaires and sub-studies will explore in depth these side effects. Extended analyses of CT practice and toxicities will be presented. Citation Format: Cottu PH, Amar Y, Pistilli B, Bonsang-Kitzis H, Lesur A, Lerebours F, Vanlemmens L, Tredan O, Levy C, Jouannaud C, Fournier M, Soulie P, Rigal O, Giacchetti S, Arnaud A, Arsene O, Savignoni A, Mesleard C, Andre F, Arveux P. CANTOCHEM: Analysis of chemotherapy practice and early side effects in the 6090 first patients from the prospective CANTO cohort [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 P6-12-18.

Background About 20% of breast cancer (BC) patients will develop distant metastases. HER2-positive (HER2+) disease is associated with poorer prognosis. However, outcome of HER2+ BC patients has dramatically improved since the use of trastuzumab. Although most HER2+ metastatic BC (MBC) patients will eventually develop progressive disease within one year of trastuzumab-based treatment, some are long-term responders (LTR). Few data on these patients are available. Methods The primary objective was to assess overall survival (OS) of HER2+ MBC patients treated with trastuzumab as 1st-line at the Institut Curie, based on institution-specific data included in the French Epidemiological Strategy and Medical Economics (ESME) program for MBC patients established in 2014 by Unicancer. Long-term responders (LTR) were defined as having a non-progressive disease for at least 2 years under 1st-line trastuzumab. Secondary objectives included progression-free survival (PFS), disease-free interval (DFI), prediction factors for LTR status by univariate and multivariate analysis: characteristics of patients (age, BMI, menopausal status), of primary tumour (e.g. hormone receptor (HR) status), of treatment (e.g. endocrine therapy, partner for trastuzumab combination), number and type of metastases. Results From 2008 to 2014, 2990 MBC patients were identified in the Curie-ESME MBC database. Of these, 460 had HER2+ disease. Sixteen patients with second primary malignancy were excluded. Of the 444 remaining patients, 340 received 1st-line trastuzumab and could be analyzed. With a 42.5-month median follow-up time, the mean age at metastatic diagnosis was 55.7 years, 59.4% had a HR-positive disease and 43.2% had de novo metastases or occurring within 6 months after adjuvant treatment. DFI was >24 months in 47.9% of patients, and 78.5% received 1st-line trastuzumab combined with taxane-based chemotherapy (CT). In 87 patients (25.6%) classified as LTR, median PFS was 56.2 months (CI95% 41.53-not reached) vs. 10.9 months in non-LTR (CI95% 9.46-11.8). Median OS in LTR is not reached versus 44.3 months in non-LTR (CI95% 37.9-49.1). Median age, menopausal status, BMI, pathological characteristics and treatment for primary BC were similar in both groups. The following factors were predictive of LTR status by univariate analysis: number of metastatic sites ( 3, p=0.022); endocrine treatment for metastatic disease (p=0.002); absence of central nervous system metastases (p=0.035); and taxane-based 1st- line CT (p=0.032). In multivariate analysis, only number of metastatic sites and taxane-based 1st-line CT were predictive of LTR status. In contrast, age, DFI, visceral disease, and adjuvant trastuzumab-based treatment did not influence outcome. Although not statistically significant, HR+ status was more frequent in LTR versus non-LTR patients (66.7% versus 56.9%). Conclusions With a median follow-up of 42.5 months, we found that more than 95% of LTR to 1st-line trastuzumab were still alive and could achieve a median PFS longer than 4.6 years. Although some clinical factors are clearly associated with better outcome, further investigations are needed to identify the mechanisms of resistance or sensitivity to trastuzumab. Citation Format: Kaczmarek E, Saint-Martin C, Pierga J-Y, Brain E, Rouzier R, Dubot C, Savignoni A, Mouret-Fourme E, Simon G, Carton M, Lerebours F. Long-term survival in HER2-positive metastatic breast cancer treated with first-line trastuzumab: Real-life results from the Curie ESME database [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 P5-21-14.

