Search

Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) are two cancer-derived blood biomarkers that inform on patient prognosis and treatment efficacy in breast cancer. We prospectively evaluated the clinical validity of quantifying both CTCs (CellSearch) and ctDNA (targeted next-generation sequencing). Their combined value as prognostic and early monitoring markers was assessed in 198 HER2-negative metastatic breast cancer patients. All patients were included in the prospective multicenter UCBG study COMET (NCT01745757) and treated by first-line chemotherapy with weekly paclitaxel and bevacizumab. Blood samples were obtained at baseline and before the second cycle of chemotherapy. At baseline, CTCs and ctDNA were respectively detected in 72 and 74% of patients and were moderately correlated (Kendall’s τ = 0.3). Only 26 (13%) patients had neither detectable ctDNA nor CTCs. Variants were most frequently observed in TP53 and PIK3CA genes. KMT2C/MLL3 variants detected in ctDNA were significantly associated with a lower CTC count, while the opposite trend was seen with GATA3 alterations. Both CTC and ctDNA levels at baseline and after four weeks of treatment were correlated with survival. For progression-free and overall survival, the best multivariate prognostic model included tumor subtype (triple negative vs other), grade (grade 3 vs other), ctDNA variant allele frequency (VAF) at baseline (per 10% increase), and CTC count at four weeks (≥5CTC/7.5 mL). Overall, this study demonstrates that CTCs and ctDNA have nonoverlapping detection profiles and complementary prognostic values in metastatic breast cancer patients. A comprehensive liquid-biopsy approach may involve simultaneous detection of ctDNA and CTCs.

Background In the phase III OlympiAD trial, olaparib significantly increased progression-free survival (PFS) compared with chemotherapy of physician's choice in patients with germline BRCA-mutated (gBRCAm), human epidermal growth factor 2 (HER2)-negative metastatic breast cancer (mBC). The phase IIIb LUCY trial assessed the clinical effectiveness of olaparib in similar patients, in a setting reflecting clinical practice. Methods This open-label, single-arm trial of olaparib (300 mg, twice daily) enrolled patients with BRCAm, HER2-negative mBC who had received taxane and/or anthracycline in the (neo)adjuvant/metastatic setting and not more than two lines of prior chemotherapy for mBC. Patients with hormone receptor–positive mBC had progressed on at least one line of endocrine therapy in an adjuvant/metastatic setting and were unsuitable for further endocrine treatment. This interim analysis was planned after 160 PFS events. Results Of 563 patients screened, 252 patients with gBRCAm were enrolled and received at least one dose of olaparib. The median investigator-assessed PFS was 8.11 months (95% confidence interval [CI], 6.93–8.67; 166/252 events [65.9% maturity]). The investigator-assessed clinical response rate was 48.6%, and median time to first subsequent treatment or death was 9.66 months (95% CI, 8.67–11.14). The most common treatment-emergent adverse events (TEAEs; >20% patients) were nausea, anaemia, asthenia, vomiting and fatigue. Eleven patients (4.4%) discontinued treatment because of a TEAE. Grade 3 or higher TEAEs occurred in 64 patients (25.4%), including anaemia (33 patients; 13.1%). Conclusion Olaparib was clinically effective in patients with gBRCAm, HER2-negative mBC with safety outcomes consistent with previous findings. ClinicalTrials.gov identifier: NCT03286842 .

Background: The HER2-targeted antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) demonstrated efficacy in heavily pretreated HER2-over- and HER2-low expressing ABC (1, 2). We aimed to assess the activity of T-DXd in HER2-over-, HER2-low and HER2-nul expressing ABC, to describe the drug mechanisms of action in the 3 cohorts and to identify biomarkers associated to drug response or resistance. Study Description: DAISY is a multicenter, open-label phase II trial designed to assess the efficacy of single agent T-DXd at 5.4 mg/kg dose in ABC with extensive biomarkers analysis. Three cohorts of patients were included: Cohort 1 (HER2 over-expressing: HER2 3+ on immunohistochemistry (IHC) or HER2 IHC2+/in situ hybridization [ISH]+), Cohort 2 (HER2 low-expressing: IHC1+ or IHC2+/ISH-) and cohort 3 (HER2-nul: IHC0+). Biopsy of metastatic sites was performed: at baseline, on treatment (mandatory for cohort 1, optional for cohort 2/3) and at tumor progression; blood samples for ctDNA were collected at baseline. The primary endpoint was the Best Overall Response (BOR) in each cohort, according to the investigator assessment. Secondary endpoints were BOR by central assessment, clinical benefit rate, duration of response (DOR), progression-free (PFS), overall survival (OS) and safety. Results:185 women and 1 man were enrolled between November 2019 and March 2021. Among the patients enrolled in the safety population (see Table 1), median (range) age was 55 (24-82) years, all received at least one prior line of therapy and 12 patients were TN. Table 2 shows investigator-reported T-Dxd activity in the 3 cohorts at a median follow-up of 10.1 months [95%CI: 9.2-11.1]. A total of 170 patients (95%) had at least one treatment-related toxicity. Key grade ≥3 treatment-related toxicities included neutropenia (10.6% of patients), fatigue (5.6%), leucopenia (4.5%), vomiting (4.5%) and anemia (3.4%). A total of 4 patients had drug-related interstitial lung disease or pneumonitis (grade 1 in 3 patients and grade 2 in 1 patient), 11 patients discontinued treatment due to treatment-related adverse events. No drug-related deaths occurred. Conclusions: T-DXd showed clinically meaningful activity in patients with HER2-overexpressing ABC and interestingly also in those with HER2low and HER2-nul ABC. Safety profile was consistent with previous reports. 1.Modi S et al N Engl J Med 2020 2.Mosi S et al J Clin Oncol 2020 Table 1.Analysis populationsTotalCohort 1 (HER2 over-expressing)Cohort 2 (HER2 low-expressing)Cohort 3 (HER2 non-detected)Enrolled population186727440Safety population*179687338 (including 12 TN)Full analysis Set**176687236TN: Triple Negative. *: safety population = enrolled population except 7 patients who did not receive at least one dose of study drug. **: Full Analysis Set = safety population except 3 patients (2 who did not have a valid first post-baseline assessment of disease status or who did not have progressive disease and 1 who did not have at least one radiologically measurable lesion according to RECIST v1.1) Table 2.T-DXd activity in the three cohorts according to investigator assessmentTotalCohort 1Cohort 2Cohort 3BOR confirmedn/N82/176 (46.6%)47/68 (69.1%)24/72 (33.3%)11/36 (30.6%)[95%CI][39.1; 54.2][56.7; 79.8][22.7; 45.4]16.3; 48.1]Median DORmonths7.69.97.66.8[95%CI][6.2; 9.7][5.4; NR][4.4; 8.7][2.8; 8.3]Median PFSmonths6.911.16.74.2[95%CI][6.7; 8.7][8.4; NR][4.6; 8.5][2.1; 6.9]NR: Not Reached Citation Format: Véronique Diéras, Elise Deluche, Amélie Lusque, Barbara Pistilli, Thomas Bachelot, Jean-Yves Pierga, Frédéric Viret, Christelle Levy, Laura Salabert, Fanny Le Du, Florence Dalenc, Christelle Jouannaud, Laurence Venat-Bouvet, Jean-Philippe Jacquin, Xavier Durando, Thierry Petit, Céline Mahier - Aït Oukhatar, Thomas Filleron, Maria Fernanda Mosele, Magali Lacroix-Triki, Agnès Ducoulombier, Fabrice André. Trastuzumab deruxtecan (T-DXd) for advanced breast cancer patients (ABC), regardless HER2 status: A phase II study with biomarkers analysis (DAISY) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD8-02.

