First-line real-world treatment patterns and survival outcomes in women younger or older than 40 years with metastatic breast cancer in the real-life multicenter French ESME cohort.

AIM: To describe first-line treatment patterns, overall survival (OS) and real-world progression-free survival (rwPFS) in young women (<40) with metastatic breast cancer (mBC), as compared to women aged 40-69. MATERIALS AND METHODS: Data on adult women diagnosed with mBC (2008-2017) were extracted from the ESME mBC database (NCT03275311) which includes consecutive patients starting first-line metastatic treatment in one of the 18 French Comprehensive cancer centers. We reported first-line therapeutic strategy and prognostic factors of OS and rwPFS for women aged < 40 and 40-69. RESULTS: In total, 14,897 mBC women were included (1512 aged <40). HR+ /HER2- mBC was the most frequent subtype. First-line treatment differed between young patients and older ones for HR+ /HER2- and Triple Negative (TN) mBC. Median OS for women aged < 40 and 40-69, respectively, was 46.9 and 46.2 months for HR+ /HER2- mBC; 13.5 and 15.2 for TN mBC; and, 60.7 and 55.1 for HER2 + mBC. Median rwPFS under first line treatment was 11.6 and 11.9 months for HR+ /HER2- in women aged < 40 and 40-69, respectively; 5.5 and 5.9 for TN, and, 13.3 and 12.9 for HER2 + . Factors associated with shorter OS and rwPFS were similar for both women aged < 40 and 40-69 and included ≥ 3 metastatic sites, visceral metastases, and longer MFI, with time-varying effects observed for several prognostic factors. CONCLUSION: Young women presented more frequently with TN and HER2 + subtypes and aggressive mBC than women aged 40-69 did. Prognostic factors of OS and rwPFS were quite similar between age groups and mBC subtypes.

Association between progression-free survival and overall survival in women receiving first-line treatment for metastatic breast cancer: evidence from the ESME real-world database.

BACKGROUND: Overall survival (OS) is the gold standard endpoint to assess treatment efficacy in cancer clinical trials. In metastatic breast cancer (mBC), progression-free survival (PFS) is commonly used as an intermediate endpoint. Evidence remains scarce regarding the degree of association between PFS and OS. Our study aimed to describe the individual-level association between real-world PFS (rwPFS) and OS according to first-line treatment in female patients with mBC managed in real-world setting for each BC subtype (defined by status for both hormone-receptor [HR] expression and HER2 protein expression/gene amplification). METHODS: We extracted data from the ESME mBC database (NCT03275311) which gathers deidentified data from consecutive patients managed in 18 French Comprehensive Cancer Centers. Adult women diagnosed with mBC between 2008 and 2017 were included. Endpoints (PFS, OS) were described using the Kaplan-Meier method. Individual-level associations between rwPFS and OS were estimated using the Spearman's correlation coefficient. Analyses were conducted by tumor subtype. RESULTS: 20,033 women were eligible. Median age was 60.0 years. Median follow-up duration was 62.3 months. Median rwPFS ranged from 6.0 months (95% CI 5.8-6.2) for HR-/HER2 - subtype to 13.3 months (36% CI 12.7-14.3) for HR + /HER2 + subtype. Correlation coefficients were highly variable across subtypes and first-line (L1) treatments. Among patients with HR - /HER2 - mBC, correlation coefficients ranged from 0.73 to 0.81, suggesting a strong rwPFS/OS association. For HR + /HER2 + mBC patients, the individual-level associations were weak to strong with coefficients ranging from 0.33 to 0.43 for monotherapy and from 0.67 to 0.78 for combined therapies. CONCLUSIONS: Our study provides comprehensive information on individual-level association between rwPFS and OS for L1 treatments in mBC women managed in real-life practice. Our results could be used as a basis for future research dedicated to surrogate endpoint candidates.

Early Locoregional Breast Surgery and Survival in de novo Metastatic Breast Cancer in the Multicenter National ESME Cohort.