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: Amongst metastatic breast cancer (MBC) patients (pts), those with triple-negative breast cancer (mTNBC) have a poor prognosis. Although chemotherapy (CT) remains the cornerstone therapy, its benefit on outcome is not established beyond second line while side effects increase and impair quality of life. Factors predicting for efficacy might help guiding in the treatment decision process. The purpose of this study was to evaluate factors predicting for progression-free survival (PFS) and overall survival (OS) in the third or fourth line treatment in pts with mTNBC within the National multicenter ESME cohort, and to build a nomogram based on the selected variables. Methods: The ESME (Epidemiological Strategy and Medical Economics) MBC database (NCT03275311) is a unique national Metastatic Breast Cancer cohort built from existing information systems, pharmacy records and patients’ electronic medical records (EMR), with homogenous on-site collected information. This prospective cohort includes all consecutive pts who initiated a first-line treatment for a MBC between 2008 and 2016 in one of the 18 French Comprehensive Cancer Centers. We searched for independent prognostic factors under third and fourth line chemotherapy (PFS3 and PFS4, OS3 and OS4) for mTNBC patients, using COX proportional hazard regression models. Variables included in the model were pts and tumour (primary cancer and MBC) characteristics, as well as observed PFS under previous lines of therapy. We built prognostic nomograms based on main prognostic factors retrieved. Nomograms’ prediction ability were evaluated by concordance index (C-index), calibration and subgroup analysis. We used a 6-month cut-off for each PFSx. Results: Among 22266 women in the ESME cohort, 2922 had a mTNBC. 1792 (61%), 1074 (37%) and 598 (20%) mTNBC pts respectively received at least 2, 3 or 4 lines of CT in the metastatic setting, with a median follow-up of 53.3 months (range 4.6-103). The median PFS3, PFS4, OS3 and OS4 were 2.3 months 95%CI [2.3-2.5], 2.1 months 95%CI [1.9-2.3], 6.6 months 95%CI [6.3-7.2] and 5.9 months 95%CI[5.2-6.4], respectively. PFS1, PFS2 and number of metastatic sites ≤3 at baseline were identified as prognostic factors by multivariate analysis both for OS3 and OS4 (HR 0.76 95%CI[0.66-0.88], HR 0.55 95%CI[0.46-0.65], HR 1.36 95%CI[1.14-1.62], all p Conclusion: The previous duration of each PFS is a major prognostic factor of PFS and OS in TNBC in 3rd or 4rd of CT among mTNBC pts. However, nomograms predicting for PFS and OS this setting do not reach a clinical utilityTable 1: PFS and OS according to previous PFS duration Previous PFS 1/2 (months)N=OS3 months [95%CI]HR [95%CI]pPFS3 months[95%CI]HR [95%CI]p≤6/≤65245.2 [4.7-5.9]16/≤63127.3 [6.4-8.7]0.71 [0.61; 0.82]2.4 [2.2-2.6]0.86 [0.75; 1]≤6/>611211.3 [8.1-13.4]0.48 [0.38; 0.6]2.7 [2.3-3.5]0.69 [0.56; 0.85]>6/>612611.9 [9.9-15.2]0.43 [0.34; 0.54]3.5 [3.2-4.1]0.52 [0.42; 0.64]Previous PFS1/2/3N=OS4 months [95%CI]HR [95%CI]PFS4 months [95%CI]HRp≤6/≤6 /≤62284.5 [3.9-5.4]16357.0 [4.1-10.9]0.7 [0.47; 1.04]2.1 [1.8-2.8]0.83 [0.57; 1.2]>6/≤6 />6176.9 [4.3-NA]0.7 [0.4; 1.22]3.0 [1.6-NA]0.54 [0.31; 0.94]>6/≤6 /≤61665.6 [4.7-6.7]0.65 [0.52; 0.8]2.3 [1.9-2.7]0.66 [0.54; 0.81]>6/>6 /≤6567.8 [4.9-11.1]0.54 [0.38; 0.75]2.1 [1.8-2.4]0.87 [0.64; 1.18]≤6/>6 /≤6608.1 [6.7-12.7]0.45 [0.33; 0.63]2.4 [1.9-3.0]0.65 [0.49; 0.88]≤6/>6 />61316.7 [5.9-NA]0.3 [0.16; 0.57]4.2 [2.3-NA]0.32 [0.17; 0.59]>6/>6 />62310.7 [8.5-NA]0.25 [0.14; 0.45]4.8 [3.4-8.0]0.33 [0.21; 0.51] Citation Format: Luc Cabel, Matthieu Carton, Barbare Pistilli, Florence Dalenc, Laurence Vanlemnens, Christelle Levy, William Jacot, Marc Debled, Agnes Loeb, Bruno Coudert, Thubault De la Motte Rouge, Lilian Laborde, Carine Laurent, Emmanuel Chamorey, Damien Parent, Thierry Petit, Marie-Ange Mouret-Reynier, Geneviève Perrocheau, Claire Labreveux, Thomas Bachelot, Mathieu Robain, Florence Lerebours. Prediction of PFS and OS under third and fourth line chemotherapy among metastatic triple-negative breast cancer patients in the national multicenter ESME metastatic breast cancer cohort [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-06-18.

