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Background Pemphigus is a serious and rare chronic bullous autoimmune disease. It is characterized by mucocutaneous erosions secondary to autoantibodies directed against desmogleins 1 and 3, proteins involved in intercellular adhesion mechanisms. The occurrence of pemphigus is based on the triggering of genetic and external environmental factors such as drugs, infection and more rarely radiotherapy. To date, only 16 cases of radiation-induced pemphigus are described in a context of breast cancer treatment. Case presentation: We present the case of a 76-year-old woman who had a recurrence of pemphigus vulgaris limited to the irradiation field after exposure to an adjuvant radiotherapy treatment for a bilateral triple negative breast cancer. The onset was bilateral limited to the irradiation area and was treated effectively with local and systemic corticosteroids. After a rigorous review of the literature, only 16 cases of breast cancer radiation-induced pemphigus appeared. In contrast to several cases, the rash was limited to the irradiated area and improved with systemic corticosteroids. Conclusions Pemphigus is a very rare side effect of radiotherapy, notably in breast cancer. For more than three-quarters of the described cases in the literature, this condition occurs within three months following the end of treatment. After systemic immunosuppressive treatment, this disease disappears in the vast majority of the reported cases.

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

Background: Nowadays, the assessment of health related quality of life (HRQOL) in women with breast cancer (BC) has become very important, with the improvement of their prognosis and the growing number of BC survivors. HRQOL is therefore a main endpoint in cancer therapeutic care and its improvement should be an important goal of BC treatment. The aim of this study was to assess HRQOL at the end of acute treatment in BC patients using data of the multicenter prospective French CANTO cohort. Methods: CANTO (NCT 01993498) is a multicenter prospective observational study (26 centers in France) whose main objective is to study the chronic toxicities of anticancer treatments in 12,000 women with localized stages I to III BC. HRQOL was assessed at baseline and at the end of acute treatments (surgery +/- radiotherapy +/- chemotherapy) using the EORTC-QLQ-C30 questionnaire and its BC specific module, the EORTC-QLQ-BR23 questionnaire. The EORTC-QLQ-C30 is composed of 30 items which allow generating 15 scales which are: 5 functional scales, 8 symptom scales, a global health status and a financial difficulties scale. The EORTC-QLQ-BR23 comprises 23 items and contains 4 functional scales and 4 symptoms scales. The minimal clinically important change score (MCID) was defined as a mean difference of at least 10 points in HRQOL scores between the baseline and the end of acute treatments (M0). Mixed linear model was used to assess the determinants of HRQOL For the dimensions with MCID. Results: from March 2012 to December 2014, 5801 BC patients were included in the CANTO cohort. The mean age at diagnostic was 57 years (SD=11.5) and 22.1 % of patients was single. Ninety percent of women had a good performance status and 79 % did not have comorbidities. Most of patients underwent surgery (99.7%), among which 77% by conservative surgery, and respectively 90.3 % were treated with radiotherapy, 80.2 % with hormone therapy and 53.3 with chemotherapy. Out of 23 dimensions, treatments for the disease did not impact the HRQOL of patients for global health status and 17 others dimensions of the QLQ-C30 and QLQ-BR23. However, with the means change score (MD) over 10 points, body image functional scale (MD= -14, p Conclusion: Results of this study did not show an impact of acute treatments for early stage BC on global health status of patients. The most affected dimensions, by the treatments, were body image, pain, breast symptoms, arm symptoms and upset by hair loss. Overweight, anxiety, depression, education level, hormonal status and chemotherapy were the main determinant of HRQOL. Citation Format: Oumar Billa, Olivia Dialla, Sarah Dauchy, Barbara Pistilli, Paul-Henri Cottu, Anne Lesur, Florence Lerebour, Olivier Tredan, Laurence Vanlemmens, Christelle Jouannaud, Christelle Levy, Charles Cecile, Anne Laure Martin, Sibille Everhard, Florence Joly, Charles Coutant, Fabrice Andre, Patrick Arveux, Sandrine Dabakuyo-Yonli. Health related quality of life at the end of acute treatments for early stage breast cancer patients [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 P1-17-04.

Proof of concept studies has reported that circulating endothelial cell (CEC) count may be associated with the outcome of HER2-negative metastatic breast cancer (mBC) patients treated by chemotherapy and the anti-VEGF antibody bevacizumab. We report the results obtained in an independent prospective validation cohort (COMET study, NCT01745757). The main baseline criteria were HER2-negative mBC, performance status 0–2 and no prior chemotherapy for metastatic disease. CECs were detected by CellSearch® from 4 ml of blood at baseline and after 4 weeks of weekly paclitaxel and bevacizumab therapy. CEC counts (considered both as a continuous variable and using the previously described 20 CEC/4 ml cutoff) were associated with clinical characteristics and progression-free survival (PFS). CEC count was obtained in 251 patients at baseline and in 207 patients at 4 weeks. Median baseline CEC count was 22 CEC/4 ml (range 0–2231). Baseline CEC counts were associated with performance status (p = 0.02). No statistically significant change in CEC counts was observed between baseline and 4 weeks of therapy. High baseline CEC count was associated with shorter PFS in univariate and multivariate analyses (continuous: p

Background Metastatic breast cancer (MBC) behaviour differs depending on hormone receptors (HR) and human epidermal growth factor receptor (HER2) statuses. Methods The kinetics of central nervous system (CNS) metastases (CNS metastasis-free survival, CNSM-FS) and subsequent patient’s prognosis (overall survival, OS) according to the molecular subtype were retrospectively assessed in 16703 MBC patients of the ESME nationwide multicentre MBC database (Kaplan–Meier method). Results CNS metastases occurred in 4118 patients (24.6%) (7.2% at MBC diagnosis and 17.5% later during follow-up). Tumours were HER2−/HR+ (45.3%), HER2+/HR+ (14.5%), HER2+/HR− (14.9%) and triple negative (25.4%). Median age at CNS metastasis diagnosis was 58.1 years (range: 22.8–92.0). The median CNSM-FS was 10.8 months (95% CI: 16.5–17.9) among patients who developed CNS metastases. Molecular subtype was independently associated with CNSM-FS (HR = 3.45, 95% CI: 3.18–3.75, triple-negative and HER2−/HR+ tumours). After a 30-month follow-up, median OS after CNS metastasis diagnosis was 7.9 months (95% CI: 7.2–8.4). OS was independently associated with subtypes: median OS was 18.9 months (HR = 0.57, 95% CI: 0.50–0.64) for HER2+/HR+ , 13.1 months (HR = 0.72, 95% CI: 0.65–0.81) for HER2+/HR−, 4.4 months (HR = 1.55, 95% CI: 1.42–1.69) for triple-negative and 7.1 months for HER2−/HR+ patients (p Conclusions Tumour molecular subtypes strongly impact incidence, kinetics and prognosis of CNS metastases in MBC patients. Clinical trial registration NCT03275311.