Background: CTX + dual HER2-targeting monoclonal antibodies (mAb) remains a standard of care for treatment (Tx) of both HER2+ early-stage and MBC. However, when the SOPHIA trial was launched, limited Tx options existed after progression on T, pertuzumab (P), and ado-trastuzumab emtansine. M, an Fc-engineered anti-HER2 mAb, targets the same epitope as T and exerts similar antiproliferative effects. M enhances CD16A-mediated ADCC compared to T. Furthermore, M treatment is associated with increased HER2-specific T- and B-cell responses and increased T-cell clonality compared to baseline. The phase 3 SOPHIA (NCT02492711) study demonstrated PFS benefit of M vs T, both + CTX, in HER2+ MBC pts. M improved PFS over T, with a 24% relative risk reduction (HR .76; 95% CI .59-.98; P=.033; median, 5.8 [95% CI 5.5-7.0] months (mo) vs 4.9 [95% CI 4.2-5.6] mo (Rugo HS, et al. JAMA Oncol 2021), resulting in FDA approval. Median OS after 270 mortality events (2nd interim analysis) was 21.6 mo with M vs 19.8 mo with T (HR .89; 95% CI .69-1.13; P=.33). Here we report final OS after 385 events, as well as updated safety.Methods: Pts with disease progression after ≥2 lines of anti-HER2 Tx, including P, and 1-3 lines of Tx for HER2+ MBC were randomized 1:1 to CTX + either M (15 mg/kg) or T (8 mg/kg loading dose, then 6 mg/kg), both given IV every 3 weeks. Randomization was stratified by number of metastatic sites (≤2, >2), lines of Tx for MBC (≤2, >2), and CTX choice (capecitabine, eribulin, gemcitabine, or vinorelbine). Sequential primary end points were central-blinded review of PFS and OS.Results: The intent-to-treat (ITT) population comprised 536 pts (M, 266; T, 270). At the median follow-up of 20.2 mo among all ITT pts, pts received a median of 7 cycles of M + CTX vs 6 cycles of T + CTX. Median OS after 385 events in the ITT population was 21.6 mo with M vs 21.9 mo with T (HR .95; 95% CI .77-1.17; P=.62; Table). Based on a prespecified, non-α-allocated exploratory analysis, a numerical OS advantage in favor of the M arm was observed in the subgroup of pts homozygous for the CD16A-158F low-affinity allele (median OS, 23.6 vs 19.2 mo; HR .72; 95% CI .52-1.00; nominal P=.05). In contrast, in the small subgroup of CD16A-158V homozygotes, median OS was longer for T vs M (31.1 mo vs 22.0 mo; HR 1.77; 95% CI 1.01-3.12; nominal P=.04). Grade ≥3 adverse events (AE) occurred in 146 pts (55.3%) receiving M vs 141 pts (53.0%) receiving T. Serious AEs were seen in 47 pts (17.8%) receiving M vs 51 pts (19.2%) receiving T. Incidence of infusion-related reactions was higher with M (36 [13.6%]) vs T (9 [3.4%]). Left ventricular dysfunction requiring delay or cessation of M/T administration occurred in 4 pts (1.5%) receiving M and in 7 pts (2.6%) receiving T. Conclusions: The median OS in the ITT population was not statistically different between the 2 arms. An exploratory analysis of CD16A genotyping indicates a numerical OS advantage in favor of M in F homozygous pts, along with a numerical OS advantage in favor of T in V homozygous pts. Safety of M + CTX was similar to previous reports and consistent with M FDA-approved label. Studies of M in HER2+ breast cancer pts with different CD16A allelic variants are warranted, including MARGOT, the neoadjuvant investigator-initiated study on the efficacy of M vs T in pts carrying F-allelic variants of CD16A. Median OSITT analysisPrespecified, non-α-allocated exploratory analysis (n=506)N=536CD16A-158F carriers (F/F and F/V)(n=437)CD16A-158F homozygotes (F/F)(n=192)CD16A-158F/V heterozygotes(n=245)CD16A-158V homozygotes (V/V)(n=69)aM + CTX, mo21.6 (n=266)23.3 (n=221)23.6 (n=102)21.3 (n=119)22.0 (n=37)T + CTX, mo21.9 (n=270)20.8 (n=216)19.2 (n=90)22.0 (n=126)31.1 (n=32)HR (95% CI)0.95 (0.77-1.17)0.86 (0.69-1.08)0.72 (0.52-1.00)0.96 (0.71-1.30)1.77 (1.01-3.12)P value0.620.19b0.05b0.78b0.04bAbbreviations: CTX, chemotherapy; HR, hazard ratio; ITT, intent to treat; M, margetuximab; mo, months; OS, overall survival; T, trastuzumab. Cutoff date: June 14, 2021. aThis subgroup was characterized by an imbalance in poor prognostic features. bNominal P value. Citation Format: Hope Rugo, Seock-Ah Im, Fatima Cardoso, Javier Cortes, Giuseppe Curigliano, Antonino Musolino, Mark D. Pegram, Thomas Bachelot, Gail S. Wright, Cristina Saura, Santiago Escrivá-de-Romaní, Michelino De Laurentiis, Gary N. Schwartz, Timothy Pluard, Francesco Ricci, William Gwin, III, Christelle Levy, Ursa Brown-Glaberman, Jean-Marc Ferrero, Maaike de Boer, Sung-Bae Kim, Katarína Petráková, Denise A. Yardley, Orit Freedman, Erik H. Jakobsen, Einav Nili Gal-Yam, Rinat Yerushalmi, Peter A. Fasching, Emily Ashley, Shengyan Hong, Minori Rosales, William J. Gradishar. Phase 3 SOPHIA study of margetuximab (M) + chemotherapy (CTX) vs trastuzumab (T) + CTX in patients (pts) with HER2+ metastatic breast cancer (MBC) after prior anti-HER2 therapies: Final overall survival (OS) analysis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD8-01.

Patients with metastatic breast cancer (MBC) often require inpatient palliative care (IPC). However, mounting evidence suggests age-related disparities in palliative care delivery. This study aimed to assess the cumulative incidence function (CIF) of IPC delivery, as well as the influence of age.The national ESME (Epidemio-Strategy-Medical-Economical)-MBC cohort includes consecutive MBC patients treated in 18 French Comprehensive Cancer Centres. ICD-10 palliative care coding was used for IPC identification.Our analysis included 12,375 patients, 5093 (41.2%) of whom were aged 65 or over. The median follow-up was 41.5 months (95% confidence interval [CI], 40.5-42.5). The CIF of IPC was 10.3% (95% CI, 10.2-10.4) and 24.8% (95% CI, 24.7-24.8) at 2 and 8 years, respectively. At 2 years, among triple-negative patients, young patients (65 yo) had a higher CIF of IPC than older patients after adjusting for cancer characteristics, centre and period (65+/65: β = -0.05; 95% CI, -0.08 to -0.01). Among other tumour sub-types, older patients received short-term IPC more frequently than young patients (65+/65: β = 0.02; 95% CI, 0.01 to 0.03). At 8 years, outside large centres, IPC was delivered less frequently to older patients adjusted to cancer characteristics and period (65+/65: β = -0.03; 95% CI, -0.06 to -0.01).We found a relatively low CIF of IPC and that age influenced IPC delivery. Young triple-negative and older non-triple-negative patients needed more short-term IPCs. Older patients diagnosed outside large centres received less long-term IPC. These findings highlight the need for a wider implementation of IPC facilities and for more age-specific interventions.

Background Metastatic breast cancer (MBC) may require inpatient palliative care (IPC) but literature suggests age-related disparities in palliative care delivery. This study, based on real-world data, aimed to assess the cumulative incidence function (CIF) of IPC delivery and if age is an independent factor, taking into account the competing risk of death. Methods The national multicenter ESME (Epidemio-Strategy-Medical-Economical)-MBC cohort includes consecutive MBC patients treated in the 18 French Comprehensive Cancer Centers. IPC identification used ICD-10 palliative care coding. Main analysis first estimated pseudo values of 2-year and 8-year CIF of IPC. Linear regression models estimated the mean changes of pseudo-values (2 models: 2-year and 8-year CIF of IPC). Results Our analysis included 12375 patients, 5093 (41.2%) of whom were aged 65 or over. The median follow-up was 41.5 months (95% CI, 40.5-42.5). The CIF of IPC was 10.3% (95% CI, 10.2-10.4) and 24.8% (95% CI, 24.7-24.8) at two and eight years, respectively. At two years, among triple-negative patients, young patients ( Conclusions We found a relatively low CIF of IPC and that age influenced IPC delivery. Young triple negative and older non-triple negative patients needed more short-term IPC. Older patients diagnosed outside large centres received less long-term IPC. These findings highlight the need for a wider implementation of IPC facilities and for more age-specific interventions. Key messages Our study highlighted particular challenge for older MBC patients diagnosed outside large French Comprehensive Cancer Centers. By identifying age at MBC diagnosis as a factor of IPC delivery, this report supports a wider implementation of IPC facilities and more age-specific interventions.

Introduction We aimed to investigate whether 18F-FDG PET metabolic heterogeneity reflects the heterogeneity of estrogen receptor (ER) and progesterone receptor (PR) expressions within luminal non-metastatic breast tumors and if it could help in identifying patients with worst event-free survival (EFS). Materials and methods On 38 PET high-resolution breast bed positions, a single physician drew volumes of interest encompassing the breast tumors to extract SUVmax, histogram parameters and textural features. High-resolution immunochemistry (IHC) scans were analyzed to extract Haralick parameters and descriptors of the distribution shape. Correlation between IHC and PET parameters were explored using Spearman tests. Variables of interest to predict the EFS status at 8 years (EFS-8y) were sought by means of a random forest classification. EFS-8y analyses were then performed using univariable Kaplan-Meier analyses and Cox regression analysis. When appropriate, Mann-Whitney tests and Spearman correlations were used to explore the relationship between clinical data and tumoral PET heterogeneity variables. Results For ER expression, correlations were mainly observed with 18F-FDG histogram parameters, whereas for PR expression correlations were mainly observed with gray-level co-occurrence matrix (GLCM) parameters. The strongest correlations were observed between skewness_ER and uniformity_HISTO (ρ = −0.386, p = 0.017) and correlation_PR and entropy_GLCM (ρ = 0.540, p = 0.001), respectively. The median follow-up was 6.5 years and the 8y-EFS was 71.0%. Random forest classification found age, clinical stage, SUVmax, skewness_ER, kurtosis_ER, entropy_HISTO, and uniformity_HISTO to be variables of importance to predict the 8y-EFS. Univariable Kaplan-Meier survival analyses showed that skewness_ER was a predictor of 8y-EFS (66.7 ± 27.2 versus 19.1 ± 15.2, p = 0.018 with a cut-off value set to 0.163) whereas other IHC and PET parameters were not. On multivariable analysis including age, clinical stage and skewness_ER, none of the parameters were independent predictors. Indeed, skewness_ER was significantly higher in youngest patients (ρ = −0.351, p = 0.031) and in clinical stage III tumors (p = 0.023). Conclusion A heterogeneous distribution of ER within the tumor in IHC appeared as an EFS-8y prognosticator in luminal non-metastatic breast cancers. Interestingly, it appeared to be correlated with PET histogram parameters which could therefore become potential non-invasive prognosticator tools, provided these results are confirmed by further larger and prospective studies.

Background Cancer-related microangiopathic haemolytic anaemia (MAHA) is a rare but life-threatening paraneoplastic syndrome. Only single cases or small series have been reported to date. We set up a retrospective multicentre study focusing on breast cancer-related MAHA. Methods Main inclusion criteria were known diagnosis of breast cancer, presence of schistocytes and either low haptoglobin or cytopenia and absence of any causes of MAHA other than breast cancer, including gemcitabine- or bevacizumab-based treatment. Patient characteristics, treatments and outcome were retrieved from digital medical records. Results Individual data from 54 patients with breast cancer-related MAHA were obtained from 7 centres. Twenty-three (44%) patients had a breast tumour with lobular features, and most primary tumours were low grade (grade I/II, N = 39, 75%). ER+/HER2−, HER2+ and triple-negative phenotypes accounted for N = 33 (69%), N = 7 (15%) and N = 8 (17%) cases, respectively. All patients had stage IV cancer at the time of MAHA diagnosis. Median overall survival (OS) was 28 days (range 0–1035; Q1:10, Q3:186). Independent prognostic factors for early death (≤ 28 days) were PS > 2 (OR = 7.0 [1.6; 31.8]), elevated bilirubin (OR = 6.9 [1.1; 42.6]), haemoglobin Conclusions Breast cancer-related MAHA appears to be a new feature of invasive lobular breast carcinoma. Prognostic factors and scores may guide clinical decision-making in this serious but not always fatal condition.

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.