OBJECTIVE: The aim was to evaluate the impact of local surgery performed during the year after MBC diagnosis on patients' outcomes from a large reallife cohort. SUMMARY BACKGROUND DATA: Locoregional treatment for patients with MBC at the time of diagnosis remains debated. METHODS: Women with newly diagnosed, de novo stage IV MBC and who started MBC treatment between January 2008 and December 2014 in one of the 18 French Comprehensive Cancer Centers were included (NCT03275311). The impact of local surgery performed during the first year on overall survival (OS) and progression-free survival (PFS) was evaluated by the Cox proportional hazards model in a 12 month-landmark analysis. RESULTS: Out of 16,703 patients in the ESME database, 1977 had stage IV MBC at diagnosis, were alive and progression-free at 12 months and eligible for this study. Among them, 530 (26.8%) had received primary breast cancer surgery within 12 months. A greater proportion of patients who received surgery had less than 3 metastatic sites than the no-surgery group (90.8% vs 78.2%, P < 0.0001). Surgery within 12 months was associated with treatment with chemotherapy, HER2-targeted therapy (89.1% vs 69.6%, P < 0.0001) and locoregional radiotherapy (81.7% vs 32.5%, P < 0.0001). Multivariable analyses showed that surgery performed within 12 months was associated with longer OS and PFS (adjusted HR [95%CI] = 0.75 [0.61-0.92] and 0.72 [0.63-0.83], respectively), which were also affected by pattern and number of metastatic sites, histological subtype, and age. CONCLUSIONS: In the large ESME cohort, surgery within 1 year after de novo MBC diagnosis was associated with a significantly better OS and PFS.

Comparison of Management and Outcomes in ERBB2-Low vs ERBB2-Zero Metastatic Breast Cancer in France.

Importance: ERBB2-low (ie, ERBB2 immunohistochemistry score of 1+ or 2+ in the absence of ERBB2 gene amplification) breast cancer (BC) is a new entity, with emerging dedicated treatments. Little is known about its prognosis and response to conventional therapy compared with ERBB2-zero breast tumors (ie, those with an immunohistochemistry score of 0). Objective: To compare the outcomes for patients with ERBB2-low metastatic BC (MBC) with those of patients with ERBB2-zero MBC. Design, Setting, and Participants: This cohort study was conducted from the Epidemiological Strategy and Medical Economics MBC platform and included patients with MBC treated between 2008 and 2016 in 18 French comprehensive cancer centers. The data analysis was conducted from July 16, 2020, to April 1, 2022. Main Outcomes and Measures: The main outcome was overall survival (OS), and the secondary outcome was progression-free survival under first-line treatments (PFS1). Results: The median (range) age was 60.0 (22.0-103.0) years. Among 15 054 patients with MBC, 4671 (31%) had ERBB2-low MBC and 10 383 (69%) had ERBB2-zero MBC. The proportion of ERBB2-low cancers was higher among patients with hormone receptor-positive MBC than those with hormone receptor-negative disease (4083 patients [33.0%] vs 588 patients [21.0%]). With a median follow-up of 49.5 months (95% CI, 48.6-50.4 months), the median OS of the ERBB2-low group was 38.0 months (95% CI, 36.4-40.5 months) compared with 33.9 months (95% CI, 32.9-34.9 months) for the ERBB2-zero group (P < .001). After adjustment for age, visceral metastases, number of metastatic sites, de novo disease, period of care, and hormone receptor status, patients with ERBB2-low MBC had slightly better OS compared with patients with ERBB2-zero MBC (adjusted hazard ratio, 0.95; 95% CI, 0.91-0.99; P = .02). In contrast, PFS1 did not differ by ERBB2 status (adjusted hazard ratio, 0.99; 95% CI, 0.95-1.02; P = .45). No significant differences in OS and PFS1 were observed in multivariate analyses by hormone receptor status and types of frontline treatment. Conclusions and Relevance: In this large cohort study, patients with ERBB2-low MBC had a slightly better OS than those with completely ERBB2-zero tumors, but identical PFS1, which could help guide treatment selection.

Efficacy of trastuzumab emtansine (T-DM1) and lapatinib after dual HER2 inhibition with trastuzumab and pertuzumab in patient with metastatic breast cancer: Retrospective data from a French multicenter real-life cohort.

