Cetuximab versus methotrexate in first-line treatment of older, frail patients with inoperable recurrent or metastatic head and neck cancer (ELAN UNFIT): a randomised, open-label, phase 3 trial.

BACKGROUND: At present, there is no established standard treatment for frail older patients with recurrent or metastatic head and neck squamous cell carcinoma. We aimed to compare the efficacy and safety of cetuximab to those of methotrexate (the reference regimen) in this population. METHODS: This randomised, open-label, phase 3 trial was done at 20 hospitals in France. Patients aged 70 years or older, assessed as frail by the ELAN Geriatric Evaluation, with recurrent or metastatic head and neck squamous cell carcinoma in the first-line setting and with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were eligible for inclusion. Patients were randomly assigned (1:1) to receive cetuximab 500 mg/m2 intravenously every 2 weeks or methotrexate 40 mg/m2 intravenously every week, with minimisation by ECOG performance status, type of disease evolution, Charlson Comorbidity Index score, serum albumin concentration, and geriatrician consultation. To avoid deterministic minimisation and assure allocation concealment, patients were allocated with a probability of 0·80 to the treatment that most reduced the imbalance. Treatment was continued until disease progression or unacceptable toxicity, whichever occurred first. The primary endpoint was failure-free survival (defined as the time from randomisation to disease progression, death, discontinuation of treatment, or loss of 2 or more points on the Activities in Daily Living scale, whichever occurred first) and was analysed in the intention-to-treat population. 151 failures expected out of 164 patients were required to detect a hazard ratio (HR) of 0·625 with 0·05 alpha error, with 80% power. A futility interim analysis was planned when approximately 80 failures were observed, based on failure-free survival. Safety analyses included all patients who received at least one dose of the study drug. This study is registered on ClinicalTrials.gov (NCT01884623) and was stopped for futility after the interim analysis. FINDINGS: Between Nov 7, 2013, and April 23, 2018, 82 patients were enrolled (41 to the cetuximab group and 41 to the methotrexate group); 60 (73%) were male, 37 (45%) were aged 80 years or older, 35 (43%) had an ECOG performance status of 2, and 36 (44%) had metastatic disease. Enrolment was stopped for futility at the interim analysis. At the final analysis, median follow-up was 43·3 months (IQR 30·8-52·1). At data cutoff, all 82 patients had failure; failure-free survival did not differ significantly between the groups (median 1·4 months [95% CI 1·0-2·1] in the cetuximab group vs 1·9 months [1·1-2·6] in the methotrexate group; adjusted HR 1·03 [95% CI 0·66-1·61], p=0·89). The frequency of patients who had grade 3 or worse adverse events was 63% (26 of 41) in the cetuximab group and 73% (30 of 41) in the methotrexate group. The most common grade 3-4 adverse events in the cetuximab group were fatigue (four [10%] of 41 patients), lung infection (four [10%]), and rash acneiform (four [10%]), and those in the methotrexate group were fatigue (nine [22%] of 41), increased gamma-glutamyltransferase (seven [17%]), natraemia disorder (four [10%]), anaemia (four [10%]), leukopenia (four [10%]), and neutropenia (four [10%]). The frequency of patients who had serious adverse events was 44% (18 of 41) in the cetuximab group and 39% (16 of 41) in the methotrexate group. Four patients presented with a fatal adverse event in the cetuximab group (sepsis, decreased level of consciousness, pulmonary oedema, and death of unknown cause) as did two patients in the methotrexate group (dyspnoea and death of unknown cause). INTERPRETATION: The study showed no improvement in failure-free survival with cetuximab versus methotrexate. Patients with an ECOG performance status of 2 did not benefit from these systemic therapies. New treatment options including immunotherapy should be explored in frail older patients with recurrent or metastatic head and neck squamous cell carcinoma, after an initial geriatric evaluation, such as the ELAN Geriatric Evaluation. FUNDING: French programme PAIR-VADS 2011 (sponsored by the National Cancer Institute, the Fondation ARC and the Ligue Contre le Cancer), GEMLUC, GEFLUC, and Merck Santé. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Observational, prospective, phase 4 study in patients with first-line recurrent and/or metastatic squamous cell carcinoma of the head and neck treated with cetuximab and platinum-based therapy: DIRECT.