Background/aim Vinorelbine is indicated for use in the treatment of MBC as a single agent or in combination but there is little real world data on this molecule and even less on its oral form. We exploited the Unicancer Epidemiology Strategy Medical-Economics (ESME) metastatic breast cancer (MBC) database to investigate current patterns of use of oral vinorelbine (OV), as well as outcomes of patients receiving this drug. Patients and methods Data were collected retrospectively from women and men treated for MBC between 2008 and 2014 at one of 18 French Comprehensive Cancer Centres. The efficacy of OV was evaluated in terms of progression-free (PFS) and overall survival (OS) and treatment duration. The population and patterns of OV usage were also described. Results A total of 1806 patients (11% of the ESME MBC database) were included in this analysis. OV was prescribed as monotherapy (46%) or in combination (29%), especially with capecitabine. mainly in later treatment lines. Median PFS was 3.3 months: 2.9 months for single agent, 3.6 months for combination therapy. Median OS was 40.9 months. Conclusion Real-world data offer complementary results to the data from traditional clinical trials, but they concern a much larger population. In this ESME MBC cohort, OV was only prescribed to a small subset of MBC patients. OV was mainly given as single agent to patients with heavily pre-treated MBC; less commonly, it was co-administered with capecitabine or anti-HER2, in earlier lines of therapy. PFS was modest but in line with previous reports.

The impact of single-agent antibodies against programmed death-ligand 1 (PD-L1) as maintenance therapy is unknown in patients with metastatic breast cancer. The SAFIR02-BREAST IMMUNO substudy included patients with human epidermal growth factor receptor type 2 (Her2)-negative metastatic breast cancer whose disease did not progress after six to eight cycles of chemotherapy. Patients (n = 199) were randomized to either durvalumab (10 mg kg

Aim Real-world data inform the outcome comparisons and help the development of new therapeutic strategies. To this end, we aimed to describe the full characteristics and outcomes in the Epidemiological Strategy and Medical Economics (ESME) cohort, a large national contemporary observational database of patients with metastatic breast cancer (MBC). Methods Women aged ≥18 years with newly diagnosed MBC and who initiated MBC treatment between January 2008 and December 2016 in one of the 18 French Comprehensive Cancer Centers (N = 22,109) were included. We assessed the full patients’ characteristics, first-line treatments, overall survival (OS) and first-line progression-free survival, as well as updated prognostic factors in the whole cohort and among the 3 major subtypes: hormone receptor positive and HER2-negative (HR+/HER2−, n = 13,656), HER2-positive (HER2+, n = 4017) and triple-negative (n = 2963) tumours. Results The median OS of the whole cohort was 39.5 months (95% confidence interval [CI], 38.7–40.3). Five-year OS was 33.8%. OS differed significantly between the 3 subtypes (p Conclusions The ESME program represents a unique large-scale real-life cohort on MBC. This study highlights important situations of high medical need within MBC patients. Database registration clinicaltrials.gov Identifier NCT032753.

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.

Early-onset of breast cancer (under the age of 40) represents only 7% of all breast cancers, but is the most common cancer in this age group in women. It is also known to be of worse prognosis, with a more aggressive tumoral behavior. The interaction of different prognostic factors contributes to the complexity of this population: tumor burden and biological features (using classical histopronostic features and genomic data) show differences from older women. Nevertheless, the prognostic impact of age varies according to the histological subtypes and seems pejorative mainly for the luminal subtype, probably with a crucial role of the hormonal environment and the treatments targeting the endocrine sensitivity of these tumors. In other subtypes, the influence of young age appears to be less significant, especially in HER2+ breast cancers.

Purpose Genomic tests can identify ER-positive HER2-negative localized breast cancer patients who may not benefit from adjuvant chemotherapy. Such tests seem especially interesting in “intermediate” clinico-pathological risk categories. The psychological impact of the decision uncertainty in these women remains largely unexplored. We assessed the clinical and psychological impact of EndoPredict® (EpClin), a clinico-genomic test, in these patients. Methods This multicenter, single arm prospective study (NCT02773004) enrolled patients for which adjuvant chemotherapy was uncertain, based on predefined criteria. The primary endpoint was the proportion of change between initial adjuvant decision and final administration of chemotherapy. Secondary endpoints included post-test (Day 17) and 1-year patient reported outcomes. Results One third of 200 evaluable patients had a high EpClin score (≥3.32867; 10 years cumulative risk of distance failure ≥10%). The overall change rate of chemotherapy decision was 72/200 (35.8%, 95% CI 29.2–42.4). Chemotherapy was withdrawn in 57 cases (28.4% [22.2–34.8]) and added in 15 (7.5% [3.8–11.2]. 6 changes (8%) were based on patients’ decisions. Anxiety and distress levels increased at Day 17 when adding chemotherapy after the test result (p, Highlights • EndoPredict ® (EpClin) allowed a chemotherapy decision modification in 35% of the patients included in the Adendom trial. • Patient-physician concertation is important: 8% of treatment changes are based on patients’ will. • A single-step decision including the test appears preferable to limit anxiety and distress.

Background Endocrine therapy is recommended as a first-line treatment for hormone receptor-positive metastatic breast cancer (HR+MBC) patients. No biomarker has been validated to predict tumor progression in that setting. We aimed to prospectively compare the risk of early progression according to circulating ESR1 mutations, CA-15.3, and circulating cell-free DNA in MBC patients treated with a first-line aromatase inhibitor (AI). Methods Patients with MBC treated with a first-line AI were prospectively included. Circulating biomarker assessment was performed every 3 months. The primary objective was to determine the risk of progression or death at the next follow-up visit (after 3 months) in case of circulating ESR1 mutation detection among patients treated with a first-line AI for HR+MBC. Results Overall, 103 patients were included, and 70 (68%) had progressive disease (PD). Circulating ESR1 mutations were detected in 22/70 patients with PD and in 0/33 patients without progression (p ESR1-mutated patients, 18/22 had a detectable mutation prior to progression, with a median delay of 110 days from first detection to PD. The detection of circulating ESR1 mutations was associated with a 4.9-fold (95% CI 3.0–8.0) increase in the risk of PD at 3 months. Using a threshold value of 25% or 100%, a CA-15.3 increase was also correlated with progression (p p = 0.003, respectively). In contrast to ESR1, the CA-15.3 increase occurred concomitantly with PD in most cases, in 27/47 (57%) with a 25% threshold and in 21/25 (84%) with a 100% threshold. Using a threshold value of either 25% or 100%, cfDNA increase was not correlated with progression. Conclusion The emergence of circulating ESR1 mutations is associated with a 4.9-fold increase in the risk of early PD during AI treatment in HR+MBC. Our results also highlighted that tracking circulating ESR1 mutations is more relevant than tracking CA-15.3 or cfDNA increase to predict progression in this setting. Trial registration ClinicalTrials.gov, NCT02473120. Registered 16 June 2015—retrospectively registered after one inclusion (first inclusion 1 June 2015)

Background We aimed at predicting fatigue after breast cancer treatment using machine learning on clinical covariates and germline genome-wide data. Methods We accessed germline genome-wide data of 2799 early-stage breast cancer patients from the Cancer Toxicity study (NCT01993498). The primary endpoint was defined as scoring zero at diagnosis and higher than quartile 3 at 1 year after primary treatment completion on European Organization for Research and Treatment of Cancer quality-of-life questionnaires for Overall Fatigue and on the multidimensional questionnaire for Physical, Emotional, and Cognitive fatigue. First, we tested univariate associations of each endpoint with clinical variables and genome-wide variants. Then, using preselected clinical (false discovery rate < 0.05) and genomic (P Results Statistically significant clinical associations were found only with Emotional and Cognitive Fatigue, including receipt of chemotherapy, anxiety, and pain. Some single nucleotide polymorphisms had some degree of association (P Conclusions Genomic analyses in this large cohort of breast cancer survivors suggest a possible genetic role for severe Cognitive Fatigue that warrants further exploration.

Background Despite improved prognosis of HER2+ eBC since the introduction of trastuzumab in the adjuvant setting in 2006, disease recurrences still occur in some patients after a few years. We aimed to describe in real life the long-term follow-up to assess disease-free and metastasis-free survival of patients with HER2+ eBC treated with adjuvant trastuzumab. Methods This was a multicenter, retrospective, cohort study assessing HER2+ eBC patients diagnosed between 2009 and 2010 and treated with adjuvant trastuzumab. Data were collected from patient’s medical charts. Disease-free survival (DFS), and metastatic-free survival (MFS) were evaluated in the overall population and within subgroups according to hormonal and nodal status. Results In the overall population (n=2,311) at 7 years, the DFS rate was 76.3% [95%CI 74.5%-78.2%], and the MFS rate was 84.2% [82.6%-85.8%]. According to hormonal status, the 7-year DFS rate was significantly higher in hormone-receptor positive (HR+) than hormone-negative (HR-) patients [80.5% vs . 69.2%; p

Background: Platinum-based chemotherapy regimens (PtCT) have been shown to increase treatment efficacy when combined to neoadjuvant standard of care treatment of triple negative breast cancers (TNBC). In the metastatic breast cancer (MBC) setting, preclinical and clinical data suggest that PtCT could be more efficient than non-platinum based ones (non-PtCT) among patients (pts) with germline BRCA1/2 mutations (gBRCAm). However, published data remain controversial on this topic, particularly for MBC. We evaluated the progression-free (PFS) and overall survival (OS) under first-line PtCT and non-PtCT among gBRCAm carriers in ESME, a nationwide real-life MBC database. Methods: ESME MBC database (NCT03275311), is a unique national cohort of all consecutive pts who initiated a first-line treatment for MBC between 2008 and 2016 in one of the 18 French Comprehensive Cancer Centers. Women with HER2- MBC and known hormone receptors (HR) and gBRCA1/2 (before or in the 6 first months of metastatic disease, gBRCAm / wild type / not tested) status, who received a first-line MBC CT were selected. Patients with other germinal mutations were considered as wild type. Primary objectives were OS and PFS under first-line CT (PtCT vs. non-PtCT) in the TNBC gBRCA1/2m population.Secondary objectives were OS and PFS during first-line CT (PtCT vs. non-PtCT) in the TNBC wild-type and “not tested” population, as well as among the HR+/HER2- pts.To avoid guarantee time bias related to oncogenetic testing, analyses were performed at baseline (CT initiation) and different landmark time points (3-month or 6-month after CT initiation). Thus, BRCA status was defined according to oncogenetic testings performed before the landmark time, and patients who progressed or censored before the landmark time were excluded. Results: 10,164 pts (2,794 TNBC; 7,370 HR+/HER2-) were included in this analysis. Pts who received PtCT were significantly younger, affected by a gBRCA1/2m, had a high histological grade and/or TNBC tumor, with more frequent visceral and central nervous system spreading than non PtCT ones. Median follow-up was 51.1 months [95%CI 49.6; 52.6]. All reported results were based on the gBRCA status defined at CT initiation and on multivariable analysis adjusted on age at MBC diagnosis, de novo MBC status, type and number of metastases. In the gBRCA1/2m TNBC population (N=132), PtCT was independently associated with a better PFS compared to non-PtCT (HR=0.56, 95%CI 0.38-0.84, p=0.005), without significant difference in OS (HR=0.79, 95%CI 0.51-1.23, p=0.29).No difference was seen in wild-type BRCA1/2 TNBC pts (N=269) according to the CT regimen, while, in the larger population of untested TNBC (N=2,393), PtCT was associated with worse OS (HR=1.18, 95%CI 1.03-1.34, p=0.016) compared to non-PtCT regimens, without significant difference in PFS (HR=1.07, 95%CI 0.95-1.22, p=0.26). No significant difference was seen regarding PFS nor OS in gBRCA1/2m HR+/HER2- pts (N=124) and in the wild-type BRCA1/2 HR+/HER2- population.However, in the larger population of untested HR+/HER2- pts (N=6,836), PtCT was independently associated with worse OS (HR=2.15, 95%CI 1.79-2.59, p Citation Format: William Jacot, Amélie Lusque, Audrey Mailliez, Thibault De la Motte Rouge, Luc Cabel, Christelle Levy, Anne Patsouris, Isabelle Desmoulins, Lionel Uwer, Marianne Leheurteur, Mathieu Robain, Olivier Caron, Thomas Bachelot, Thomas Filleron, Jean-Sébastien Frenel, Suzette Delaloge. Efficacy of Platinum-based first-line chemotherapy among metastatic breast cancer (MBC) patients according to the germline BRCA1/2 mutational status: An analysis of the French ESME MBC database [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 PD10-11.