PURPOSE: Trastuzumab-emtansine (T-DM1), as well as lapatinib plus capecitabine were proven effective in two Phase III studies, following first-line trastuzumab plus a taxane. The introduction of dual HER2 blockade by trastuzumab and pertuzumab as first-line has positioned T-DM1 into second-line, and lapatinib plus capecitabine beyond, without formal evaluation of these strategies. METHODS: ESME Data Platform (NCT03275311) included individual data from all patients aged ≥18 years, in whom first-line treatment for metastatic breast cancer (MBC) was initiated between January 1, 2008 and December 31, 2016 in one of the 18 French Comprehensive Cancer Centers. The efficacy of T-DM1 and lapatinib plus capecitabine combination, following double blockade associating trastuzumab and pertuzumab were evaluated in this national real-life database. Eligibility criteria were: female, MBC, HER2+ tumor, first-line taxane-based chemotherapy and dual HER2-blockage by trastuzumab plus pertuzumab. Cohort A received second-line T-DM1, and Cohort B second-line T-DM1 and third or fourth-line lapatinib plus capecitabine. RESULTS: Cohort A comprised 233 patients, and Cohort B 47 patients. Median progression-free survival (PFS) was 7.1 months in Cohort A and 4.6 months in Cohort B. Median overall survival were 36.7 months and 12.9 months, respectively. PFS was significantly dependent on the preceding treatment line's duration. In cohort A, HER2 expression status was a significant predictive factor of PFS. CONCLUSION: First-line trastuzumab plus pertuzumab do not markedly diminish T-DM1's efficacy in second-line. Similarly, sequential treatment with trastuzumab plus pertuzumab then T-DM1 does not noticeably modify the efficacy of lapatinib plus capecitabine.

Progression-free survival on endocrine therapy, before or after chemotherapy, in hormone receptor-positive HER2-negative metastatic breast cancer.

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

Impact of body mass index on overall survival in patients with metastatic breast cancer.

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.

Persistent taxane-induced neuropathy in elderly patients treated for localized breast cancer.

Breast cancer is the most common cancer among women. Localized breast cancer treatments involve taxanes which are often responsible for acute peripheral neuropathy. The persistence of taxane-induced peripheral neuropathy (TIPN) is scarcely described among elderly women. A monocenter historical cohort study including all women over 65 years of age treated between 2001 and 2016 with a taxane-based chemotherapy for localized breast cancer was carried out at the Paul Strauss Regional Comprehensive Cancer Center. All cases included were followed up for at least 2 years, deaths from causes unrelated to TIPN were excluded. We report on the frequency and risk factors and establish a prognostic score of persistent Common Terminology Criteria for Adverse Events (CTCAE) grade 2 and 3 TIPN. Among the 302 included patients, 21% and 9% developed persistent TIPN of grade 2 and 3, respectively. Two patients died from complications of grade 3 TIPN. Risk factors of persistent grade 2 and higher neuropathy included age (P < .0001), body mass index (P < .0001), and diabetes (P = .0093). Persistent TIPN was more frequent with paclitaxel than docetaxel (OR = 5.43; P < .0001). Patients presenting all four major risk factors had a 97.2% probability of developing long-term symptoms against 1.2% for patients showing no risk factor. We therefore identified 3 prognostic groups. TIPN is a frequent and sometimes severe persistent side effect of breast cancer treatment among elderly women with a major impact on health-related quality of life. Chemotherapy regimens without taxane could therefore be a valid option in elderly patients with neurotoxicity risk factors.

Palliative care delivery according to age in 12,000 women with metastatic breast cancer: Analysis in the multicentre ESME-MBC cohort 2008-2016.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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: ß = -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: ß = 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: ß = -0.03; 95% CI, -0.06 to -0.01). CONCLUSION: 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.

Real-world Evaluation of Oral Vinorelbine in the Treatment of Metastatic Breast Cancer: An ESME-MBC Study.

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.

Contemporary outcomes of metastatic breast cancer among 22,000 women from the multicentre ESME cohort 2008-2016.

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 < 0.0001) with a median OS of 43.3 (95% CI, 42.5-44.5) in HR+/HER2-; 50.1 (95% CI, 47.6-53.1) in HER2+; and 14.8 months (95% CI, 14.1-15.5) in triple-negative subgroups, respectively. Beyond performance status, the following variables had a constant significant negative prognostic impact on OS in the whole cohort and among subtypes: older age at diagnosis of metastases (except for the triple-negative subtype), metastasis-free interval between 6 and 24 months, presence of visceral metastases and number of metastatic sites ≥ 3. 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.