BACKGROUND: Cetuximab plus platinum-based therapy (PBT) followed by cetuximab maintenance until progression (EXTREME) is a guideline-recommended first-line treatment option in recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). DIRECT (Dose Intensity RElative to CeTuximab) was the first phase 4 observational study evaluating EXTREME administration in the real-world setting. AIMS: The primary aim of this study was to assess the relative dose intensity of cetuximab in patients with R/M SCCHN treated with first-line cetuximab according to the EXTREME regimen. METHODS AND RESULTS: Patients were ≥18 years old and eligible to receive cetuximab/PBT. Primary endpoint was cetuximab relative dose intensity (RDI). Of prospectively enrolled patients (n = 157), 119 received ≥1 cycle of EXTREME. Practices differing from the EXTREME trial were 5-fluorouracil omission (14%), maintenance cetuximab given every other week (54%), prior cetuximab, disease-free interval <6 months. 64% of patients reached cetuximab RDI ≥80%; mean cetuximab RDI was 88%. 46% of patients received maintenance cetuximab (mean RDI, 91%). Median progression-free survival and overall survival were 4.5 and 9.4 months. No new/unexpected safety findings were observed. CONCLUSIONS: The DIRECT study showed that first-line cetuximab plus PBT was a feasible, beneficial first-line treatment regimen in patients with R/M SCCHN in the real-world setting.

Non-pegylated liposomal doxorubicin (NPLD, Myocet®) + carboplatin in patients with platinum sensitive ovarian cancers: A ARCAGY-GINECO phase IB-II trial.

BACKGROUND: Carboplatin and pegylated liposomal doxorubicin combination is a standard regimen in platinum-sensitive recurrent ovarian cancer patients. The pegylated liposomal doxorubicin shortage from 2011 to 2013 urged assessment of the efficacy and tolerance of non-pegylated liposomal doxorubicin in combination with carboplatin. METHODS: MYCA was a multicenter 2-step phase Ib-II single arm trial meant to assess the safety and efficacy of carboplatin AUC 5 mg/min.mL combined with non-pegylated liposomal (dose escalation from 40 to 50 mg/m2 during phase Ib step; and 50 mg/m2 during phase II step), every 4 weeks in patients with platinum-sensitive relapse. The primary objective was disease control rate (DCR) at 12 months. RESULTS: From 2012 to 2014, 87 patients were enrolled. They were treated as second (78%) or third line (22%) treatment. Total of 67 patients (78%) completed 6 cycles. G-CSF support was prescribed to 58% patients. The DCR at 12 months was 30.0% (95% CI, 20.3-39.7); the median PFS was 10.0 months (95% CI, 8.6-11.0). The median overall survival was 28.1 months (95% CI, 22.3-32.5); and the objective response rate was 58% (95% CI, 47-68). Grade 3-4 neutropenia, anemia and thrombocytopenia were observed in 17%, 13% and 1%, respectively; febrile neutropenia in 6%. One patient who did not receive GCSF support died from febrile neutropenia. CONCLUSION: Non-pegylated liposomal doxorubicin-carboplatin combination exhibits an acceptable safety profile, with GCSF prophylaxis. Acknowledging the lack of direct comparison, efficacy in terms of 12 month DCR was comparable with standard treatments.

Induction chemotherapy followed by either chemoradiotherapy or bioradiotherapy for larynx preservation: the TREMPLIN randomized phase II study.

PURPOSE: To compare the efficacy and safety of induction chemotherapy (ICT) followed by chemoradiotherapy (CRT) or bioradiotherapy (BRT) for larynx preservation (LP). PATIENTS AND METHODS: Previously untreated patients with stage III to IV larynx/hypopharynx squamous cell carcinoma received three cycles of ICT-docetaxel and cisplatin 75 mg/m(2) each on day 1 and fluorouracil 750 mg/m(2) per day on days 1 through 5. Poor responders (< 50% response) underwent salvage surgery. Responders (≥ 50% response) were randomly assigned to conventional radiotherapy (RT; 70 Gy) with concurrent cisplatin 100 mg/m(2) per day on days 1, 22, and 43 of RT (arm A) or concurrent cetuximab 400 mg/m(2) loading dose and 250 mg/m(2) per week during RT (arm B). Primary end point was LP at 3 months. Secondary end points were larynx function preservation (LFP) and overall survival (OS) at 18 months. RESULTS: Of the 153 enrolled patients, 116 were randomly assigned after ICT (60, arm A; 56, arm B). Overall toxicity of both CRT and BRT was substantial following ICT. However, treatment compliance was higher in the BRT arm. In an intent-to-treat analysis, there was no significant difference in LP at 3 months between arms A and B (95% and 93%, respectively), LFP (87% and 82%, respectively), and OS at 18 months (92% and 89%, respectively). There were fewer local treatment failures in arm A than in arm B; salvage surgery was feasible in arm B only. CONCLUSION: There is no evidence that one treatment was superior to the other or could improve the outcome reported with ICT followed by RT alone (French Groupe Oncologie Radiothérapie Tête et Cou [GORTEC] 2000-01 trial [Induction CT by Cisplatin, 5FU With or Without Docetaxel in Patients With T3 and T4 Larynx and Hypopharynx Carcinoma]). The protocol that can best compare with RT alone after ICT is still to be determined.