12022 Background: CRF is among the most common and troublesome symptoms experienced by BCS. While preventing severe post-tx CRF is a major survivorship need, limited tools exist to predict this risk. We aimed to describe the long-term prevalence rates and to identify BCS that are more likely to develop severe CRF. Methods: CANTO is a multicenter, prospective clinical study of stage I-III BCS (NCT01993498). Longitudinal data were collected at diagnosis (dx), 0.5 (T1), 1 (T2) and 3 (T3) years post-tx. The primary outcome of interest was severe post-tx global CRF (score ≥ 40/100, EORTC QLQ-C30). Secondary outcomes were physical, emotional and cognitive dimensions of CRF (QLQ-FA12). Multivariable logistic regression models retained associations with severe CRF by bootstrapped Augmented Backwards Elimination, validated using 10-fold internal cross-validation and overoptimism-corrected AUC. Results: Among 6619 BCS, mean age at dx was 56.5 years (SD 11.5), mean BMI was 25.9 Kg/m2 (SD 5.4), 53.3% and 80.8% received chemotherapy (CT) and hormonotherapy (HT), respectively. Prevalence rates of severe global CRF were 25.0% (dx), 35.6% (T1), 34.0% (T2) and 31.6% (T3). Severe post-tx global CRF was consistently associated with higher BMI, worse insomnia and pain, and severe pre-tx CRF. Receipt of CT increased odds of severe CRF at T1, whereas associations of HT with CRF emerged at T2 and T3 (Table). The estimated risk of severe CRF at T3 was 14% for a BCS with BMI 23.0 Kg/m2 and no concomitant symptoms at dx, whereas it was 82% for a BCS with BMI 32.0 Kg/m2, severe insomnia, pain and pre-tx CRF, receiving HT. Anxiety and depression at dx were consistently retained in models of severe post-tx emotional and cognitive CRF (all p

BACKGROUNDPertuzumab increases the rate of pathological complete response in the preoperative context and increases overall survival among patients with metastatic disease when it is added to trastuzumab and chemotherapy for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. In this trial, we investigated whether pertuzumab, when added to adjuvant trastuzumab and chemotherapy, improves outcomes among patients with HER2-positive early breast cancer.METHODSWe randomly assigned patients with node-positive or high-risk node-negative HER2-positive, operable breast cancer to receive either pertuzumab or placebo added to standard adjuvant chemotherapy plus 1 year of treatment with trastuzumab. We assumed a 3-year invasive-disease-free survival rate of 91.8% with pertuzumab and 89.2% with placebo.RESULTSIn the trial population, 63% of the patients who were randomly assigned to receive pertuzumab (2400 patients) or placebo (2405 patients) had node-positive disease and 36% had hormone-receptor-negative disease. Disease recurrence occurred in 171 patients (7.1%) in the pertuzumab group and 210 patients (8.7%) in the placebo group (hazard ratio, 0.81; 95% confidence interval [CI], 0.66 to 1.00; P = 0.045). The estimates of the 3-year rates of invasive-disease-free survival were 94.1% in the pertuzumab group and 93.2% in the placebo group. In the cohort of patients with node-positive disease, the 3-year rate of invasive-disease-free survival was 92.0% in the pertuzumab group, as compared with 90.2% in the placebo group (hazard ratio for an invasive-disease event, 0.77; 95% CI, 0.62 to 0.96; P = 0.02). In the cohort of patients with node-negative disease, the 3-year rate of invasive-disease-free survival was 97.5% in the pertuzumab group and 98.4% in the placebo group (hazard ratio for an invasive-disease event, 1.13; 95% CI, 0.68 to 1.86; P = 0.64). Heart failure, cardiac death, and cardiac dysfunction were infrequent in both treatment groups. Diarrhea of grade 3 or higher occurred almost exclusively during chemotherapy and was more frequent with pertuzumab than with placebo (9.8% vs. 3.7%).CONCLUSIONSPertuzumab significantly improved the rates of invasive-disease-free survival among patients with HER2-positive, operable breast cancer when it was added to trastuzumab and chemotherapy. Diarrhea was more common with pertuzumab than with placebo. (Funded by F. Hoffmann-La Roche/Genentech; APHINITY ClinicalTrials.gov number, NCT01358877.)

Purpose Optimal duration of adjuvant chemotherapy in the treatment of early-stage breast cancer remained to be investigated rigorously for the standard regimens in widespread use in North America (doxorubicin/cyclophosphamide, AC) and Europe (5-fluorouracil/epirubicin/cyclophosphamide, FEC). Whether six cycles of FEC 100 present an advantage, or not, compared with only four cycles was tested directly in a phase III prospective multicentre trial. Patients and methods Between 2002 and 2006, 1515 women between 18 and 65°years of age, with node negative N(−) high-risk early-stage breast cancer, were included in the study following breast surgery and axillary lymph node dissection or procedure by sentinel node technique. Inclusion in the study required tumour size T ≥ 1 cm and at least one of the high-risk factors: T > 2 cm, negative oestrogen receptor/progesterone receptor (ER– and PR–), Scarff-Bloom-Richardson (SBR) grade II or III and age ≤ 35°years. Patients were randomly assigned to either six FEC 100 (Arm A) or four FEC 100 (Arm B). The trial was powered to detect an absolute difference ≥6% in disease-free survival (DFS) at 5°years. Results At 6.1°years median follow-up, with 91 (12%) events recorded in Arm A versus 106 (14%) in Arm B, no statistically significant risk increase was associated with four versus six FEC 100: DFS (hazard ratio (HR) = 1.18; CI 95% [0.89–1.56], P = .24) and overall survival (OS) (HR = 1.39; CI 95% [0.91–2.13], P = .12). Conclusion Differences in chemotherapy duration did not induce notably different outcomes in our cohort of high-risk patients. Clinical trial registry number NCT00055679 , Agence National de Securite du Medicament (ANSM) – France.

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 Despite improved prognosis of HER2+ eBC since the introduction of trastuzumab in the adjuvant setting in 2006, disease recurrences still occur in some patients after a few years. We aimed to describe in real life the long-term follow-up to assess disease-free and metastasis-free survival of patients with HER2+ eBC treated with adjuvant trastuzumab. Methods This was a multicenter, retrospective, cohort study assessing HER2+ eBC patients diagnosed between 2009 and 2010 and treated with adjuvant trastuzumab. Data were collected from patient’s medical charts. Disease-free survival (DFS), and metastatic-free survival (MFS) were evaluated in the overall population and within subgroups according to hormonal and nodal status. Results In the overall population (n=2,513) at 7 years, the DFS rate was 75.8% [95%CI 74.0%-77.6%], and the MFS rate was 84.1% [82.5%-85.6%]. According to hormonal status, the 7-year DFS rate was significantly higher for HR+ than for HR- patients [80.0% vs . 68.6%; p

Background and purposeFew data are available concerning the safety of bevacizumab (B) in combination with locoregional radiation therapy (RT). The objective of this study was to evaluate the 5-year late toxicity of concurrent B and RT in non-metastatic breast cancer.Materials and methodsThis multicentre prospective study included non-metastatic breast cancer patients enrolled in phase 3 clinical trials evaluating B with concurrent RT versus RT alone. All patients received neoadjuvant or adjuvant chemotherapy and normofractionated breast or chest wall RT, with or without regional lymph node RT. B was administered at an equivalent dose of 5 mg/kg once a week for 1 year. The safety profile was evaluated 1, 3 and 5 years after completion of radiotherapy.ResultsA total of 64 patients were included between November 2007 and April 2010. Median follow-up was 60 months (12-73) and 5-year late toxicity data were available for 46 patients. The majority of tumours were triple-negative (68.8%), tumour size ConclusionConcurrent B and locoregional RT are associated with acceptable 5-year toxicity in patients with non-metastatic breast cancer. No grade ≥3 toxicity was observed.