Background In early breast cancer (BC), there has been a trend to escalate endocrine therapy (ET) and to de-escalate chemotherapy (CT). However, the impact of ET versus CT on the quality of life (QoL) of early BC patients is unknown. Here, we characterize the independent contribution of ET and CT on patient-reported outcomes (PROs) at 2 years after diagnosis. Patients and methods We prospectively collected PROs in 4262 eligible patients using the European Organization for Research and Treatment of Cancer QLQ-C30/BR23 questionnaires inside CANTO trial (NCT01993498). The primary outcome was the C30 summary score (C30-SumSc) at 2 years after diagnosis. Results From eligible patients, 37.2% were premenopausal and 62.8% postmenopausal; 81.9% received ET and 52.8% CT. In the overall cohort, QoL worsened by 2 years after diagnosis in multiple functions and symptoms; exceptions included emotional function and future perspective, which improved over time. ET (Pint = 0.004), but not CT (Pint = 0.924), had a persistent negative impact on the C30-SumSc. In addition, ET negatively impacted role and social function, pain, insomnia, systemic therapy side-effects, breast symptoms and further limited emotional function and future perspective recovery. Although CT had no impact on the C30-SumSc at 2-years it was associated with deteriorated physical and cognitive function, dyspnea, financial difficulties, body image and breast symptoms. We found a differential effect of treatment by menopausal status; in premenopausal patients, CT, despite only a non-significant trend for deteriorated C30-SumSc (Pint = 0.100), was more frequently associated with QoL domains deterioration than ET, whereas in postmenopausal patients, ET was more frequently associated with QoL deterioration, namely using the C30-SumSc (Pint = 0.004). Conclusion(s) QoL deterioration persisted at 2 years after diagnosis with different trajectories by treatment received. ET, but not CT, had a major detrimental impact on C30-SumSc, especially in postmenopausal women. These findings highlight the need to properly select patients for adjuvant ET escalation.

BackgroundWe studied the relationship between time to ipsilateral breast tumor recurrence (IBTR) and distant metastasis-free survival (DMFS) in patients with breast cancer treated by neoadjuvant chemotherapy (NAC).MethodsBetween 2002 and 2012, 1199 patients with primary breast cancer were treated with NAC. Clinical, radiological and pathological data were retrieved from medical records. Multivariate analysis was performed with the random survival forest (RSF) method, to evaluate the relationship between time to local recurrence and DMFS.ResultsTime to IBTR, local recurrence and molecular subtype were the factors most strongly associated with DMFS. In the total population, DMFS increased linearly with recurrence time, up to 50 months. For recurrences after 50 months, DMFS was similar for all times to recurrence. Considering molecular subtypes separately, the threshold was similar for the TNBC subtype (50 months), but appeared to occur later for the luminal and HER2-positive subtypes (75 months).ConclusionA threshold of 50 months seems to differentiate between early and late recurrences and could be used to guide the medical management of local breast tumour recurrences.

1060 Background: Mutations in PIK3CA (encoding PI3Kα) are present in ̃40% of HR+, HER2– ABC tumors and are associated with relative endocrine resistance and poor prognosis. ALP inhibits and degrades PI3Kα. Primary analyses of Cohorts A and B from the phase 2 BYLieve study demonstrated that ALP + endocrine therapy (ET; fulvestrant [FUL] or letrozole [LET]) is effective and safe in pts with HR+, HER2– PIK3CA-mutated ABC with prior CDK4/6i therapy. Here, we evaluate if duration of prior CDK4/6i-based therapy impacts benefit of ALP + ET in these 2 cohorts. Methods: Cohorts A and B of BYLieve included pre/postmenopausal women who received CDK4/6i + AI or FUL, respectively, as immediate prior therapy. Cohort A received ALP 300 mg PO QD + FUL 500 mg IM Q28D + C1D15; Cohort B received ALP 300 mg PO QD + LET 2.5 mg PO QD. Within each cohort, pts were divided into 2 subgroups per duration of prior CDK4/6i therapy (“high”/”low,” above/below median duration of therapy) and the association of progression-free survival (PFS) with this covariate was analyzed using stratified log-rank test and Cox PH model. This analysis included pts for whom duration of prior CDK4/6i therapy was known, and efficacy was assessed in pts with centrally confirmed PIK3CA mutation in tumor tissue. Results: Of the 126 pts in Cohort A with duration of prior CDK4/6i available, 120 had centrally confirmed PIK3CA-mutated disease; 60 were exposed to CDK4/6i for > 380 days (high) and 60 for < 380 days (low), with similar demographics/disease characteristics between subgroups. There was no significant difference in PFS between the high vs low subgroups (HR 1.03; 95% CI, 0.64-1.64; P= 0.927; median 8.0 vs 7.0 mo). Grade ≥3 adverse events (AEs) were experienced by 66.9% (n = 85) of all pts in Cohort A and 66.7% (n = 42)/68.3% (n = 43) in the high/low subgroups, respectively. Of the 123 pts in Cohort B with duration of prior CDK4/6i available, 113 had centrally confirmed PIK3CA-mutated disease; 57 were exposed to CDK4/6i for > 305 days (high) and 56 for < 305 days (low), with similar demographics/disease characteristics between subgroups. There was no significant difference in PFS between high vs low subgroups (HR 1.20; 95% CI, 0.78-1.84; P= 0.400; median 5.4 vs 5.9 mo). Grade ≥3 AEs were experienced by 69.8% (n = 88) of all pts in Cohort B and 71.0% (n = 44)/68.9% (n = 42) in the high/low subgroups, respectively. Conclusions: This analysis demonstrates that the benefit and safety profiles of ALP + ET are similar in pts with HR+, HER2– PIK3CA-mutated ABC who achieved relatively shorter duration of disease control with prior CDK4/6i vs those with longer duration of disease control, and suggests that ALP overcomes acquired resistance to CDK4/6i in these pts. Clinical trial information: NCT03056755 .