Since 2005, 12 months of trastuzumab added to chemotherapy alone is the standard of care in patients with HER2-positive breast cancer. PHARE ('Protocol for Herceptin® as Adjuvant therapy with Reduced Exposure') is the first trial comparing a reduction of adjuvant trastuzumab versus the standard 12 months. In 2012, the first analysis failed to prove that 6-months was non-inferior to 12-months of adjuvant trastuzumab (NCT00381901). The current presentation reports the final analysis. Methods: The trial was sponsored by the French National Cancer Institute (INCa) (www.e-cancer.fr), and approved by central Ethical Committee on May 15th 2006. Patients with HER2-positive early breast cancer were randomly assigned between 12 and 6 months of adjuvant trastuzumab duration. The randomization was stratified by concomitant or sequential trastuzumab administration with chemotherapy, estrogen receptor (ER) status and center. The primary objective was non-inferiority of 6- versus 12-months arms in the intent to treat population, in terms of disease-free survival (DFS) with a pre-specified hazard margin of 1.15. Overall Survival (OS) and metastasis free survival (MFS) were secondary endpoints. Results: A total of 3380 patients were randomized, their median age was 54 years (21-86). Patients and disease characteristics were well balanced between the two arms. No involved axillary node was observed in 54.5% of cases, 41.7% of tumors were ER negative. At a median follow-up of 7.5 years, 704 events counting for DFS were observed. Between the 12- and 6-months arms, the adjusted Hazard Ratio (HR) for DFS rates was 1.08 (95%CI: 0.93-1.25; p=0.39) favoring the longer exposure. The 1.15 margin of non-inferiority was included in the 95%CI. No heterogeneity in terms of treatment effect was observed, no significant difference for trastuzumab duration effects was found in any subgroups.For OS and MFS, the adjusted HR were 1.13 (95%CI 0.92-1.39) and 1.15 (95%CI 0.96-1.37), respectively. Conclusion: The choice of the non-inferiority margin will remain inherently a subject of controversy especially in the context of oncology trials where the primary outcome is survival and the least additional death could be considered unacceptable questioning the very feasibility of such trials. Nevertheless, PHARE failed to show that 6 months of adjuvant trastuzumab was non-inferior to 12 months. The standard of care should remain 12 months of adjuvant trastuzumab. Citation Format: Pivot X, Romieu G, Debled M, Pierga J-Y, Kerbrat P, Bachelot T, Espie M, Lortholary A, Fumoleau P, Serin D, Jacquin J-P, Jouannaud C, Rios M, Abadie-Lacourtoisie S, Venat-Bouvet L, Cany L, Catala S, Khayat D, Gambotti L, Pauporte I, Faure Mercier C, Paget-Bailly S, Henriques J, Grouin J-M. PHARE randomized trial final results comparing 6 to 12 months of trastuzumab in adjuvant early breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS2-07.

Background:Primary inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer. Survival of IBC patients has been improved by multimodal therapy. However 5-year overall survival (OS) still remains close to 50-60%, due to high risk of disseminated disease. Given the low incidence, prognosis of metastatic cases stages is poorly described. Methods:This study aimed to describe OS of IBC (T4d AJCC TNM classification) with upfront or recurrent metastatic disease compared with non-IBC patients in the ESME database (N=16,702 patients). OS was calculated from the diagnosis of metastasis to the date of death (from any cause), or censored to date of latest news. Secondary objectives included progression-free survival (PFS). Results:From 2008 to 2014, 7,465 patients with diagnosis of MBC and known clinical status of their primary tumor (T) were identified, including 582 IBC (T4d) and 6,883 non-IBC. As expected, metastatic IBC was associated with pejorative features compared to non-IBC, with less hormonal receptors-positive tumors (44% vs 65.6%), more HER2-positive (30% vs 18.6%) or triple-negative (25.9% vs 15.8%) cases (p Compared with non-IBC, synchronous metastatic IBC showed worse median OS and PFS (39.9 months [95%CI 34.2-45.3] vs 48.4 months [95%CI 46.3-50.8], p=0.0035; 10 months [95%CI 8.8-12.7] vs 14.5 months [95%CI 13.6-15.7], p=0.0027, respectively. Similar results were obtained in metachronous metastatic cases (20.01 months [95%CI 17.1-21.2] vs 32.8 months [95%CI 31.5-34.3], p Conclusion:In this large national and multicentric study, IBC is a major and independent factor associated with adverse outcome in metastatic setting. Of note, the independent adverse impact on PFS identified in this study may suggest a lower sensitivity of metastatic IBC to available therapeutics. However, results seem to improve in the last years. Detailed analysis according to phenotype will be available. Citation Format: Monneur A, Bertucci F, Lardy-Cleaud A, Augereau P, Debled M, Levy C, Mouret-Reynier MA, Coudert B, Mailliez A, Bachelot T, Ferrero J-M, Guiu S, Uwer L, Campone M, Cottu P, Jouannaud C, De la Motte Rouge T, Leheurteur M, Petit T, Pistilli B, Dalenc F, Simon G, Robain M, Viens P, Lerebours F, Gonçalves A. Metastatic inflammatory breast cancer: Clinical features and outcomes in the national, multicentric, real-life ESME cohort [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-17-04.

Background: Randomized trials, although not all, suggest exercise therapy improves treatment completion rates / relative dose intensity in patients with early-stage breast cancer receiving adjuvant chemotherapy (CT). In addition, preclinical studies show that exercise therapy adds to the antitumor activity of standard CT in murine models of breast cancer. We evaluated the association between exercise and pathologic complete response (pCR) rate (i.e., ypT0ypN0) in patients receiving neoadjuvant CT for operable breast cancer. Methods: Using a prospective design, patients with stage I-III breast cancer receiving anthracycline-taxane (± trastuzumab) neoadjuvant CT participating in a multicenter, national cohort study in France (CANTO, NCT01993498) completed questionnaire assessing self-reported exercise behavior (GPAQ 16). Multivariate logistic models were performed to determine the relationship between pre-CT exercise exposure (total MET-h/wk categorized into the proportion of patients meeting WHO exercise guidelines, the equivalent of ≥10 MET-h/wk), pCR rates, CT± trastuzumab dose reductions, delays, treatment completion or interruptions for the overall cohort and on the basis of clinical subtype. Results: Between March, 2012 to December, 2014, a total of 989 patients participating in CANTO received neoadjuvant CT and completed GPAQ 16. Here we present interim analyses on 608 patients. Fifty-four percent of patients engaged on of ≥10 MET-h/wk prior to CT administration. In multivariable analysis for the overall cohort, exercise exposure was not associated with higher pCR (p=0.69). The pCR rate was 27.7% for patients reporting Conclusion: On the basis of interim analyses, higher pretreatment exercise exposure is not associated with higher clinical response or treatment tolerability in breast cancer patients receiving uniform conventional neoadjuvant CT. Full results will be presented at the meeting. Citation Format: Baker JL, Di Meglio A, El Mouhebb M, Iyengar NM, Michiels S, Cottu P, Lerebours F, Coutant C, Lesur A, Tredan O, Soulie P, Vanlemmens L, Jouannaud C, Levy C, Everhard S, Martin A-L, Arveux P, Fabrice A, Vaz Luis I, Jones LW. Association between exercise, pathological complete response, and treatment tolerability in patients receiving neoadjuvant chemotherapy for operable breast cancer: Results from the CANTO study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-15-03.

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

Background High Body mass index (BMI) is a risk factor for breast cancer among postmenopausal women and an adverse prognostic factor in early-stage. Little is known about its impact on clinical outcomes in patients with metastatic breast cancer (MBC). Methods The National ESME-MBC observational cohort includes all consecutive patients newly diagnosed with MBC between Jan 2008 and Dec 2016 in the 18 French comprehensive cancer centers. Results Of 22 463 patients in ESME-MBC, 12 999 women had BMI data available at MBC diagnosis. Median BMI was 24.9 kg/m2 (range 12.1–66.5); 20% of women were obese and 5% underweight. Obesity was associated with more de novo MBC, while underweight patients had more aggressive cancer features. Median overall survival (OS) of the BMI cohort was 47.4 months (95% CI [46.2–48.5]) (median follow-up: 48.6 months). Underweight was independently associated with a worse OS (median OS 33 months; HR 1.14, 95%CI, 1.02–1.27) and first line progression-free survival (HR, 1.11; 95%CI, 1.01; 1.22), while overweight or obesity had no effect. Conclusion Overweight and obesity are not associated with poorer outcomes in women with metastatic disease, while underweight appears as an independent adverse prognostic factor., Highlights • This is the first large multicenter cohort reporting BMI’s effect on outcomes among patients with metastatic breast cancer. • Overweight or obese status does not negatively influence outcome of metastatic breast cancer patients, whatever the subtype. • Underweight is a strong negative independent prognostic factor on outcomes, whatever the subtype.