Purpose We conducted a double-randomised phase III trial to evaluate a concomitant taxane-anthracycline regimen in node-positive breast cancer and the efficacy of trastuzumab in the human epidermal growth factor receptor 2 (HER2)–positive subpopulation. Methods A total of 3010 patients with node-positive breast cancer were randomly assigned to receive 6 cycles of 500 mg/m2 of fluorouracil, 100 mg/m2 of epirubicin and 500 mg/m2 of cyclophosphamide (FEC) or 75 mg/m2 of epirubicin and 75 mg/m2 of docetaxel (ED). Patients with HER2-positive tumours were secondary randomly assigned to either trastuzumab or observation. The primary end-point was disease-free survival (DFS) in the two chemotherapy arms. Results After a 115-month median follow-up, DFS was not significantly better in the ED arm (DFS: 70%, 95% confidence interval [CI]: 67–72) than in the FEC arm (DFS: 68%, 95% CI: 65–70; hazard ratio [HR] = 0.88, 95% CI: 0.77–1.01; p = 0.064). The OS was not different between FEC (OS: 80%, 95% CI: 78–83) and ED (OS: 81%, 95% CI: 79–83); HR = 0.97, 95% CI: 0.81–1.16; p = 0.729). ED appeared more toxic. In the 528 HER2-positive subset, there was trend for a higher DFS, in the intention-to-treat population, in the trastuzumab arm (DFS: 68%, 95% CI: 61–74) than in the observation arm (DFS: 60%, 95% CI: 54–66; HR = 0.77, 95% CI: 0.57–1.03; p = 0.079). In the per-protocol population, DFS was significantly higher in the trastuzumab arm (DFS: 70%, 95% CI: 63–76) than in the observation arm (DFS: 59%, 95% CI: 53–65; HR = 0.69, 95% CI: 0.51–0.94; p = 0.0156). The OS was not different between these 2 arms. Conclusion This study did not show superiority of the concomitant anthracycline-taxane arm which was more toxic in high-risk node-positive breast cancer patients. Long-term results of the HER2-positive subpopulation are in line with those of the other adjuvant trastuzumab trials but quantitatively less pronounced mostly because of lack of power.

Background Corresponding with improved survival among patients with breast cancer, the awareness of the long-term effects of cancer treatments has increased. CANcer TOxicities (CANTO) aims to identify predictors of development and persistence of long-term toxicities in patients treated for stages I–III breast cancer and to characterise their incidence, as well their impact. In this paper, we describe the methodology used in this study and provide a first characterisation of the study population.Methods CANTO (NCT01993498) is a French prospective, longitudinal cohort study enrolling patients with invasive cT0-cT3cN0-3M0 breast cancer of 26 French cancer centres. Patients are assessed at diagnosis, 3–6 (M0), 12 (M12), 36 (M36) and 60 (M60) months after completion of primary surgery, chemotherapy or radiotherapy whichever comes last. CANTO collects clinical, treatment, toxicity data, an extensive list of validated patient-reported outcomes (focusing on quality of life, psychological and behavioural questionnaires) and ad hoc socioeconomic questionnaires. Blood collection is performed at diagnosis, M0, M12, M36 and M60. Biologic sub-studies are ongoing (eg, microbiotic and cognitive sub-study).Results Enrolment started in 2012; by October 2018, 12 012 patients had been enrolled. Data collected have a low missing completion rate (

For luminal metastatic breast cancer (MBC), endocrine therapy (ET) is the recommended initial treatment before chemotherapy. Our objective was to evaluate the efficacy of multiple ET lines in a real-life study.The Breast Cancer Epidemiological Strategy and Medical Economics (ESME) project analysed data from all patients with systemic treatment for MBC initiated between 2008 and 2014 in one of the 18 French Comprehensive Cancer Centres. The primary end-point was the successive progression-free survival (PFS) evaluation.The ESME research programme included 9921 patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 (HER2) negative (HER2-) MBC. Before any chemotherapy, 4195 (43.4%), 1252 (29.8%) and 279 (6.6%) patients received one, two or three ET ± targeted therapy, respectively. The median PFS for first-, second- and third-line ET ± targeted therapy was 11.5 (95% confidence interval [CI], 10.8-12.1), 5.8 (95% CI, 5.3-6.1) and 5.5 (95% CI, 4.6-6.3) months, respectively. In a multivariate analysis, time from diagnosis to metastatic recurrence (P 0.0001), presence of symptoms at metastatic relapse (P = 0.01), number of metastatic sites (P = 0.0003) and their localisation (P 0.0001) were prognostic factors for PFS1. Duration of previous PFS was the only prognostic factor for subsequent PFS (10% threshold). Ten percent of the patients showed long-term response to ET, with a total treatment duration before chemotherapy ≥43.6 months.Median PFS in our HR+/HER2- real-life cohort is similar to median first-line PFS reported in clinical trials, regardless of ET used as second- and third-line treatment. Despite the international consensus on early initiation of ET, the latter is not prescribed in most of the cases. Patients with a low tumour burden may achieve prolonged response on ET.

Background Group-based trajectory modeling is particularly important to identify subgroups of patients with pathological cognitive changes after cancer treatment. To date, only one study has explored cognitive trajectories in older patients with cancer. The present article describes objective cognitive changes before to after adjuvant treatment in older adults with early-stage breast cancer (EBC) after adjuvant treatment compared with healthy controls. Patients and Methods Participants were patients ≥65 years of age with newly diagnosed EBC and healthy controls (age-, sex-, and education-matched). The pretreatment assessment was conducted before adjuvant therapy, and the post-treatment assessment after the end of the first adjuvant treatment. Objective cognitive changes before to after treatment were evaluated based on the Reliable Change Index for cognitive decline accounting for cognitive impairment status. Results The sample consisted of women newly diagnosed with EBC (n = 118) and healthy controls (n = 62). Five patterns of changes before to after treatment were identified based on the presence of cognitive decline and cognitive impairment. The distribution of these five change patterns was statistically significant (p = .0001). Thirty-six percent of patients had phase shift changes, 31% without initial objective cognitive impairment developed impairment, 15% had a normal aging, 12% had a nonpathological decline, and 6% experienced accelerated cognitive decline. Conclusion This study described for the first time objective cognitive changes before to after treatment of older adults with EBC immediately after the end of adjuvant treatment. A longer-term remote follow-up of adjuvant treatment is needed to better understand the cognitive trajectories of older patients with EBC. Implications for Practice After the end of adjuvant treatment, 31% of older adults with early-stage breast cancer without initial objective cognitive impairment developed impairment, and 6% experienced accelerated cognitive decline. Initial cognitive functioning should be included in the balance of benefits and harms of systemic therapy for patients who are likely to be at highest risk for cognitive decline after cancer treatments. Regular cognitive follow-up of patients who had cognitive impairment before cancer treatment should monitor symptoms suggestive of neurodegenerative disease and avert the effect of cognitive disorders on patients’ autonomy.

Microinvasive in situ ductal carcinomas of the breast are rare and of good prognosis. They are grouped with early stage invasive carcinomas in the TNM 2017 classification. This study assessed practitioners' treatment decisions and their justifications in comparison to the literature.Three clinical cases were evaluated by anonymous forms regarding sentinel node decisions, tumour bed boost irradiation and hormone therapy.Sentinel lymph node was performed by 93.1%, 100% and 44.4% of the practitioners respectively. Radiation boost was a treatment option chosen by 62.1% and 61.1% of practitioners in both clinical cases. Hormone therapy was advocated for 65.5%, 94.7% and 50.0% patients depending on the clinical case.The therapeutic attitude proposed in microinvasive breast carcinomas was heterogeneous in this study, reflecting the absence of specific recommendations. In view of the existing literature, it is not currently possible to propose recommendations for these three therapeutic options. Prospective cohorts and meta-analyses of the microinvasive subgroup could provide answers.

International audience; Cognitive deficits are a major complaint in breast cancer patients, even before chemotherapy. Comprehension of the cerebral mechanisms related to cognitive impairment in breast cancer patients remains difficult due to the scarcity of studies investigating both cognitive and anatomical imaging changes. Furthermore, only some of the patients experienced cognitive decline following chemotherapy, yet few studies have identified risk factors for cognitive deficits in these patients. It has been shown that education level could impact cognitive abilities during the recovery phase following chemotherapy. Our main aim was to longitudinally evaluate cognitive and anatomical changes associated with cancer and chemotherapy in breast cancer patients. Our secondary aim was to assess the impact of education level on cognitive performances and gray matter (GM) atrophy in these patients. Twenty patients were included before chemotherapy (T1), 1 month (T2) and 1 year (T3) after chemotherapy. Twenty-seven controls without a history of cancer were assessed at T1 and T3 only. Cluster groups based on education level were defined for both groups and were further compared. Comparison between patients and controls revealed deficits in patients on verbal episodic memory retrieval at T1 and T3 and on executive functions at T3. After chemotherapy, breast cancer patients had GM atrophy that persisted or recovered 1 year after chemotherapy depending on the cortical areas. Increase in GM volumes from T1 to T3 were also found in both groups. At T2, patients with a higher level of education compared to lower level exhibited higher episodic memory retrieval and state anxiety scores, both correlating with cerebellar volume. This higher level of education group exhibited hippocampal atrophy. Our results suggest that, before chemotherapy, cancer-related processes impact cognitive functioning and that this impact seems exacerbated by the effect of chemotherapy on certain brain regions. Increase in GM volumes after chemotherapy were unexpected and warrant further investigations. Higher education level was associated, 1 month after the end of chemotherapy, with greater anxiety and hippocampal atrophy despite a lack of cognitive deficits. These results suggest, for the first time, the occurrence of compensation mechanisms that may be linked to cognitive reserve in relationship to state anxiety. This identification of factors, which may compensate cognitive impairment following chemotherapy, is critical for patient care and quality of life.