Elevated HER2 extracellular domain level in primary breast cancer with HER2 overexpression predicts early failure of adjuvant trastuzumab.

AIM: To investigate in a prospective study the prognostic value of serum HER2 extracellular domain (ECD) level in patients with primary breast cancer overexpressing HER2 treated with adjuvant chemotherapy and trastuzumab. PATIENTS AND METHODS: All the patients treated for primary breast cancer with chemotherapy and adjuvant trastuzumab from April 1, 2005 to December 31, 2006 at the Centre de Lutte Contre le Cancer de Haute Normandie were enrolled in this prospective study. HER2 ECD was measured in frozen serum by a commercial kit with a cut-off value of 15 ng/ml. RESULTS: Sixty-five patients were enrolled. Seven patients (11%) had an elevated serum HER2 ECD level (mean=25.1 ng/ml, range 15.1-38.9 ng/ml). During follow-up, 13 patients (20%) developed metastases and seven patients (11%) died. Death was related to breast cancer metastases in six patients (9%). Out of the seven patient with elevated serum HER2 ECD level, five (71%) developed metastases and three (43%) died of metastases during follow-up. Multivariate analysis showed that elevated serum HER2 ECD level was the unique factor for both disease-free survival (p<0.0006) and overall survival (p=0.008) in this series. CONCLUSION: Elevated serum HER2 ECD level is a strong prognostic factor in primary breast cancer overexpressing HER2 treated with adjuvant therapy of trastuzumab. In addition, our results suggest that it could predict failure of adjuvant therapy of trastuzumab.

Ovarian cancer: Stat3, RhoA and IGF-IR as therapeutic targets.

Seeking to improve ovarian cancer therapy, we compared biological characteristics of the moderately-aggressive OVCAR-3 cell line with two highly aggressive ovarian cancer cell populations: the SK-OV-3 cell line, and HASCJ primary cells isolated from the ascitic fluid of a patient with FIGO stage IV ovarian cancer. Secretion of angiogenic factors was not discriminative, whereas cell invasion through Matrigel and vasculogenic mimicry were much greater in the more aggressive cells. Among 10 agents tested for their ability to decrease cancer cell aggressivity using these two models, inhibitors of Stat3, IGF-IR and Rho GTPase were found to be the most promising.

Intratumoural level of SDF-1 correlates with survival in head and neck squamous cell carcinoma.

The SDF-1/CXCR4 pathway has been suggested to play a role in the metastatic dissemination of various tumours. We assessed the prognostic impact of SDF-1 and CXCR4 expression in head and neck squamous cell carcinoma (HNSCC). Seventy-one HNSCC samples collected at the time of initial diagnosis were retrospectively analysed. SDF-1 and CXCR4 expression levels were measured using real-time RT-PCR and correlated to survival. After a median follow-up of 45 months, 25 patients (35%) died of cancer (group D), and 46 patients (65%) were alive or dead without evidence of HSNCC evolution (group A). The median level of CXCR4 expression was 0.33 and 0.29 in groups A and D, respectively (P=0.93), showing no correlation with recurrence or survival. By contrast, the median level of SDF-1 expression was significantly different in the A and D groups (2.41 vs 1.16, respectively, P=0.018). Using the median level as a cut-off, patients with low SDF-1 had poorer metastasis-free (P=0.026), disease-free (P=0.006) and overall specific survival rates (P=0.002). The prognostic value of SDF-1 was confirmed by a multivariate analysis. In this series of 71 HNSCC patients, the SDF-1 expression level correlated significantly with metastatic evolution and overall survival.

TP53 status for prediction of sensitivity to taxane versus non-taxane neoadjuvant chemotherapy in breast cancer (EORTC 10994/BIG 1-00): a randomised phase 3 trial.