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

Benefits of physical activity are widely demonstrated for early stage cancers but few studies have focused on metastatic disease. The purpose of this study was to determine the impact of physical activity on survival in patients with metastatic breast cancer. We conducted a secondary analysis of the national, multicentric, non-randomized, prospective cohort SNPs to Risk of Metastasis (StoRM) study. The level of physical activity was self-reported at inclusion and divided into three categories of physical activity: light level, moderate level, and vigorous level. Overall, 833 patients (56.2%) completed the physical activity questionnaire at baseline on average physical activity during the previous year: 11.6% had a light level of physical activity, 69.0% achieved moderate levels of physical activity and 19.3% reported vigorous levels of physical activity. After adjustment for confounding, physical activity was not statistically significantly associated with overall survival in the whole population. Subgroup analysis identified that both vigorous and moderate physical activity were associated with statistically significantly improved overall survival compared to light physical activity level only in the HER2 positive subgroup (HR 0.23; 95% CI 0.07–0.70, p = 0.01 and HR 0.38; 95% CI 0.15–0.96, p = 0.04). Physical activity done during the previous year was associated with survival in HER2 positive metastatic breast cancer patients. These results suggest that overall survival in metastatic breast cancer patients could be improved through physical activity which should be considered as a complementary intervention for these individuals. The study showed that moderate/vigorous levels of physical activity were associated with better overall survival, and that these associations remained statistically significant in multivariate analysis in the HER2 positive subgroup. These results have clinical relevance and justify the recommendations for physical activity interventions in metastatic breast cancer.

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.

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 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.

The aims of the present study were to describe treatment patterns and survival outcomes in patients with central nervous system metastases (CNSM) selected among metastatic breast cancer (MBC) patients included in a retrospective study from the Epidemiological Strategy and Medical Economics (ESME) MBC cohort.Neurological progression-free survival (NPFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Significant contributors to NPFS were determined using a multivariate Cox proportional hazards model.After a median follow-up of 42.8 months, of 16 701 patients included in the ESME MBC database, CNSM were diagnosed in 24.6% of patients. The most frequent treatments after diagnosis of CNSM were whole-brain radiotherapy (WBRT) (45.2%) and systemic treatment (59.3%). Median OS and NPFS were 7.9 months (95% CI: 7.2-8.4) and 5.5 months (95% CI: 5.2-5.8), respectively. In multivariate analysis, age70 years (vs50 years; HR = 1.40; 95% CI: 1.24-1.57), triple-negative tumours (vs HER2-/HR+; HR = 1.87; 95% CI: 1.71-2.06), HER2+/HR-tumours (vs HER2-/HR+; HR = 1.14; 95% CI: 1.02-1.27), ≥3 metastatic sites (vs 3; HR = 1.32; 95% CI: 1.21-1.43) and ≥3 previous treatment lines (vs 3; HR = 1.75; 95% CI: 1.56-1.96) were detrimental for NPFS. A time interval between selection and CNSM diagnosis superior to 18 months (vs9 months; HR = 0.88; 95% CI: 0.78-0.98) was associated with longer NPFS.This study describes current treatment patterns of MBC patients in a "real life" setting. Despite advances in stereotactic radiation therapy, most of the patients still received WBRT. More research is warranted to identify patient subsets for tailored treatment strategies.

We report the case of an asymptomatic 66-year-old woman referred for initial staging of an invasive ductal breast carcinoma. Initial workup incidentally revealed a bone tumor of right sacral wing corresponding to a giant cell tumor (GCT). We present the imaging characteristics of GCT on Tc-HDP bone scan (doughnut sign), F-FDG PET/CT (intense and heterogeneous uptake of a prominent geographic lytic lesion with partial rupture of cortical), and MRI (hyposignal with gadolinium enhancement on T1-weighted images and heterogeneous hypersignal on T2-weighted images). GCT is a benign but locally aggressive primary bone tumor, constituting a pitfall and diagnostic challenge.

Background There is no large prospective trial assessing mid-term adverse effects of adjuvant chemotherapy. In order to address this question, we developed CANTO (CANcer TOxicities - NCT01993498 - http://etudecanto.org/), a prospective trial dedicated to the quantification of side effects after treatment for patients with early breast cancer and to develop predictors of such toxicities. The aim of this presentation is to assess chemotherapy (CT) practice and to report toxicities that persist 3-6 months after CT. Methods CANTO is a prospective study enrolling newly diagnosed invasive cT0-cT3, cN0-3, M0 breast cancer patients (pts) of 26 French comprehensive cancer centers. The study has included 10 500 patients at the time of submission. Pts are assessed at diagnosis, 3-6, 12, 36, 48 and 60 months after treatment completion. CANTO collects >100 items related to toxicities. In the current study, we focus on the first set of data available from the trial (1st database lock, n=6090). We here assess CT practice and toxicities at 3 months. Results Information about (neo)adjuvant CT (NACT/ACT) is available in 5805 pts (96%). Median age at diagnosis was 57y (22-93). Pts had HR+/HER2-, HER2+ or triple negative (TN) tumors in 74%, 15% and 11% of cases. Ki67 was assessed in 70%, and genomic tests in 1% of pts, respectively. Overall, 3074 pts (53%) received CT, either adjuvant (ACT: 76%) or neoadjuvant (NACT: 24%). ACT/NACT pts (84%) received a sequential anthracyclines–taxanes based 6 courses CT schedule. CT was administered in 44.7%, 87.2% and 92.3% of HR+/HER2+/TN tumors, respectively. ACT was administered in 73.2% of pT2+ pts (vs 36.0% in pT0-1 – p We focus here on clinically most relevant patient reported symptoms at 3 m (any grade). side effects at 3m no CT (%)CT (%)p valuePain76.682.1 Pain complaint was recorded in 3596 pts (97.2% of pts with available data), with a median value of 4 on the VAS (range 1-10). In ACT/NACT pts, muscle and joint pain were predominant. Neurological symptoms were seen in 3024 pts (59%), the most frequent pertaining to cognitive disorder (attention trouble, CT: 61.2% vs noCT: 56% - p=.06) and peripheral neuropathy (overall 31%). Paresthesias and sensory neuropathy were much more frequent in CT vs noCT pts: respectively 37.3% vs 20.3% and 25.7% vs 12.8% (both p Conclusions In this real life, prospective cohort, CT is frequently prescribed and appears in good compliance with current guidelines. Overall, symptoms burden at treatment completion is strikingly high, and much higher in pts receiving CT. A special attention should be given to pain and neurological symptoms. Dedicated questionnaires and sub-studies will explore in depth these side effects. Extended analyses of CT practice and toxicities will be presented. Citation Format: Cottu PH, Amar Y, Pistilli B, Bonsang-Kitzis H, Lesur A, Lerebours F, Vanlemmens L, Tredan O, Levy C, Jouannaud C, Fournier M, Soulie P, Rigal O, Giacchetti S, Arnaud A, Arsene O, Savignoni A, Mesleard C, Andre F, Arveux P. CANTOCHEM: Analysis of chemotherapy practice and early side effects in the 6090 first patients from the prospective CANTO cohort [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-12-18.

HannaH (NCT00950300) and PrefHer (NCT01401166) studies validated the subcutaneous (H-s.c.) formulation of trastuzumab as effective and safe as intravenous (H-i.v.) and highly preferred by patients in early breast cancer. The present randomised MetaspHer trial (NCT01810393) is the first study assessing patient's preference in metastatic setting. Methods Patients with HER2-positive metastatic breast cancer who completed a first line chemotherapy with trastuzumab and achieved a long-term response lasting more than 3 years were randomised to receive 3 cycles of 600-mg fixed-dose adjuvant H-s.c., followed by 3 cycles of standard H-i.v., or the reverse sequence. Primary end-point was overall preference for H-s.c. or H-i.v. at cycle six, assessed by Patient Preference Questionnaire (PPQ). Secondary end-points included healthcare professional (HCP) satisfaction; safety and tolerability; quality of life. Results Hundred and thirteen patients were randomised and treated. H - s.c. was preferred by 79/92 evaluable intent-to-treat patients (85.9%, 95% confidence interval [CI; 78.8–93.0]; p Conclusion The safety was consistent with the known H-i.v. and H-s.c. profiles without safety concern raised. Definitively, patients preferred H-s.c. as reported in early stage by PrefHer study.