Background: Two large clinical trials have reported divergent results in their initial analysis of the benefit of aromatase inhibitors compared to tamoxifen in women with ductal carcinoma in situ (DCIS) (IBIS-II and NSABP B-35). Here, we report blinded 12-year median follow-up efficacy and adverse event data for the IBIS-II trial, which compared anastrozole to tamoxifen in women with hormone receptor positive DCIS and focus on the post-treatment follow-up period.Methods: A multi-centre randomised trial of 1mg/day anastrozole (N=1471) vs. 20mg/day tamoxifen (N=1509) for five years was conducted in postmenopausal women with locally excised DCIS diagnosed between 2003 and 2009. The primary objective of this analysis was to determine the efficacy of anastrozole compared to tamoxifen in preventing recurrences overall, and in particular in the post 5-year treatment period. Secondary endpoints included type of recurrence, breast cancer mortality, other cancers, cardiovascular disease, fractures, adverse events and non-breast cancer deaths.Results: After a median follow-up of 11.6 years (IQR 9.9 to 13.4), a total of 221 breast cancer recurrences (7.4%) have been recorded. No difference in overall recurrence was observed (102 (6.9%) anastrozole vs. 119 (7.9%) tamoxifen; HR=0.87 (0.67-1.14), P=0.32) overall (Table), in the 5-year treatment period (HR=0.82 (0.53-1.27), P=0.37), or the post treatment follow-up period (HR=0.91 (0.65-1.27), P=0.57). Oestrogen receptor (ER) positive breast cancers were reduced by 28% with anastrozole when compared to tamoxifen (58 vs. 82; HR=0.72 (0.52-1.01), P=0.056) but this did not reach significance. In contrast, no effect was observed for ER-negative breast cancer with anastrozole (Table). No significant difference for the reduction in invasive breast cancer recurrence was observed with anastrozole when compared to tamoxifen (Table). Invasive ER-positive breast cancer was non-significantly reduced by 24% with anastrozole when compared to tamoxifen (44 vs. 59; HR=0.76 (0.51-1.12), P=0.17). A total of 127 deaths have been reported, with no significant difference in all-cause mortality between the two treatment arms (61 vs. 66; HR=0.94 (0.67-1.33), P=0.74). Only 7 deaths from breast cancer (3 vs. 4) were reported, with so few deaths from breast cancer at 12 years, any impact on survival is unlikely to emerge with longer follow-up. 214 cancers other than breast were reported, with a non-significant decrease observed with anastrozole (97 vs. 117, OR=0.84 (0.63-1.12), P=0.22). Endometrial (2 vs. 13, OR=0.16 (0.02-0.0.69)), ovarian cancer (1 vs. 9, OR=0.11 (0.003-0.82)), and non-melanoma skin cancer (11 vs. 21) were less common with anastrozole. Significantly higher rates of fractures (181 vs. 145, OR=1.32 (1.04-1.68)) and transient ischaemic attacks (15 vs. 5, OR=3.10 (1.07-10.92)) were observed with anastrozole compared to tamoxifen. A comprehensive adverse event profile will be reported. Conclusions: No clear efficacy differences were seen between the two treatments, although the data suggests possible greater efficacy for anastrozole over tamoxifen for prevention of ER-positive breast cancers. There were some clear differences in adverse events and anastrozole may be more appropriate for some women with contraindications for tamoxifen. Table: Number of events and Hazard Ratios (95% CI) according to treatment allocation.Anastrozole(N=1471)Tamoxifen(N=1509)HR (95% CI)Any recurrence1021190.87 (0.67-1.14)ER-positive58820.72 (0.52-1.01)ER-negative24151.63 (0.86-3.11)Invasive66760.89 (0.64-1.23)ER-positive44590.76 (0.51-1.12)ER-negative17121.44 (0.69-3.02)DCIS35420.85 (0.54-1.33)ER-positive14230.62 (0.32-1.21)ER-negative732.38 (0.61-9.20)Numbers do not add up due to missing information Citation Format: Ivana Sestak, Jack Cuzick, Bernardo Bonanni, Nigel Bundred, Christelle Levy, Sibylle Loib, Patrick Neven, Michael Stierer, Chris Holcombe, Robert Coleman, John Forbes, Anthony Howell. 12 year results of anastrozole versus tamoxifen for the prevention of breast cancer in postmenopausal women with locally excised ductal carcinoma in-situ [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 GS2-02.

Objectives: The key objectives of CONTESSA are to evaluate the efficacy and safety of tesetaxel plus a reduced dose of capecitabine as an all-oral regimen versus capecitabine alone in patients with HER2-, HR+ MBC previously treated with a taxane. Rationale: Tesetaxel is a novel, oral taxane with several properties that make it unique, including: oral administration with a low pill burden; a long (8-day) terminal plasma half-life in humans, enabling infrequent, once-every-3 weeks (Q3W) dosing; no observed hypersensitivity reactions; and significant activity against chemotherapy-resistant breast cancer cell lines. More than 1,000 patients have been treated with tesetaxel in clinical studies. Tesetaxel had encouraging monotherapy activity in a Phase 2 study in 38 patients with HER2-, HR+ MBC, with a confirmed objective response rate (ORR) per RECIST 1.1 of 45% and median progression-free survival (PFS) of 5.4 months (Seidman et al, 2018 ASCO Annual Meeting). Methodology: CONTESSA is a multinational, multicenter, randomized (1:1), Phase 3 registration study comparing tesetaxel (27 mg/m2 on Day 1 of a 21-day cycle) plus a reduced dose of capecitabine (1,650 mg/m2/day on Days 1-14 of a 21-day cycle) to the approved dose of capecitabine alone (2,500 mg/m2/day on Days 1-14 of a 21-day cycle) in patients with HER2-, HR+ MBC who have received no more than one chemotherapy regimen for advanced disease and have received a taxane in the (neo)adjuvant setting. There was no restriction on the disease-free interval following taxane therapy. The primary endpoint is PFS assessed by an Independent Radiologic Review Committee (IRC). CONTESSA was designed with 90% power to detect a 2.5-month improvement in median PFS (HR=0.71). Secondary endpoints are overall survival (OS), ORR and disease control rate. Results: CONTESSA, which enrolled 685 patients, met the primary endpoint of improved PFS as assessed by the IRC. Median PFS was 9.8 months for tesetaxel plus a reduced dose of capecitabine versus 6.9 months for capecitabine alone, an improvement of 2.9 months [HR=0.716 (95% CI: 0.573-0.895); p=0.003]. ORR was 57% for tesetaxel plus a reduced dose of capecitabine versus 41% for capecitabine alone (p=0.0002). OS data are immature. Tesetaxel plus capecitabine was associated with a manageable side effect profile consistent with previous clinical studies. Grade ≥3 treatment-emergent adverse events (TEAEs) that occurred in ≥5% of patients (tesetaxel plus capecitabine vs. capecitabine alone) were: neutropenia (71.2% vs. 8.3%); diarrhea (13.4% vs. 8.9%); hand-foot syndrome (6.8% vs. 12.2%); febrile neutropenia (12.8% vs. 1.2%); fatigue (8.6% vs. 4.5%); hypokalemia (8.6% vs. 2.7%); leukopenia (10.1% vs. 0.9%); and anemia (8.0% vs. 2.1%). TEAEs resulting in treatment discontinuation in ≥1% of patients (tesetaxel plus capecitabine vs. capecitabine alone) were: neutropenia or febrile neutropenia (4.2% vs. 1.5%); neuropathy (3.6% vs. 0.3%); diarrhea (0.9% vs. 1.5%); and hand-foot syndrome (0.6% vs. 2.1%). Treatment discontinuation due to any adverse event occurred in 23.1% of patients treated with tesetaxel plus capecitabine versus 11.9% of patients treated with capecitabine alone. Grade 2 alopecia occurred in 8.0% of patients treated with tesetaxel plus capecitabine versus 0.3% of patients treated with capecitabine alone. Grade ≥3 neuropathy occurred in 5.9% of patients treated with tesetaxel plus capecitabine versus 0.9% of patients treated with capecitabine alone. Conclusion: An all-oral regimen of tesetaxel plus a reduced dose of capecitabine significantly improved PFS versus capecitabine alone. Neutropenia was the most frequent Grade ≥3 TEAE. Rates of clinically significant alopecia and neuropathy were low. Citation Format: Joyce O'Shaughnessy, Lee Schwartzberg, Martine Piccart, Hope S. Rugo, Denise A Yardley, Javier Cortes, Michael Untch, Nadia Harbeck, Gail S. Wright, Igor Bondarenko, John Glaspy, Zbigniew Nowecki, Fadi Kayali, Arlene Chan, Christelle Levy, Mei-Ching Liu, Sung-Bae Kim, Julie Lemieux, Alexey Manikhas, Sara Tolaney, Elaine Lim, Andrea Gombos, Agostina Stradella, Mark Pegram, Peter Fasching, Laszlo Mangel, Vladimir Semiglazov, Veronique Dieras, Luca Gianni, Michael A Danso, Jeff Vacirca, Stew Kroll, Joseph O'Connell, Kevin Tang, Thomas Wei, Andrew Seidman. Results from CONTESSA: A phase 3 study of tesetaxel plus a reduced dose of capecitabine versus capecitabine alone in patients with HER2-, hormone receptor + (HR+) metastatic breast cancer (MBC) who have previously received a taxane [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 GS4-01.

International audience; Few data are currently available regarding the efficacy and safety of T-DM1 in breast cancer (BC) patients with unselected brain metastases (BM), since most clinical trials have excluded BM patients or have only included highly selected patients. HER2 + BC patients with BM treated with T-DM1 in 5 French centers were included in this retrospective study. Clinical management was performed according to the product guidelines. Efficacy was evaluated recording tumor response rates, progression-free (PFS) and overall survival, treatment compliance, and safety. Thirty nine patients received T-DM1, among whom 82 % presented with concomitant extra-cerebral disease. Median number of previous metastatic chemotherapy and HER2-directed targeted therapy regimens was 2 (range 0-8) and 1 (0-7), respectively. Thirty six patients had received BM loco-regional treatment (72 % whole-brain radiation therapy). After a median follow-up of 8.1 months (1.4-39.6), 24 patients had progressed (first site of progression: brain 14; meningeal 2; outside of the central nervous system 5; both intra- and extra-cerebral 3), 12 patients had died (disease progression), and 27 patients were still alive. Median number of T-DM1 cycles was 8 (1-43). There were 17 partial responses (44 %) and 6 patients achieved disease stabilization (59 % clinical benefit rate). Median PFS was 6.1 months (95 %CI 5.2-18.3), with one- and two-year PFS rates of 33 and 17 %, respectively. Treatment was well tolerated, without unexpected toxicities, treatment delay, or dose reduction. In this retrospective study, T-DM1 appeared to be an effective and well-tolerated therapeutic option in unselected HER2 + BC patients with BM. These findings require a prospective validation.