BACKGROUND: TP53 has a crucial role in the DNA damage response. We therefore tested the hypothesis that taxanes confer a greater advantage than do anthracyclines on breast cancers with mutated TP53 than in those with wild-type TP53. METHODS: In an open-label, phase 3 study, women (age <71 years) with locally advanced, inflammatory, or large operable breast cancers were randomly assigned in a 1:1 ratio to either a standard anthracycline regimen (six cycles of intravenous fluorouracil 500 mg/m², epirubicin 100 mg/m², and cyclophosphamide 500 mg/m² every 21 days [FEC100], or fluorouracil 600 mg/m², epirubicin 75 mg/m², cyclophosphamide 900 mg/m² [tailored FEC] starting on day 1 and then every 21 days) or a taxane-based regimen (three cycles of docetaxel 100 mg/m², intravenously infused over 1 h on day 1 every 21 days, followed by three cycles of intravenous epirubicin 90 mg/m² and docetaxel 75 mg/m² on day 1 every 21 days [T-ET]) at 42 centres in Europe. Randomisation was by use of a minimisation method that stratified patients by institution and initial tumour stage. The primary endpoint was progression-free survival (PFS) according to TP53 status. Analysis was by intention to treat. This is the final analysis of this trial. The study is registered with ClinicalTrials.gov, number NCT00017095. FINDINGS: 928 patients were enrolled in the FEC group and 928 in the T-ET group. TP53 status was not assessable for 183 (20%) patients in the FEC group and 204 (22%) patients in the T-ET group mainly because of low tumour-cell content in the biopsy. 361 primary endpoint events were recorded in the FEC group and 314 in the T-ET group. In patients with TP53-mutated tumours, 5-year PFS was 59·5% (95% CI 53·4-65·1) in the T-ET group (n=326) and 55·3% (49·2-60·9) in the FEC group (n=318; hazard ratio 0·84, 98% CI 0·63-1·14; p=0·17). In patients with TP53 wild-type tumours, 5-year PFS was 66·8% (95% CI 61·4-71·6) in the T-ET group (n=398) and 64·7% (59·6-69·4) in the FEC group (n=427; 0·89, 98% CI 0·68-1·18; p=0·35). For all patients, irrespective of TP53 status, 5-year PFS was 65·1% (95% CI 61·6-68·3) in the T-ET group and 60·8% (57·3-64·2) in the FEC group (0·85, 98% CI 0·71-1·02; p=0·035). At the sites using FEC100 versus T-ET, the most common grade 3 or 4 adverse events were febrile neutropenia (75 [9%] of 803 vs 173 [21%] of 809, respectively), and neutropenia (653 [81%] vs 730 [90%], respectively). At the sites using tailored FEC versus T-ET, the most common grade 3 or 4 adverse events were febrile neutropenia (ten [8%] of 118 vs 26 [22%] of 116, respectively), and neutropenia (100 [85%] vs 115 [99%], respectively). Two patients died of toxicity during or within 30 days of chemotherapy completion and without disease relapse (one in each group). INTERPRETATION: Although TP53 status was prognostic for overall survival, it was not predictive of preferential sensitivity to taxanes. TP53 status tested by use of the yeast assay in this patient population cannot be used to select patients for an anthracycline-based chemotherapy versus a taxane-based chemotherapy. FUNDING: US National Cancer Institute, La Ligue Nationale Contre le Cancer, European Union, Pharmacia, and Sanofi-Aventis.

Clinical Improvement and Prolonged Survival With High Dose Intrathecal Methotrexate for Carcinomatous Meningitis Secondary to a Lung Adenocarcinoma.

Carcinomatous meningitis (CM) is a devastating complication of advanced cancers. No standard treatment is available for CM secondary to solid tumors. In particular, very few data have been published for CM related to lung adenocarcinoma. Herein we report the case of a 39-year old woman treated for a metastatic lung adenocarcinoma, without EGFR mutation, complicated by a CM. Intrathecal administrations of high dose methotrexate produced both a clinical improvement of symptoms related to CM and an unusually delayed survival.

Impact of liposomal doxorubicin-based adjuvant chemotherapy on autonomy in women over 70 with hormone-receptor-negative breast carcinoma: A French Geriatric Oncology Group (GERICO) phase II multicentre trial.