Background The potential prognostic value of hypertension and proteinuria of anti- vascular endothelial growth factor (VEGF) drugs has not been assessed in routine clinical practice so far in metastatic renal cell carcinoma (mRCC). The objectives were to (i) assess the prevalence of proteinuria and hypertension at baseline; (ii) their incidence under anti-VEGF drug treatment; and (iii) evaluate a possible link with overall survival. Methods Patients from 8 centers were included between 2009 and 2011 with a follow-up of 1 year. They were naïve of any previous anti-VEGF drug treatment and planned to be started on one. The results of the group of patients with mRCC receiving sunitinib are presented. Results A total of 1,124 patients were included, among whom 137 had mRCC and 112 received sunitinib. At inclusion, hypertension prevalence was 44%, proteinuria 16%, hematuria 8%, mean modification of diet in renal disease (MDRD) formula 69 mL/min/1.73m2. The incidence of de novo proteinuria and hypertension during follow-up was 75% and 21%, respectively. Among patients with de novo proteinuria, 76% afterwards improved/normalized. Mean MDRD was 72 at the end of follow-up. No thrombotic microangiopathy was reported. Baseline or de novo proteinuria or hypertension were not associated with OS in mRCC patients treated with sunitinib. Conclusions These results showed that (i) hypertension and proteinuria were frequent at baseline in mRCC patients; (ii) de novo hypertension and proteinuria frequently occur under sunitinib treatment; and (iii) neither hypertension nor proteinuria, either at baseline or de novo, were associated with overall survival in our cohort of “real-life” patients.

Background: Genomic tests can identify ER-positive Her2-negative localized breast cancer (BC) patients (pts) who may not drive any benefit from adjuvant chemotherapy (CT). Several genomic tests have reached a high level of analytical and clinical validity, as well as clinical utility in such situation. Recent results suggest that the safe de–escalation of adjuvant chemotherapy may be most beneficial in pts with clinical high or indetermediate risk, as assessed by classical variables or online tools, through the use of a genomic test. The clinical risk though remains quite uncertain with variable definition and grey zones. The present study aimed at determining if EPclin clinico-genomic test had a significant impact on treatment decision making among pts with predefined intermediate /borderline clinical risk. Patients and methods: Women were eligible for the present study if they had complete surgical removal of a localized ER+ Her2- pN0 or pN1mi BC, and were considered by the multidisciplinary team meeting (MTM) of the center as being in a "grey zone" of uncertain CT benefit based on classical clinic-pathological assessment. The MTM1 proposed a decision (chemo/no chemo). After informed consent, an EPclin signature classified the tumor as low risk (EPclin Score < 3.3, no chemo advised) or high risk (> 3.3, a theoretical indication for adjuvant chemo). Primary end point was the proportion of change between initial adjuvant CT decision at MTM1 and final administration of CT (yes/no). A 5 steps Fleming design was planned, considering that a change rate of 15% or less was not acceptable (low clinical utility). A one-step design was used (unilateral α = 2.5% and β = 1%). Results: 203 pts were included, of whom 198 are evaluable for the main end point. 74% of the tumors were grade 2, 72% T1 , 25% T2, 3% T3; 16% were pN1mi and 84% pN0. Median age was 57. EpClin® was low risk in 67% and high risk in 33% of the cases. The global rate of decision change between MTM1 and final administration of CT was 70/198 (35.4% IC-95% = [28.7-42.1]), with 55 (27.7%) decreases and 15 (7.6%) increases in CT indication. 27% instead of 47% of all pts finally received CT (43% decrease in CT prescription). In the multivariate analysis, the factors associated to decrease for less CT were EPclin score (OR 0.11 [0.03-0.35]), proliferation (OR 1.08 [1.03-1.13]) and higher grades (OR 5.22 [1.04-26.08]); while EPclin score was positively (OR 76.6 [7.11-824.8]), but higher grades inversely (OR 0.06 [0-0.86]) associated to an increase in CT administration. Of note, the change in final decision occurred after the MTM2 and after report of the results and discussion with the patient in 9 of the 70 cases (12% of changes; 4.5% of the whole population)(8 decreases and 1 increase in CT administration). Conclusion: Adendom met its primary objective, with 35% of intermediate clinico-pathological risk pts getting significant therapeutic changes upon the receipt of an EPclin gene expression profile. 43% of these "intermediate risk" pts planned for CT avoided it. 12% of the changes were discrepant with the test's results and occurred after discussion with the patient. Citation Format: Penault-Llorca F, Kwiatkovski F, Grenier J, Levy C, Leheurteur M, Uwer L, Derbel O, Le Rol A, Jacquin J-P, Jouannaud C, Quenel-Tueux N, Girre V, Foa C, Guardiola E, Lortholary A, Catala S, Lemonnier J, Delaloge S. UCBG 2-14: A prospective multicenter non-randomized trial evaluating the effect of EndoPredict® (EPclin®) clinico-genomic test on treatment decision making among patients with intermediate clinical risk [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-05-10.

BACKGROUND: Lapatinib (L) plus trastuzumab (T) with weekly paclitaxel significantly increased the pathologic complete response (pCR) rate compared with the anti-human epidermal growth factor receptor 2 (HER2) agent alone plus paclitaxel. The event-free survival (EFS) and overall survival (OS) by the treatment arms L + T vs. T and L vs. T and the relationship between pCR and EFS/OS both in the whole study population and according to hormone receptor-negative and hormone receptor-positive cohorts after a median follow-up of 6.7 years were assessed. PATIENTS AND METHODS: Four hundred fifty-five patients with HER2-positive early breast cancer randomly received L 1500 mg/day (n = 154), T (common dose, n = 149) or L 1000 mg/day plus T (n = 152) for 6 weeks, followed by the assigned anti-HER2 treatment combined with paclitaxel weekly × 12. After surgery, patients received 3 cycles of fluorouracil, epirubicin and cyclophosphamide. The primary end-point was pCR (ypT0/is; for current analysis, it is ypT0/is ypN0), and the secondary end-points were EFS and OS. RESULTS: Six-year EFS rates were 67%, 67% and 74% with L, T and L + T, respectively (L vs T: hazard ratio [HR], 0.98 [95% confidence interval {CI}, 0.64-1.51; P = .93]; L + T vs T: HR, 0.81 [95% CI, 0.52-1.26; P = .35]). Six-Year OS rates were 82%, 79% and 85% for L, T and L + T, respectively (L vs T: HR, 0.85 [95% CI, 0.49-1.46; P = .56]; L + T vs T: HR, 0.72 [95% CI, 0.41-1.27; P = .26]). In landmark analyses, patients with a pCR had a significantly higher 6-year EFS (77% and 65%) and OS (89% and 77%) compared with those without a pCR for both overall and the hormone receptor-negative cohort. CONCLUSION: Achieving a pCR is important in HER2-positive disease and translates into better long-term outcome with regard to EFS and OS. ispartof: EUROPEAN JOURNAL OF CANCER vol:118 pages:169-177 ispartof: location:England status: published