Background: In metastatic breast cancer (MBC), monitoring circulating tumor DNA (ctDNA) can detect mutation associated with resistance to treatment and its variations reflect changes in tumor burden. We prospectively monitored CTC and ctDNA during first line chemotherapy for MBC. Methods: The French cohort COMET is a prospective study including first line HER2- negative pts receiving weekly paclitaxel and bevacizumab. Blood samples were obtained at baseline (BL) and before the second cycle of chemotherapy (C2). ctDNA was analyzed by targeted resequencing (custom panel 220kb) SNV (28 genes + 8 promoters and CNA (18 genes). Results: For ctDNA, out of 196 pts analyzed, 147 had at least one somatic mutation (SNV) detected in plasma (75%). Despite no complete overlap, 24 pts (12%) had no CTC nor ctDNA detected at baseline. Including Copy Number Variation analysis (CNV), the number of patients without detectable ctDNA at baseline could be reduced to 18 (9%). The average number of mutations per pt was 2.4 (range 1 to 9). Median Allelic Frequency (MAF) was 9.1%. Most commonly mutated genes were TP53 and GATA3 with 14% and 7% of all mutations, respectively. TP53 mutations were detected in 31 % of patients and were associated with a shorter progression-free and overall survival. PI3KCA mutations were detected in 23.2% of the pts, were correlated with presence of bone metastasis and had no prognostic value. ESR1 was mutated in 10.6% of the pts, restricted to the ER+ subgroup and had no impact on overall survival. At baseline, CTC and ctDNA levels were correlated (r = 0.40, p < 0.0001). CTC detection was correlated with TP53 mutations detection but not with mutations PI3KCA or ESR1. Only 68 pts (36%) had detectable ctDNA at C2 with a MAF of 2% (0.3%-40%). 52.8% of patients positive for ctDNA at D1C1 became negative at D1C2 and only one negative at baseline became positive at C2. Correlation rate with CTC was the same after one cycle of chemotherapy (r = 0.40). Median follow-up was 53 months and median OS was 32 months. At multivariate analysis, triple negative status, detectable ctDNA at C2, CTC ≥5 at C2 and grade 3 on primary tumor were independent prognostic for OS. Conclusion: Early decrease of CTC and/or ctDNA after one cycle of chemotherapy are independent predictive markers of favorable outcome. Compared to CTC, ctDNA allows monitoring of tumor burden during chemotherapy and specific detection of targetable mutations as PI3KCA, HER2 or BRCA. Citation Format: Jean-Yves Pierga, Amanda Silveira, Elodie Girard, Veronique Lorgis, Marie-Laure Tanguy, Benoit Albaud, Olivier Tredan, Coraline Dubot, Caroline Hego, William Jacot, Anthony Goncalves, Marc Debled, Christelle Levy, Jean-Marc Ferrero, Christelle Jouannaud, Marie-Ange Mouret-Reynier, Florence Dalenc, Sylvain Baulande, Jerome Lemonnier, Frederique Berger, Francois-Clement Bidard, Charlotte Proudhon. Predictive and prognostic value of circulating tumor DNA (ctDNA) compared to circulating tumor cells (CTC) in a prospective cohort of metastatic breast cancer patients: The UCBG COMET trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3390.

1040 Background: Despite advances, pretreated HER2+ MBC remains incurable with ongoing need for new therapies. Investigational M has similar HER2 binding and antiproliferative effects as T. Relative to T, M Fc engineering increases binding affinity for both variants of activating Fc receptor (FcR) CD16A and decreases affinity for inhibitory FcR CD32B, coordinately activating innate and adaptive immunity. In a Phase 3 (P3) trial, M prolonged PFS over T (Table). Second interim OS results from Sept 2019 also favor M (hazard ratio [HR], 0.89; 95% CI 0.69–1.13; nominal P=0.326). Methods: SOPHIA (NCT02492711), an open-label P3 trial, enrolled pts with HER2+ MBC after pertuzumab and 1–3 lines of prior treatment (Tx) for MBC. Randomization was 1:1 to M (15 mg/kg IV q3w + Ctx) or T (6 [8 for loading dose] mg/kg IV q3w + Ctx), stratified by met sites (≤2, >2), lines of Tx for met disease (≤2, >2), and Ctx choice, including capecitabine (Cap), eribulin (Eri), gemcitabine (Gem), or vinorelbine (Vin). Primary endpoints were central blinded PFS and OS, assessed sequentially using the stratified log-rank test. Results: Investigator chemotherapy choices and results by chemotherapy are shown in the table. Subjects receiving Eri and Gem had the lowest PFS hazards ratios (HRs), favoring M over T, although no statistical significance of individual chemotherapy subgroups was seen. There was variable toxicity among Ctx subgroups, and fewer subjects receiving Cap had Ctx related Grade 3 or higher (>=Gr 3) AEs. In this unblinded study, more subjects on M than T in all subgroups discontinued Ctx while continuing study antibody. Conclusions: In combination with chemotherapy in pretreated HER2+ MBC, M improved PFS over T. Safety was manageable in all Ctx subgroups. Differences among HRs for chemotherapy subgroups may be driven by selection bias and/or sensitivity differences. Clinical trial information: NCT02492711 . [Table: see text]

2527 Background: Isolated central nervous system (CNS) progression on first-line systemic therapy with Trastuzumab (T) and Pertuzumab (P) for HER2-positive metastatic breast cancer (MBC) is a therapeutic challenge. Our aim was to describe the clinical outcome and current treatment strategies for such patients in a large retrospective cohort. Methods: Patients (pts) were selected among all MBC pts included in the French Epidemiological Strategy and Medical Economics (ESME) database involving 18 specialized cancer centers (NCT03275311). CNS progression-free survival (CNS-PFS), progression-free survival (PFS) and overall survival (OS) from diagnostic of brain metastases (BM) were estimated using the Kaplan-Meier method. Results: Between January 2008 and December 2016, 995 pts were treated with first-line T and P for their HER2-positive MBC. They were 55 years old in median, with tumors expressing hormone-receptors in 62%. A total of 132 pts (13%) experienced isolated CNS progression on T and P, with a median time from metastatic diagnosis to CNS progression of 12 months. It was the first CNS progression for 108 pts (82%) while 24 (18%) already had BM at time of metastatic relapse. After CNS progression, T and P were continued for 58% of pts (n = 73). The remaining 47 pts were switched to another HER2-directed therapy (T-DM1 for 57%, T alone or combined with chemotherapy for 36% and lapatinib for 21%). Among those 132 pts, 37% received whole-brain radiotherapy, 18% stereotactic radiation therapy, and 11% surgery. Systemic treatment was combined with CNS-directed therapy for 50% of pts. Median follow-up is 21 months (95%CI: 14.9-25.5) from the diagnosis of CNS metastases. Median OS (mOS) of the 132 pts is 35 months (95%CI: 29.2-53,6), and median PFS 7 months (95%CI: 6.3- 9.2). A total of 77 pts (58.3%) experienced a new CNS progression with a median CNS-PFS of 9 months (95%CI: 7.6-12,0). Patient who stayed on T and P had a significantly better OS in comparison to pts who were switched to another systemic HER2-directed therapy (mOS not evaluable vs23 months), whereas PFS and CNS-PFS were similar between groups. Conclusions: In this real life setting, isolated CNS progression occurred among 13% of pts with HER2+ MBC on first-line treatment with T and P, after a median time of 12 months. Following current ASCO recommendations, continuation of T and P after CNS-directed therapy, seemed to be adequate. Nevertheless, time to subsequent progression is short and better therapeutic options are needed.

e14107 Background: There is increasing interest in using e-health systems for symptom monitoring and alert triggering. ZEMY, a new software medical device, was developed to improve symptom management and enhance patient and health care team interactions. Methods: This was a three-month open-label, interventional, single arm study conducted at five French sites. Adult women with breast cancer (BC) initiating oral and/or parenteral cancer treatment received a smartphone with ZEMY installed and verbal training. Patients started cancer treatment on Day 1 and were followed for three months. Patients entered data for ten prespecified symptoms. The ZEMY software made recommendations to patients on the self-management of symptoms and transmitted automatic messages to the health care team. Primary outcome was patient feasibility response at 3 months (completion of ≥3 symptom reports and a report completion rate of ≥60% per patient). Secondary objectives included ZEMY symptom management, usability and satisfaction, and device deficiencies (DDs). Results: Overall, 54 patients were enrolled (Jun 2018 to Jan 2019) and 52 (96.3%) completed the study. Thirty-one (57.4%) patients were responders; this was not significantly higher than the predefined cut-off and ZEMY feasibility was not demonstrated. Forty-seven (87.0%) patients had ≥3 completed symptom reports and 33 (66.0%) patients had a report completion rate of ≥60% (missing: n = 4). In subgroup analyses, 22/30 (73.3%) patients with locally advanced BC and 24/36 (66.7%) patients aged 40–60 years were responders. ZEMY patient recommendations and health care team automatic messages were considered relevant at least once in > 74% of cases for five of the six symptoms that were reported at least once by more than 1/3 of patients (diarrhea, nausea, fatigue, cutaneous and mucosal toxicities, and anxiety/depression). Using a 0–10 visual analogue scale, mean ZEMY satisfaction score was higher for patients than investigators (6.3 ±2.9 vs 4.4 ±1.5). Overall, 95 DDs were reported in 37 (68.5%) patients. Main reasons for DDs were inappropriate recommendations (n = 51) and device malfunction (n = 36). Conclusions: The primary endpoint of the study was not reached; however, higher response rates were observed in subgroups versus the overall population, indicating that ZEMY may be useful in symptom management in these patients. Generally, patients had a favorable opinion of ZEMY. The DD rate observed indicates the need for better user support in the future. Clinical trial information: NCT03558490.

Objectif Evaluer la macrostructure du sommeil de patientes traitees pour un cancer du sein et son influence sur la consolidation en memoire prospective (MP). Methodes Dix-huit patientes traitees par hormonotherapie pour un cancer du sein et 21 volontaires sains de meme âge et niveau d’etudes ont realise le protocole. Le sommeil etait evalue a l’aide de questionnaires (ISI et PSQI) et de la polysomnographie (PSG). La tâche de MP (memoire des actions a realiser dans le futur) consistait a memoriser neuf intentions puis a les rappeler dans un environnement virtuel apres une nuit de sommeil (nocturne) ou apres une journee de veille (diurne). Le rappel des intentions etait declenche par un evenement (event-based [EB]) ou par un horaire (time-based [TB]). Resultats Les scores d’ISI et de PSQI des patientes sont inferieurs a ceux des controles. Les patientes ont plus de reveils apres endormissement (WASO) et de reveils superieurs a 15 s que les controles. Les scores de MP sont plus eleves en session nocturne comparee a la session diurne, dans les deux groupes. Chez les patientes, le score de rappel TB est inferieur aux controles en session nocturne et correle positivement au nombre d’eveils superieurs a 15 s. Conclusion Les patientes traitees pour un cancer du sein par hormonotherapie ont un sommeil plus fragmente, qui pourrait etre responsable des deficits de performances en MP. Le sommeil semble, neanmoins, avoir un effet benefique sur la consolidation de la MP des patientes.