Management and outcome of male metastatic breast cancer in the national multicenter observational research program Epidemiological Strategy and Medical Economics (ESME).

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.

Bevacizumab plus neoadjuvant chemotherapy in patients with HER2-negative inflammatory breast cancer (BEVERLY-1): a multicentre, single-arm, phase 2 study.

BACKGROUND: Addition of bevacizumab to standard chemotherapy in the neoadjuvant setting in patients with HER2-negative metastatic breast cancer improves progression-free survival and the proportion of patients achieving pathological complete response. In the BEVERLY-1 (UCBG-0802) trial we aimed to assess the addition of bevacizumab to neoadjuvant and adjuvant chemotherapy in the treatment of patients with HER2-negative inflammatory breast cancer. METHODS: We did this phase 2, single-arm trial at 20 hospitals in France. We enrolled women aged 18 years or older who had non-metastatic HER2-negative inflammatory breast cancer. Patients underwent 3-week treatment cycles, receiving neoadjuvant intravenous fluorouracil (500 mg/m(2)), epirubicin (100 mg/m(2)), cyclophosphamide (500 mg/m(2)), and bevacizumab (15 mg/kg) during cycles 1-4, then docetaxel (100 mg/m(2)) and bevacizumab during cycles 5-8. 2-4 weeks after surgery, patients received adjuvant radiotherapy, hormone therapy (if they had a hormone receptor-positive tumour), and adjuvant intravenous bevacizumab. The primary endpoint was pathological complete response in breast and axillary lymph nodes after neoadjuvant treatment, determined after centralised review in accordance with Sataloff classification and assessed in the intention-to-treat population. Our analysis of toxic effects included all patients who received at least one dose of bevacizumab. The trial is complete and follow-up is ongoing. This study is registered with ClinicalTrials.gov, number NCT00820547. FINDINGS: Between Jan 16, 2009, and Sept 8, 2010, we enrolled 101 patients, one of whom withdrew consent before treatment, leaving 100 patients in the primary endpoint analysis. After neoadjuvant therapy, 19 (19% [95% CI 12-28]; p=0·16) of 100 patients achieved a pathological complete response according to centralised review. The most frequent grade 3-4 events during the neoadjuvant phase were neutropenia (89 [89%] of 100 patients), febrile neutropenia (37 [37%]), and mucositis (23 [23%]) and during the adjuvant phase the most frequent grade 3-4 adverse event was proteinuria (5 [7%] of 75 patients). One (1%) patient died of thrombotic microangiopathy after cycle 1, which was thought to be related to bevacizumab. Two patients (3%) developed transitory heart failure. 48 (48%) patients had serious adverse events, the most frequent of which was febrile neutropenia (28 [28%]). INTERPRETATION: Our results suggest that the addition of bevacizumab to neoadjuvant and adjuvant chemotherapy does not provide clinical benefit to patients with non-metastatic HER2-negative inflammatory breast cancer. Longer follow-up and correlative studies to identify patients who might benefit from bevacizumab are needed. FUNDING: Roche, La Ligue Nationale contre le Cancer, UNICANCER, and Chugai Pharma.

Diagnosis of pediatric gastric, small-bowel and colonic volvulus.

Digestive volvulus affects the stomach, small bowel and mobile segments of the colon and often has a developmental cause. Reference radiologic examinations include upper gastrointestinal contrast series for gastric volvulus, possibly with ultrasonography for small-bowel volvulus, and contrast enema for colonic volvulus. Treatment is usually surgical. This pictorial essay describes the embryological development and discusses the clinical and radiologic presentation of volvulus, depending on location, and details the appropriate radiologic examinations.

Semi-quantitative evaluation of estrogen receptor expression is a strong predictive factor of pathological complete response after anthracycline-based neo-adjuvant chemotherapy in hormonal-sensitive breast cancer.