Summary Background In 2013, the interim analysis of the Protocol for Herceptin as Adjuvant therapy with Reduced Exposure (PHARE) trial could not show that 6 months of adjuvant trastuzumab was non-inferior to 12 months. Here, we report the planned final analysis based on the prespecified number of occurring events. Methods PHARE is an open-label, phase 3, non-inferiority randomised trial of patients with HER2-positive early breast cancer comparing 6 months versus 12 months of trastuzumab treatment concomitant with or following standard neoadjuvant or adjuvant chemotherapy. The study was undertaken in 156 centres in France. Eligible patients were women aged 18 years or older with non-metastatic, operable, histologically confirmed adenocarcinoma of the breast and either positive axillary nodes or negative axillary nodes but a tumour of at least 10 mm. Participants must have received at least four cycles of a chemotherapy for this breast cancer and have started receiving adjuvant trastuzumab-treatment. Eligible patients were randomly assigned to either 6 months or 12 months of trastuzumab therapy duration between the third and sixth months of adjuvant trastuzumab. The randomisation was stratified by concomitant or sequential treatment with chemotherapy, oestrogen receptor status, and centre. The primary objective was non-inferiority in the intention-to-treat population in the 6-month group in terms of disease-free survival with a prespecified hazard margin of 1·15. This trial is registered with ClinicalTrials.gov, number NCT00381901. Findings 3384 patients were enrolled and randomly assigned to either 12 months (n=1691) or 6 months (n=1693) of adjuvant trastuzumab. One patient in the 12-month group and three patients in the 6-month group were excluded, so 1690 patients in each group were included in the intention-to-treat analysis. At a median follow-up of 7·5 years (IQR 5·3–8·8), 704 events relevant to disease-free survival were observed (345 [20·4%] in the 12-month group and 359 [21·2%] in the 6-month group). The adjusted hazard ratio for disease-free survival in the 12-month group versus the 6-month group was 1·08 (95% CI 0·93–1·25; p=0·39). The non-inferiority margin was included in the 95% CI. No differences in effects pertaining to trastuzumab duration were found in any of the subgroups. After the completion of trastuzumab treatment, rare adverse events occurred over time and the safety analysis remained similar to the previously published report. In particular, we found no change in the cardiac safety comparison, and only three additional cases in which the left ventricular ejection fraction decreased to less than 50% have been reported in the 12-month group. Interpretation The PHARE study did not show the non-inferiority of 6 months versus 12 months of adjuvant trastuzumab. Hence, adjuvant trastuzumab standard duration should remain 12 months. Funding The French National Cancer Institute.

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Background: Due to better molecular classification and new treatment options, epidemiology and prognosis of mBC is rapidly changing. Clinical data extracted from randomized studies are only relevant to specific subpopulations and retrospective studies are prone to selection bias. SToRM is a prospective clinical trial that aims to create a cohort of 1500 mBC patients, with the ultimate goal of identifying germ line polymorphisms associated with prognosis of breast cancer (BC) and response to treatment in the metastatic phase. Material and methods: Any newly (within 1 year) diagnosed mBC patients were eligible. Whole blood samples were drawn and germline DNA extracted for genetic analysis. Extensive epidemiologic data, disease history from primary diagnosis to metastatic spread, pathological characteristics and ER, PR and HER2 status were collected. Patients are prospectively followed until death. Genotyping using the HumanCoreExome chipset from Illumina is currently underway and will be completed in early summer 2015. Results: 1502 patients were included from March 2012 to May 2014 from 71 French institutions. Median age at metastatic relapse was 60 years (range 26-93). Median time from primary diagnosis to metastatic relapse was 30 months (range 0-473) with 24% of patients already metastatic at initial diagnosis. 78% of patients were ER+, 18% were HER2+ and only 16% were triple negative. Molecular subtype classification derived from pathological data following St Gallen consensus recommendations is presented below: n (%)Luminal A like261 (22.2%)Luminal B like HER2 negative476 (40.5%)Luminal B like HER2 positive134 (11.4%)HER2 positive non Luminal (ER-)111 (9.5%)Triple negative193 (16.4%)Missing data327 64% of the patients had received previous adjuvant treatment, among which 81% received adjuvant chemotherapy and 9% trastuzumab. At metastatic relapse, loco-regional progression, liver, lung and bone metastasis were documented in 301 (20%), 494 (33%), 410 (27%) and 1017 (68%) patients respectively. 313 patients (21%) had bone only metastatic disease. First line treatment included: chemotherapy (71%), endocrine therapy (50%) and anti-HER2 treatments (17%). Survival data will be presented at the meeting. Conclusion: Despite a theoretically better prognosis and widespread use of adjuvant hormonal treatment, ER+/HER2- breast cancer still account for more than 60% of mBC. The proportion of patients with HER2+ disease (18%) and triple negative disease (16%) is consistent with percentages observed in early BC populations. In comparison with a cohort of "cured", localized cancer, such as the SIGNAL/PHARE study, GWAS analysis will allow for the identification of genetic polymorphisms correlated with treatment resistance. Fundamentally, such variants will provide insight into the molecular mechanisms responsible for host-genetic influence on BC progression. From a clinical perspective, genetic variants that predispose to metastatic disease can serve as stratification variables in future clinical trials, particularly as the development of new treatment options for resistant BC is needed. Citation Format: Bachelot T, Lavergne E, Romieu G, Rios M, Heudel P-E, Roemer-Becuwe C, Jouannaud C, Tredan O, Chaigneau L, Arnedos M, Orfeuvre H, Petit T, Quenel-Tueux N, Jacquin J-P, Ferrero J-M, Moullet I, Abadie-Lacourtoisie S, Penault-Llorca F, Blanc E, Cox D. SToRM: A prospective clinical trial of 1502 metastatic breast cancer (mBC) patients with detail of clinical presentation, molecular subtype, treatment modalities, prognosis and GWAS genotyping. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-08-06.

Background: 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.

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.

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.

Background: Increased levels of CTC and a persistent elevated level after just one cycle of chemotherapy are very strong and independent markers of worse progression-free survival (PFS) and overall survival (OS) in patients (pts) with metastatic breast cancer (MBC) (Bidard et al, Lancet Oncol 2014). ctDNA can be used to detect mutation associated with resistance to treatment. It has also been shown that dynamic changes in ctDNA levels closely reflect changes in tumor burden. We prospectively monitored CTC and ctDNA early variations during first line chemotherapy for MBC. Patients & methods: The French cohort COMET is a prospective study including first line HER2 negative patients (pts) receiving weekly paclitaxel and bevacizumab according to EMA approved combination. The aim of this cohort is to evaluate clinical, biological and radiological parameters associated with pts outcome (CTC, serum markers, ctDNA, pharmacogenomic polymorphisms, metabolomic parameters, visceral fat, serum estradiol level and quality of life). We present here the first planned analysis on pts evaluated for CTC (CellSearch) and ctDNA using targeted sequencing (Roche SeqCap technology) of a panel of 46 genes and 8 promoters, using unique molecular identifiers to increase ctDNA detection sensitivity. Blood samples were obtained at baseline (BL) and before the second cycle of chemotherapy (C2). Results: From 09/2012 to 5/2014, 218 pts were included in this substudy. Median age was 55 years and 22% of pts had triple negative BC. At BL, 70% of pts had ≥1 detectable CTC per 7.5 ml of blood (median 4 CTC, range 1- 30,000) and 37% at C2. With a threshold of ≥5 CTC, 47% of pts were positive at BL and 22% at C2. For ctDNA, out of the first 141 pts analyzed, 105 had at least one somatic mutation detected in plasma (74%). The average number of mutations per pt was 2.7 and most commonly mutated genes were TP53 and PIK3CA. ESR1 was found mutated in 9% of all cases and restricted to the ER+ subgroup. Median Allelic Frequency was 10% (range 0.6-83%). Only 33% of pts had detectable ctDNA at C2. At BL, CTC and ctDNA levels were correlated (r=0.46, p Conclusion: This is the largest prospective cohort assessing the respective prognostic values of early CTC and ctDNA changes in homogenously treated first line MBC patients. Analysis of mutations profile variations and comparison with primary tumor and metastasis biopsies are ongoing and may reveal early mechanisms of resistance. Citation Format: Pierga J-Y, Silveira A, Lorgis V, Tanguy M-L, Tredan O, Dubot C, Jacot W, Goncalves A, Debled M, Levy C, Ferrero J-M, Jouannaud C, Luporsi E, Mouret-Reynier M-A, Dalenc F, Lemonnier J, Berger F, Proudon C, Bidard F-C. Circulating tumor DNA (ctDNA) and circulating tumor cells (CTC) predictive value in HER2 negative metastatic breast cancer patients treated with first line weekly paclitaxel and bevacizumab: Results of a prospective cohort from the French Breast Cancer InterGroup Unicancer (UCBG): COMET study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD2-03.