Objectif L’objectif de cette etude etait d’analyser les spindles, acteurs fondamentaux de la consolidation mnesique au cours du sommeil, et leurs liens avec la consolidation d’intentions en memoire prospective (memoire des actions a realiser dans le futur, MP) chez des patientes traitees pour un cancer du sein. Methodes Nous avons enregistre le sommeil par PSG chez 18 patientes traitees par hormonotherapie pour un cancer du sein et 21 participantes controles appariees en âge et niveau d’etude. Les caracteristiques des spindles ont ete quantifiees automatiquement (ASEEGA software, Physip). La tâche de MP, realisee en realite virtuelle, consistait a memoriser 9 intentions le soir et a les rappeler le lendemain matin (session nocturne). Un rappel a 10 minutes de 9 autres intentions etait aussi realise dans une precedente session. Resultats Les patientes presentent des scores de MP inferieurs a ceux des controles lors de la session nocturne mais pas lors du rappel a 10 minutes. Le nombre de spindles ne differe pas entre les groupes, mais leur frequence est acceleree chez les patientes par rapport aux controles. Nous n’observons pas de lien entre la frequence des spindles et les scores de MP, quel que soit le groupe. Conclusion Nos resultats montrent, chez les patientes traitees par hormonotherapie pour un cancer du sein, des modifications subtiles en sommeil NREM et suggerent que les difficultes de MP dans le cancer du sein ne sont pas dependantes de troubles de la consolidation mnesique au cours du sommeil.

Background and Aims: Because of its low prevalence, metastatic breast cancer (MBC) in males is managed based on clinical experience with women. Using a real-life database, we aim to provide a comprehensive analysis of male MBC characteristics, management and outcome. Methods: The Epidemiological Strategy and Medical Economics Data Platform collected data for all men and women ⩾18 years with MBC in 18 participating French Comprehensive Cancer Centers from January 2008 to November 2016. Demographic, clinical, and pathological characteristics were retrieved, as was treatment modality. Men were matched 1:1 to women with similar characteristics. Results: Of 16,701 evaluable patients, 149 (0.89%) men were identified. These men were older (median age 69 years) and predominantly had hormone receptor HR+/HER2– disease (78.3%). Median overall survival (OS) was 41.8 months [95% confidence interval (CI: 26.9–49.7)] and similar to women. Median progression-free survival (PFS) with first-line therapy was 9.3 months [95% CI (7.4–11.5)]. In the HR+/HER2– subpopulation, endocrine therapy (ET) alone was the frontline treatment for 43% of patients, including antiestrogens ( n = 19), aromatase inhibitors ( n = 15) with luteinizing hormone-releasing hormone (LHRH) analogs ( n = 3), and various sequential treatments. Median PFS achieved by frontline ET alone was similar in men [9.8 months, 95% CI (6.9–17.4)] and in women [13 months, 95% CI (8.4–30.9)] ( p = 0.80). PFS was similar for HR+/HER2– men receiving upfront ET or chemotherapy: 9.8 months [95% CI (6.9–17.4)] versus 9.5 months [95% CI (7.4–11.7)] ( p = 0.22), respectively. Conclusion: MBC management in men and women leads to similar outcomes, especially in HR+/HER2– patients for whom ET should also be a cornerstone. Unsolved questions remain and successfully recruiting trials for men are still lacking.

HER2-negative metastatic breast cancer (MBC) is a common setting in which chemotherapy could be effective even in later lines of treatment. Oral etoposide has demonstrated clinical activity in this setting in small-scale studies, but its efficacy has not been compared to that of other chemotherapy regimens. We used the ESME database (Epidemiological Strategy and Medical Economics), a real-life national French multicentre cohort of MBC patients initiating therapy between 1 January 2008 to 31 December 2014. HER2-negative MBC patients who received oral etoposide as > 3rd chemotherapy line and for more than 14 days were included. Primary objective was progression-free survival (PFS); secondary objectives were overall survival (OS), and propensity-score matched Cox models including comparison with other therapies in the same setting. Three hundred forty-five out of 16,702 patients received oral etoposide and 222 were eligible. Median PFS was 3.2 months [95% CI 2.8–4] and median OS 7.3 months [95% CI 5.7–10.3]. Median PFS did not significantly differ according to the therapeutic line. The only prognostic factor for both PFS and OS was the MBC phenotype (hormone receptor-positive versus triple-negative, HR = 0.71 [95% CI 0.52–0.97], p = 0.028 for PFS and HR = 0.65 [0.46–0.92], p = 0.014 for OS). After matching for the propensity score, no differential effect on PFS or OS was observed between oral etoposide and other chemotherapy regimens administered in the same setting (HR = 0.94 [95% CI 0.77–1.15], p = 0.55 for PFS and HR = 1.10 [95% CI 0.88–1.37], p = 0.40 for OS). Oral etoposide retains some efficacy in selected heavily pre-treated patients with HER2-negative MBC, with the advantages of oral administration.

Adjuvant radiation therapy in breast cancer is a standard of care, either post-lumpectomy or in case of lymph node involvement. Internal mammary chain (IMC) is more and more included in the clinical target volume, because it increases overall survival. This increase must be weighed against cardiac complications in left breast cancer. Intensity modulated radiation therapy (IMRT) is used in this indication in order to better cover target volumes, but tends to increase irradiated healthy volumes, including the heart. The average cardiac dose is higher with IMRT, while it is also predictive of cardiovascular events in patients treated in 3D. This article aims to make an inventory of the IMC irradiations, as well as a review of the mechanisms of radiation-induced cardiac toxicity and ways to diagnose it early. Cooperation between medical oncologists, radiotherapy oncologists and cardiologists is needed to better support patients.

Resume Introduction Le cancer du sein inflammatoire represente 1 a 5 % des cancers du sein. Il est de mauvais pronostic : le risque est accru de developper des metastases par rapport aux cancers du sein non inflammatoires. Le traitement est multimodal. Nous avons evalue la radiotherapie, ses indications, la technique et son impact en termes de controle local et de survie globale selon les protocoles. Methode Les series de la litterature comportant plus de 40 patientes ayant ete irradiees pour cancer du sein inflammatoire a partir de 1995 ont ete analysees. Resultats La chimiotherapie etait toujours delivree en premier. La radiotherapie adjuvante a la chirurgie permettait d’obtenir des taux a 5 ans de controle local de 63 a 92 % et de survie globale de 51 a 64 %. Sans chirurgie, le controle local avec radiotherapie etait d’environ 65 % et la survie globale de 38 % a 10 ans. En radio-chimiotherapie, les etudes etaient tres heterogenes. Les modalites de la radiotherapie ont ete detaillees avec les doses et fractionnement, volumes-cibles et les protocoles techniques (dont les bolus). Conclusion Le traitement actuel est une prise en charge multimodale integrant systematiquement la radiotherapie avec une evaluation de la reponse tumorale pour maximiser les possibilites chirurgicales.

Real-life analysis of overall survival (OS) trends among metastatic breast cancer (MBC) patients may help define medical needs and evaluate the impact of public health investments. The present study aimed to evaluate the independent impact of the year of MBC diagnosis on OS in the Epidemio-Strategy-Medical-Economical (ESME)-MBC cohort.ESME-MBC (NCT03275311) is a French, national, multicentre, observational cohort including 16,702 consecutive newly diagnosed MBC patients (01 January 2008-31 December 2014). Of 16,680 eligible patients, 15,085 had full immunohistochemistry data, allowing classification as hormone receptor-positive and HER2-negative (HR+/HER2-, N = 9907), HER2-positive (HER2+, N = 2861) or triple-negative (HR-/HER2-, N = 2317) subcohorts. Multivariate analyses of OS were conducted among the full ESME cohort and subcohorts.Median OS of the whole cohort was 37.22 months (95% confidence interval [CI], 36.3-38.04). Year of diagnosis was an independent predictor of OS (hazard ratio 0.98 [95% CI, 0.97-1.00], P = .01) together with age, subtype, disease-free interval, visceral metastases and number of organs involved. Median OS of HR+/HER2-, HER2+ and HR-/HER2- subcohorts was, respectively, 42.12 (95% CI, 40.90-43.10), 44.91 (95% CI, 42.51-47.90) and 14.52 (95% CI, 13.70-15.24) months. Year of diagnosis was a strong independent predictor of OS in HER2+ subcohort (hazard ratio 0.91 [95% CI, 0.88-0.94], P .001), but not in HR+/HER2- nor HR-/HER2- subcohorts (hazard ratio 1.00 [95% CI, 0.98-1.01], P = .80 and 1.00 [95% CI, 0.97-1.02], P = .90, respectively).The OS of MBC patients has slightly improved over the past decade. However, this effect is confined to HER2+ cases, highlighting the need of new strategies in the other subtypes.

Summary Purpose To investigate the safety and clinical activity of comprehensive human epidermal growth factor receptor (HER) family receptor inhibition using lumretuzumab (anti-HER3) and pertuzumab (anti-HER2) in combination with paclitaxel in patients with metastatic breast cancer (MBC). Methods This phase Ib study enrolled 35 MBC patients (first line or higher) with HER3-positive and HER2-low (immunohistochemistry 1+ to 2+ and in-situ hybridization negative) tumors. Patients received lumretuzumab (1000 mg in Cohort 1; 500 mg in Cohorts 2 and 3) plus pertuzumab (840 mg loading dose [LD] followed by 420 mg in Cohorts 1 and 2; 420 mg without LD in Cohort 3) every 3 weeks, plus paclitaxel (80 mg/m2 weekly in all cohorts). Patients in Cohort 3 received prophylactic loperamide treatment. Results Diarrhea grade 3 was a dose-limiting toxicity of Cohort 1 defining the maximum tolerated dose of lumretuzumab when given in combination with pertuzumab and paclitaxel at 500 mg every three weeks. Grade 3 diarrhea decreased from 50% (Cohort 2) to 30.8% (Cohort 3) with prophylactic loperamide administration and omission of the pertuzumab LD, nonetheless, all patients still experienced diarrhea. In first-line MBC patients, the objective response rate in Cohorts 2 and 3 was 55% and 38.5%, respectively. No relationship between HER2 and HER3 expression or somatic mutations and clinical response was observed. Conclusions Combination treatment with lumretuzumab, pertuzumab and paclitaxel was associated with a high incidence of diarrhea. Despite the efforts to alter dosing, the therapeutic window remained too narrow to warrant further clinical development. Trial registration: on ClinicalTrials.gov with the identifier NCT01918254 first registered on 3rd July 2013.