Absence of hormonal receptors (HR) expression is a predictive factor of high pathologic complete response (pCR) rate after neo-adjuvant chemotherapy. However, HR-positive tumors are less chemosensitive. In the present study, we evaluated the predictive value of estrogen (ER) and progesterone (PgR) semi-quantitative expression in patients with HR-positive tumors treated uniformly with antracycline-based neoadjuvant chemotherapy without hormonal treatment. Value of HR expression as a predictive factor was then evaluated in a multivariate analysis with tumor grade, Ki67 index and HER2 expression. From January 2000 and December 2006, 177 patients with HR-positive breast ductal invasive carcinoma ≥2 cm in its largest diameter were treated with six cycles of an anthracycline-based neo-adjuvant chemotherapy. Tumor grade, ER, PgR, HER2 status and Ki67 index were determined on microbiopsy performed before chemotherapy. A semi-quantitative evaluation of ER and PgR expression by IHC was performed using the Barnes'score. pCR rate was significantly different (P < 0.001) according to the ER expression score. pCR rate was 28% for low score, 9% for medium score and 3% for high score. On the contrary, pCR rate was not significantly different (P = 0.49) according to the PgR expression score. In the multivariate analysis, ER expression score (P = 0.0002) and Ki67 index (P = 0.02) were the only predictive factors of response for HR-positive tumors. pCR after anthracycline-based chemotherapy is significantly correlated with the ER expression score.

Validation of gene signatures that predict the response of breast cancer to neoadjuvant chemotherapy: a substudy of the EORTC 10994/BIG 00-01 clinical trial.

BACKGROUND: We have previously described gene-expression signatures that predict growth inhibitory and cytotoxic effects of common chemotherapeutic drugs in vitro. The aim of this study was to confirm the validity of these gene-expression signatures in a large series of patients with oestrogen-receptor-negative breast tumours who were treated in a phase III neoadjuvant clinical trial. METHODS: This trial compares a non-taxane regimen (fluorouracil, epirubicin, and cyclophosphamide [FEC] for six cycles) with a taxane regimen (docetaxel for three cycles followed by epirubicin plus docetaxel [TET] for three cycles) in women with oestrogen-receptor-negative breast cancer. The primary endpoint of the study is the difference in progression-free survival based on TP53 status and will be reported later. Predicting response with gene signatures was a planned secondary endpoint of the trial and is reported here. Pathological complete response, defined as complete disappearance of the tumour with no more than a few scattered tumour cells detected by the pathologist in the resection specimen, was used to assess chemosensitivity. RNA was prepared from sections of frozen biopsies taken at diagnosis and hybridised to Affymetrix X3P microarrays. In-vitro single-agent drug sensitivity signatures were combined to obtain FEC and TET regimen-specific signatures. This study is registered on the clinical trials site of the US National Cancer Institute website http://www.clinicaltrials.gov/ct/show/NCT00017095. FINDINGS: Of 212 patients with oestrogen-receptor-negative tumours assessed, 87 patients were excluded. 125 oestrogen-receptor-negative tumours (55 that showed pathological complete responses) were tested: 66 in the FEC group (28 that showed pathological complete responses) and 59 in the TET group (27 that showed pathological complete responses). The regimen-specific signatures significantly predicted pathological complete response in patients treated with the appropriate regimen (p<0.0001). The FEC predictor had a sensitivity of 96% (27 of 28 patients [95% CI 82-99]), specificity of 66% (25 of 38 patients [50-79]), positive predictive value (PPV) of 68% (27 of 40 patients [52-80]), and negative predictive value (NPV) of 96% (25 of 26 patients [81-99]). The TET predictor had a sensitivity of 93% (25 of 27 patients [77-98]), specificity 69% (22 of 32 patients [51-82]), PPV of 71% (25 of 35 patients [55-84]), and NPV of 92% (22 of 24 patients [74-98]). Analysis of tumour size, grade, nodal status, age, and regimen-specific signatures showed that the genomic signatures were the only independent variables predicting pathological complete response at p<0.01. Selection of patients with these signatures would increase the proportion of patients with pathological complete responses from 44% to around 70% in the patients studied here. INTERPRETATION: We have validated the use of regimen-specific drug sensitivity signatures in the context of a multicentre randomised trial. The high NPV of both signatures may allow early selection of patients with breast cancer who should be considered for trials with new drugs.