Resume Introduction Les valeurs pronostiques de l’hypertension et de la proteinurie des anti-VEGF (facteur de croissance endothelial vasculaire) n’ont pas encore ete evaluees dans la pratique clinique de routine dans le cancer du sein (CS). Les objectifs de l’etude MARS etaient d’apprecier la prevalence/incidence de la proteinurie et de l’hypertension a l’inclusion et durant le traitement par anti-VEGF, et de rechercher un lien potentiel avec la survie globale. Methodes Les patients naifs de tout anti-VEGF et debutant un traitement par anti-VEGF ont ete inclus dans 8 centres entre 2009 et 2011 avec une periode de suivi de 1 an. Les resultats du groupe de patientes atteintes de CS et traitees par bevacizumab sont presentes. Resultats Quatre cent deux patientes atteintes de CS et traitees par bevacizumab ont ete incluses. A l’inclusion, 12,4 % des patientes presentaient une hypertension, 23,9 % une proteinurie. Lors du suivi, l’incidence d’evenements de novo , proteinurie et hypertension, etait respectivement de 61,7 % et 16,8 %. Parmi les patientes avec une proteinurie de novo , 62,2 % l’ont amelioree ou normalisee par la suite. Aucune microangiopathie thrombotique n’a ete rapportee. A l’inclusion ou de novo , les analyses univariees/multivariees ont demontre que la proteinurie et l’hypertension n’etaient pas associees a la survie globale. Discussion Ces resultats montrent que la prevalence de l’hypertension et de la proteinurie a l’inclusion etait elevee et que les patientes traitees par bevacizumab developpaient frequemment une hypertension et/ou une proteinurie de novo . Enfin, ni l’hypertension ni la proteinurie, a l’inclusion ou de novo , n’etaient associees a la survie globale dans notre cohorte.

International audience; Aim: Women of reproductive age with breast cancer generally receive gonadotoxic chemotherapy. Fertility issues are of great concern for them. However, little is known on ovarian damage during chemotherapy and its evolution during long-term follow-up. The Anti-Mü llerian hormone; Ovarian reserve; Amenorrhea aim of this study was to provide a detailed description of serum anti-Mü llerian hormone (AMH) evolution during chemotherapy and 24-month follow-up.Methods: This prospective cohort study was conducted in 250 patients, aged 18e39 years, diagnosed with breast cancer and treated with adjuvant/neoadjuvant chemotherapy. Each patient underwent blood AMH measurement at each chemotherapy cycle, and at 6, 12 and 24 months after chemotherapy. Menses occurrence was also recorded.Results: Mean basal AMH level was 4.19 AE 4.84 ng/mL, and was negatively correlated with age. Serum AMH level rapidly decreased in all patients after each chemotherapy cycle to undetectable levels in most of them, and slowly increased in 45% of the patients during the 24-month follow-up. AMH decrease was significantly associated with age and basal AMH level, but not with cyclophosphamide dose and tamoxifen use. The prevalence of chemotherapy-related amenorrhoea was 92.4% at the end of chemotherapy; women with amenorrhoea being significantly older and having lower basal AMH than women who resumed menses.Conclusions: Our study confirms rapid and deep ovarian reserve alteration in young women receiving chemotherapy for breast cancer, and shows moderate AMH recovery in some patients. Although AMH cannot alone predict fertility potential, these new data emphasise the need for post-treatment ovarian insufficiency follow-up, strongly support the use of fertility preservation strategies and may provide new tools for improved counselling.

Human epidermal growth factor receptor 2-positive breast cancer is a subtype of interest regarding its outcome and the impressive impact of human epidermal growth factor receptor 2 targeted therapy. Constitutional variants may be involved in the aetiology of human epidermal growth factor receptor 2-positive breast cancer, and we propose a case–case study to test the hypothesis that single nucleotide polymorphisms may be associated with human epidermal growth factor receptor 2 status. A Genome-Wide Association Study was used in a cohort of 9836 patients from the SIGNAL/PHARE study (NCT00381901-RECF1098). The main goal was to identify variants specifically related to human epidermal growth factor receptor 2-positive breast cancer. A two-staged genotyping strategy was carried out to cover as large a proportion of the genome as possible. All subjects were genotyped using the Illumina HumanCore Exome chip set. Principal Components Analysis and k-means were then used to characterize the ancestry of the participants. A random sample of subjects from the main “European” cluster was genotyped with the Omni5 chip set. These data were then used to impute missing genotypes from the remaining subjects genotyped only using the HumanCore Exome array. From the 9836 patients, a total of 8703 cases including 3230 patients with human epidermal growth factor receptor 2-positive breast cancer were analyzed. Despite having 80% power to detect an odds ratio of 1.23 in this population, no variant achieved genome-wide significance for association with the occurrence of human epidermal growth factor receptor 2–positive breast cancer vs. any other subtype of breast tumour. Our study was unable to identify constitutional polymorphisms that are strongly associated with human epidermal growth factor receptor 2-positive status among breast cancer patients., Genetics: heredity does not explain HER2 expression A large gene-finding study failed to identify any hereditary factors linked to HER2 expression among women with breast cancer. A team in France led by Xavier Pivot from the University Hospital Center of Besançon, France, analyzed more than 500,000 single DNA letters from a cohort of 8703 patients with breast cancer, 3230 of whom had tumors with high expression of human epidermal growth factor receptor 2 (HER2) and are thus treated with for anti-HER2 targeted therapies. The researchers searched for DNA variants associated with HER2 status, but none reached the threshold for statistical significance. The findings reveal a high level of genetic diversity in women with HER2-positive breast cancer and suggest that HER2 amplification may have more to do with the intrinsic nature of the tumor than with the genetics of the patient.

Background Genome-wide association studies (GWAS) have to date identified 94 genetic variants (single nucleotide polymorphisms (SNPs)) associated with risk of developing breast cancer. A score based on the combined effect of the 94 risk alleles can be calculated to measure the global risk of breast cancer. We aimed to test the hypothesis that the 94-SNP-based risk score is associated with clinico-pathological characteristics, breast cancer subtypes and outcomes in early breast cancer. Methods A 94-SNP risk score was calculated in 8703 patients in the PHARE and SIGNAL prospective case cohorts. This score is the total number of inherited risk alleles based on 94 selected SNPs. Clinical data and outcomes were prospectively registered. Genotyping was obtained from a GWAS. Results The median 94-SNP risk score in 8703 patients with early breast cancer was 77.5 (range: 58.1–97.6). The risk score was not associated with usual prognostic and predictive factors (age; tumor, node, metastasis (TNM) status; Scarff-Bloom-Richardson grade; inflammatory features; estrogen receptor status; progesterone receptor status; human epidermal growth factor receptor 2 (HER2) status) and did not correlate with breast cancer subtypes. The 94-SNP risk score did not predict outcomes represented by overall survival or disease-free survival. Conclusions In a prospective case cohort of 8703 patients, a risk score based on 94 SNPs was not associated with breast cancer characteristics, cancer subtypes, or patients’ outcomes. If we hypothesize that prognosis and subtypes of breast cancer are determined by constitutional genetic factors, our results suggest that a score based on breast cancer risk-associated SNPs is not associated with prognosis. Trial registration PHARE cohort: NCT00381901, Sept. 26, 2006 – SIGNAL cohort: INCa RECF1098, Jan. 28, 2009 Electronic supplementary material The online version of this article (doi:10.1186/s13058-017-0888-4) contains supplementary material, which is available to authorized users.