International audience; Pregnancy-associated breast cancer (PABC) constitutes 7% of all BCs in young women. The prognosis of PABC remains controversial. In this study, we evaluated the impact of the association of pregnancy with BC on the rates of overall survival (OS), disease free survival (DFS), and distant and local recurrence-free survival. We conducted a retrospective unicenter case–control study. We enrolled PABC patients treated at our institution between 1992 and 2009. For each case, 2 BC controls were matched for age and year of diagnosis. Univariate and multivariate analyses were performed to assess the parameters associated with prognosis. Eighty-seven PABC patients were enrolled and matched with 174 controls. The univariate analysis did not reveal any significant differences in OS, DFS or distant recurrence rates between the 2 groups. Pregnancy associated status, a tumor larger than T2 and neoadjuvant chemotherapy as the primary treatment were significantly associated with an increased risk of local relapse. The multivariate analysis showed that the pregnancy associated status and the tumor size were strong prognostic factors of local recurrence. Pregnancy associated status negates the prognostic value of tumor size, as both T0–T2 and T3–T4 PABC patients have the same poor prognosis as control BC patients with T3–T4 tumors. Interestingly, although PABC patients have more locally advanced tumors, they did not have a higher rate of radical surgery than the control BC patients. Pregnancy associated status is a strong prognostic factor of local relapse in BC. In PABC patients, when possible, radical surgery should be the preferred first treatment step.

// Sandrine Tury 1 , Veronique Becette 2 , Franck Assayag 3 , Sophie Vacher 1 , Camille Benoist 1 , Maud Kamal 4 , Elisabetta Marangoni 3 , Ivan Bieche 1 , Florence Lerebours 4 , Celine Callens 1 1 Pharmacogenomic Unit, Genetics Laboratory, Institut Curie, Paris, France 2 Department of Pathology, Institut Curie, Hopital Rene Huguenin, Saint-Cloud, France 3 Laboratory of Preclinical Investigations, Translational Research Department, Institut Curie, Paris, France 4 Department of Medical Oncology, Institut Curie, Paris and Saint-Cloud, France Correspondence to: Celine Callens, email: celine.callens@curie.fr Keywords: breast cancer, PIK3CA, celecoxib, prognosis, predictive biomarker Received: April 29, 2016 Accepted: October 26, 2016 Published: November 08, 2016 ABSTRACT COX-2 expression level and prognostic value are still a matter of debate in breast cancer (BC). We addressed these points in the context of PIK3CA mutational status. Based on an interesting study of aspirin efficacy in colorectal cancer, we hypothesized that celecoxib antitumoral activity may be restricted to PIK3CA mutated BC. COX-2 mRNA expression was analyzed in 446 BC samples and in 61 BC patient-derived xenografts (PDX) using quantitative RT-PCR. The prognostic impact of COX-2 expression level was assessed independently and according to PIK3CA mutational status in our cohort and in a validation set of 817 BC. The antitumoral activity of celecoxib was tested in two triple-negative (TN) PDX with a PIK3CA wild-type (wt) or mutated genotype. COX-2 mRNA was overexpressed in 2% of BC and significantly associated with TN subtype. Metastasis-free survival (MFS) was significantly better in patients with high COX-2 expression level, the prognosis of whom was similar to patients with PIK3CA mutations. TCGA validation cohort confirmed that patients with low COX-2 expression PIK3CA wt tumors had the worse disease-free survival (DFS) compared to all other subgroups. Celecoxib had a significant antitumoral effect in PIK3CA mutated PDX only. Celecoxib antitumoral activity involved S6 ribosomal protein and AKT phosphorylation. Low expression of COX-2 has a significant negative impact on the MFS/DFS of BC patients. Antitumoral effect of celecoxib is restricted to PIK3CA mutated PDX. These results suggest that PIK3CA mutation may be a new predictive biomarker for celecoxib efficacy.