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

11566 Background: CANTO (CANcer TOxicities - NCT01993498) is a French multicenter prospective longitudinal study dedicated to the quantification and characterization of side effects after treatment for patients with stage I-III breast cancer, and to the development of predictors of toxicities. Methods: The CANTO study has included > 12,000 patients, assessed at diagnosis, and 3-6 months (T0), 15 months (T12), and year 3 and 5 after treatment completion. In the current report, we focus on key toxicities at T0 and T12 according to chemotherapy (CT) administration. For each side effect, 4 populations were defined according to its occurrence at T0 and/or T12 (no/no, no/yes, yes/no, yes/yes). Results: We analyzed 4684 patients with T0 and T12 consolidated data. Median age at diagnosis was 57y (22-89). Patients (pts) had HR+/HER2-, HER2+ or triple negative tumors in 78.9%, 12.4% and 8.7% of cases, respectively. Overall, 2516 pts (53.7%) received CT. Most CT pts (81%) received a sequential anthracyclines– taxanes schedule. As an example, a high proportion of patients presented neurological symptoms including cognitive symptoms, sensory or motor neuropathy, paresthesia, headache, etc (all grades) at either T0 or T12. Overall, CT was strongly associated with neurotoxicity at all times (OR = 2.27, p < 0.0001). However, proportions of patients with neurological side effects changed between T0 and T12. The table shows the proportions of the 4 categories of pts in the CT and no CT groups. Furthermore, at T12, neurological symptoms remained more frequent in the CT group, whether pts had symptoms at T0 (CT vs no CT, 81% vs 77%, p = 0.007) or not (CT vs no CT, 41% vs 36%, p = 0.03). Similar temporal trends were observed (with specific percentages for each considered side effect) for detailed neurological toxicities, pain and joint/bone toxicity (stratified on endocrine therapy), gastro-intestinal, pulmonary and cardiac toxicities. Conclusions: Overall, symptoms burden is extremely high at T0 and T12 after treatment, and much higher in pts receiving CT. A high temporal variability was observed in all subsets, including a clinically meaningful delayed onset of e.g. neurological side effects. Clinical trial information: NCT01993498. [Table: see text]

1529 Background: Triple-negative breast cancers (TNBC) are a heterogeneous group of tumors with poor outcome. In this study, the association between germline genetic variants and invasive disease-free survival (iDFS) was analyzed in TNBC patients. Methods: A genome wide-association study (GWAS) aimed to identify variants (single nucleotide polymorphisms – SNPs) associated with prognosis in 1121 patients with TNBC in the SIGNAL prospective cohort. Associations between gene variants and iDFS were assessed in univariate Cox regression models. Variants were combined in a score to identify risk categories. A prognostic model based on breast cancer stage and genetic variants was estimated using a multivariate Cox regression. Interaction between stage and genetic score was tested. Discrimination of the model was assessed by the Harrell’s C statistic and internal validity by bootstrap method. Results: The characteristics of the 1121 patients were representative of a population with early TNBC. Four SNPs on chromosomes 9 and 2 were found significantly associated to iDFS in univariate Cox models. Homozygous status for the most frequent allele was associated with poorer iDFS for two SNPs and this status was present in 50% and 57% of the population. For the two other SNPs, the most frequent allele was associated with more favorable iDFS. Three prognostic categories were derived from the genetic score. The following table presents the results from the multivariate Cox model including genetic score and disease stage. Clinical trial information: RECF1098. Conclusions: In a prospective cohort of 1121 patients with early TNBC, 4 genetic variants (SNPs) were associated with iDFS. A score involving SNPs provided similar prognostic indications as breast cancer stages. A search assessing the function and the role of the involved genes is ongoing.[Table: see text]

3019 Background: Circulating Tumor Cells (CTC) are independent markers of progression-free survival (PFS) and overall survival (OS) in patients (pts) with 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, Circulating Endothelial Cells (CEC), serum markers 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).We present here the final planned analysis. Results: From 09/2012 to 11/2014, 286 patients were included: 198 for ctDNA, 251 for CEC and 283 for CTC. Median age was 56 years and 23% of pts had triple negative BC. At baseline, 71% of pts had ≥1 detectable CTC per 7.5 ml of blood (median 4 CTC, range 1- 30,000). With a threshold of ≥5 CTC, 49% of pts were positive at baseline and 22% at C2. For ctDNA, out of the first 196 pts analyzed, 147 had at least one somatic mutation (SNV) detected in plasma (75%). The average number of mutations per pt was 2.4 (range 1 to 9). Most commonly mutated genes were TP53 and GATA3. ESR1 was mutated in 10.6% of the pts and restricted to the ER+ subgroup. PIK3CA was mutated in 23.2% of the pts. Median Allelic Frequency was 9.1% . Only 68 pts (36%) had detectable ctDNA at C2. At baseline, CTC and ctDNA levels were correlated (r = 0.40, p < 0.0001). Despite no complete overlap, 24 pts (12%) had no CTC nor ctDNA detected at baseline. Median follow-up was 53 months and median OS was 32 months. Detectable CTC and ctDNA at baseline and at C2 were significantly associated with decreased PFS and OS. CEC and serum markers level had no prognostic value. At multivariate analysis, triple negative status, detectable ctDNA at C2, CTC ≥5 at C2 and grade 3 on primary tumor were independent prognostic factors. Conclusions: This is the largest prospective cohort assessing the respective prognostic values of early CTC and ctDNA changes in homogenously treated first line MBC pts. Early decrease of CTC and ctDNA after one cycle of chemotherapy are independent predictive markers of favorable outcome, with a stronger value for ctDNA compared to CTC. Clinical utility of early ctDNA variations monitoring and changes in mutation profile remain to be demonstrated. Clinical trial information: NCT01745757.

Background: Anti-VEGF drugs (AVD) are widely used in cancer patients (pts). Hypertension (HTN) and proteinuria (Pu) are class-side-effects of AVD, related to the inhibition of the VEGF pathway. The MARS study has been conducted to assess the renovascular tolerance of these drugs in the clinical setting. Methods: This multicentric, prospective, observational study evaluated the renovascular safety of AVD in pts naive from any AVD, conducted in 7 centres in France, from 2009 to 2012, with a follow-up (f/u) of 1 year. Data collected included: gender, age, serum creatinine (SCr), diabetes, HTN, hematuria (Hu) and dipstick Pu, at baseline and at each visit. Results: 1124 cancer pts were included; 402 breast cancer (BC) pts received bevacizumab (1st line: 14.4%; median durations of treatment: months)). Median age at inclusion was 55 years (19-65). Visceral, bone and cerebral metastasis frequencies were 74.7, 5.1 and 2.5%, respectively. HTN prevalences: 12.4%. Baseline renal assessment retrieved: Pu 23.9%, Hu 16.2%, mean aMDRD 96.4 ml/min/1.73m2 and 14 pts with aMDRD Conclusion: These results on the renovascular safety of bevacizumab in BC pts showed that 1) TMA is rare, 2) Grade 3 Pu developed in 4.6% of pts, with no grade 4, 3) less than 17% developed HTN, and 4) aMDRD was stable. Furthermore, in case of a renovascular effect, investigators followed the recommendations from the French Society of Nephrology (Halimi JM. Nephrol Ther 2008) and no treatment withdrawal for unmanageable renovascular toxicity occurred. Renovascular effects in MARS breast cancer patients treated with bevacizumabRenovascular effectsPrevalence at inclusionIncidence during follow-up (de novo**)Pu* (All grades)23.9%61.7%Pu* (Grade 1)22.2%47.1%Pu* (Grade 2)1.7%10.0%Pu* (Grade 3)0.0%4.6%Pu* (Grade 4)0.0%0.0%Hypertension12.4%16.8%Hu* (All Hu)16.2%42.1%Hu* (Traces/+)11.7%33.2%Hu* (++)2.6%6.3%Hu* (+++)1.9%2.6%SCr increase* (All grades)-80.0%SCr increase* (Grade 1)-68.6%SCr increase* (Grade 2)-7.1%SCr increase* (Grade 3)-0.3%*NCI-CTC v4; **de novo = patients with no event at inclusion and who presented an event during follow-up. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-15-06.

Background: TNBC is an heterogeneous group of tumors for some of which the Epithelial Growth Factor Receptor pathway (EGFR) may play an important role. We evaluated the efficacy and toxicity of an anti-EGFR antibody (panitumumab) combined with a standard neoadjuvant chemotherapy in order to identify predictive biomarkers of efficacy and target biologically defined subpopulations for potential further development. Methods: Sixty patients with stage II-IIIA disease were prospectively included in this multicentre neoadjuvant study. Systemic therapy (ST) consisted of panitumumab (9 mg/kg q.3 weeks x8) combined with FEC 100 (500/100/500 mg/m2q.3 weeks x4) followed by 4 cycles of T (100 mg/m2 q.3weeks x4). All patients underwent surgery at completion of ST. Paraffin-embedded and frozen samples were systematically collected before and after ST for biologic studies. Patients characteristics are as follows: mean age 50 [27–72]; median tumor size: 40 mm [20–120]; invasive ductal carcinoma: 96.7%; Scarff-Bloom-Richardson Grade III: 71.7%, grade II: 28.3%. Complete pathological response (pCR) rate was 52.3% [95% IC: 37.3–67.5] (Sataloff's classification) and 46.7% [95% IC: 31.6–61.4](Chevallier's classification). Conservative surgery was performed in 88% of cases. Skin toxicity was the main side-effect: Cutaneous toxicity grade IV: 5%, grade III: 30%, grade II: 20%. Neutropenia grade IV: 27%; febrile neutropenia: 5%. Infection: 0%. Hand-foot syndrome grade III: 3.3%. Ungueal toxicity grade III: 1.6%, grade II: 20%. Results: We performed a ROC curve to identify the best cut-off value for KI-67, EGFR, cytokeratin 5–6 and p53 in order to predict a pCR. Tumors with more than 40% of positive cells for KI-67 and tumors with a score for EGFR greater than 70 tend to be associated with pCR according to Chevallier's classification (p = 0.06). No predictive value was identified for Cytokeratin 5–6 and p53 (p = 0.61 and p = 0.27, respectively). Immunohistochemistry results show that two thirds of tumors have more than 40% of positive cells for KI-67 and that two thirds of tumors present a score for EGFR greater than 70. About half of the tumors express cytokeratin 5–6 and p53 (cut off: 1%). Chi-squared tests were performed to assess relations between cutaneous toxicities and pCR. The cutaneous toxicities were not predictive of pCR (p = 0.94) and no correlations were found with KI-67, EGFR, Cytokeratin 5–6 and p53. In terms of BRCA1 and BRCA2 status, 35 tumors were analysed so far: BRCA1: 6 mutations (17%); BRCA2 (30 patients): 1 mutation (3.3%). Conclusions: These results suggest the possibility to identify a subpopulation with high probability of pCR (KI-67 > 40%, EGFR score > 70). Further biological studies are ongoing and will be presented at the meeting, including EGFR polymorphisms, C-met, ALDH1, pCadherine and PTEN. This will help us further define subpopulations of TNBC patients, potential targets for antiEGFR development. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-20.

Background: Hypertension (HTN) and proteinuria (Pu) are class-side-effects of anti-VEGF drugs (AVD), related to the inhibition of the VEGF pathway. The MARS study has been conducted to assess the renovascular tolerance of these drugs in the clinical setting. Methods: The MARS study is a multicentric prospective observational study of the renovascular safety of AVD in AVD-naive patients. in 7 centres from 2009 to 2011. There was no intervention on the choice of the AVD. Data collected included: gender, age, serum creatinine (SCr), diabetes, HTN, hematuria (Hu) and dipstick Pu. This sub-group analysis presents the intermediate results for the first 184 patients with breast cancer (BC) receiving bevacizumab who completed the 1-year follow-up (f/u) (out of 337 BC patients in total). Results: All these 184 patients received bevacizumab (mean and median durations of treatment: 7.8 and 8 months, respectively). Median age at inclusion was 60 years. Bone, visceral and cerebral metastasis frequencies were 75.0, 52.2 and 7.1%, respectively. Diabetes and HTN prevalences were 4.3% and 10.3%, respectively. Baseline renal assessment retrieved: Pu 13.0%, Hu 8.2%, mean aMDRD 98.8 ml/min/1.73m2 and 1.1% had aMDRD Conclusion: These results show that 1) No thrombotic micro-angiopathy remains rare, 2) Pu developed in 16.3% of patients, with no grade 3/4, 3) less than 13% developed HTN, and 4) renal function was only slightly impaired with transient elevations in SCr. Furthermore, in case of a renovascular effect, investigators followed the recommendations from the French Society of Nephrology (Halimi JM et Al. Nephrol Ther 2008) and no treatment withdrawal for unmanageable renovascular toxicity occurred. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-17-04.

International audience; Genetic polymorphisms are associated with breast cancer risk. Clinical and epidemiological observations suggest that clinical characteristics of breast cancer, such as estrogen receptor or HER2 status, are also influenced by hereditary factors. To identify genetic variants associated with pathological characteristics of breast cancer patients, a Genome Wide Association Study was performed in a cohort of 9365 women from the French nationwide SIGNAL/PHARE studies (NCT00381901/RECF1098). Strong association between the FGFR2 locus and ER status of breast cancer patients was observed (ER-positive n=6211, ER-negative n=2516; rs3135718 OR=1.34 p=5.46x10-12). This association was limited to patients with HER2-negative tumors (ER-positive n=4267, ER-negative n=1185; rs3135724 OR=1.85 p=1.16x10-11). The FGFR2 locus is known to be associated with breast cancer risk. This study provides sound evidence for an association between variants in the FGFR2 locus and ER status among breast cancer patients, particularly among patients with HER2-negative disease. This refinement of the association between FGFR2 variants and ER-status to HER2-negative disease provides novel insight to potential biological and clinical influence of genetic polymorphisms on breast tumors.

Background Bevacizumab combined with paclitaxel as first-line chemotherapy for patients with HER2-negative metastatic breast cancer (MBC) has led to mixed results in randomized trials, with an improvement in progression-free survival (PFS) but no statistically significant overall survival (OS) benefit. Real-life data could help in assessing the value of this combination. Patients and methods This study aimed to describe the outcome following first-line paclitaxel with or without bevacizumab in the French Epidemiological Strategy and Medical Economics (ESME) database of MBC patients, established in 2014 by Unicancer. The primary and secondary end points were OS and PFS, respectively. Results From 2008 to 2013, 14 014 MBC patient files were identified, including 10 605 patients with a HER2-negative status. Of these, 3426 received paclitaxel and bevacizumab (2127) or paclitaxel (1299) as first-line chemotherapy. OS adjusted for major prognostic factors was significantly longer in the paclitaxel and bevacizumab group compared with paclitaxel [hazard ratio (HR) 0.672, 95% confidence interval (CI) 0.601–0.752; median survival time 27.7 versus 19.8 months]. Results were consistent in all supportive analyses (using a propensity score for adjustment and as a matching factor for nested case–control analyses) and sensitivity analyses. Similar results were observed for the adjusted PFS, favoring the combination (HR 0.739, 95% CI 0.672–0.813; 8.1 versus 6.4 months). Conclusions In this large-scale, real-life setting, patients with HER2-negative MBC who received paclitaxel plus bevacizumab as first-line chemotherapy had a significantly better OS and PFS than those receiving paclitaxel. Despite robust methodology, real-life data are exposed to important potential biases, and therefore, results need to be treated with caution. Our data cannot therefore support extension of current use of bevacizumab in MBC.