RATIONALE: Breast cancer is a disease of ageing. Functional independence in elderly patients, measured with the Katz activities of daily living (ADL) scale, predicts overall survival and the need for welfare support. Few prospective studies have examined the feasibility of adjuvant chemotherapy and its impact on autonomy in women over 70 years of age with high-risk breast cancer. This multicentre phase II trial was designed to assess the impact of adjuvant anthracycline-based chemotherapy on these patients' autonomy. DESIGN AND METHODS: In a two-stage Fleming design, women aged ≥70 years with histologically proven hormone-receptor-negative early breast cancer and a significant risk of recurrence (pN+ or "high risk" pN0) received 4 cycles of nonpegylated liposomal doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) every 3 weeks postoperatively, on an outpatient basis. The primary endpoint was the change in the ADL score during chemotherapy. Secondary endpoints include comprehensive geriatric, quality-of-life and acceptability assessments, tolerability, and long-term outcome. The results for the primary endpoint and other scales at completion of adjuvant chemotherapy are reported here, while long-term follow-up is not yet complete. RESULTS: Forty patients (median age 75 [70-82]) were enrolled between February 2006 and November 2007. Chemotherapy had no deleterious impact on ADL, cognition, mental status, or the frequency of comorbidities. In contrast, the number of patients at risk of malnutrition, based on the Mini Nutritional Assessment, more than doubled between baseline and the end of chemotherapy, rising from 15% to 38%. Quality-of-life deteriorated in terms of social and role functioning, likely owing to fatigue, loss of appetite, nausea and vomiting. Treatment acceptability was good. The main adverse effect was neutropenia, 15% of the patients experiencing febrile neutropenia. No cardiac toxicity or toxic deaths occurred. CONCLUSION: This study demonstrates the feasibility of an adjuvant chemotherapy regimen combining nonpegylated liposomal doxorubicin and cyclophosphamide in fit elderly women <85 years with breast cancer. Although chemotherapy had an impact on social and role functioning, autonomy was not impaired and toxicity was acceptable. Special attention should be paid to nutritional status before and after treatment.

Stimulation of angiogenesis resulting from cooperation between macrophages and MDA-MB-231 breast cancer cells: proposed molecular mechanism and effect of tetrathiomolybdate.

BACKGROUND: Infiltration by macrophages (Mphi) indicates a poor prognosis in breast cancers, in particular by inducing angiogenesis. Our study aimed 1) to investigate the mechanism by which cooperation between Mphi and aggressive breast cancer cells (MDA-MB-231) induces angiogenesis; 2) to examine the effect of tetrathiomolybdate (TM) on this angiogenic activity. METHODS: Mphi coincubated with MDA-MB-231 were used as a model to mimic the inflammatory microenvironment. Angiogenesis induced by the culture media was tested in the chick chorioallantoic membrane (CAM). Mphi phenotype was evaluated by 1) expression of the M1 marker CD80, and secretion of interleukin 10 (IL-10), an M2 marker; 2) capacity to secrete Tumour Necrosis Factor alpha (TNFalpha) when stimulated by lipopolysaccharide/interferon gamma (LPS/IFNgamma); 3) ability to induce MDA-MB-231 apoptosis. To explore the molecular mechanisms involved, cytokine profiles of conditioned media from MDA-MB-231, Mphi and the coculture were characterised by an antibody cytokine array. All experiments were carried out both in presence and in absence of TM. RESULTS: Incubation of Mphi with MDA-MB-231 induced a pro-angiogenic effect in the CAM. It emerged that the angiogenic activity of the coculture is due to the capacity of Mphi to switch from M1 Mphi towards M2, probably due to an increase in Macrophage Colony Stimulating Factor. This M1-M2 switch was shown by a decreased expression of CD80 upon LPS/IFNgamma stimulation, an increased secretion of IL-10, a decreased secretion of TNFalpha in response to LPS/IFNgamma and an inability to potentiate apoptosis. At the molecular level, the angiogenic activity of the coculture medium can be explained by the secretion of CXC chemokines/ELR+ and CC chemokines. Although TM did not modify either the M2 phenotype in the coculture or the profile of the secreted chemokines, it did decrease the angiogenic activity of the coculture medium, suggesting that TM inhibited angiogenic activity by interfering with the endothelial cell signalling induced by these chemokines. CONCLUSIONS: Cooperation between Mphi and MDA-MB-231 transformed M1 Mphi to an angiogenic, M2 phenotype, attested by secretion of CXC chemokines/ELR+ and CC chemokines. TM inhibited this coculture-induced increase in angiogenic activity, without affecting either Mphi phenotype or cytokine secretion profiles.

Clinical improvement and survival in breast cancer leptomeningeal metastasis correlate with the cytologic response to intrathecal chemotherapy.

Leptomeningeal meningitis occurs in approximately 5% of metastatic breast cancers, and there is no standard treatment for this complication. We retrospectively analyzed the clinical data and cerebrospinal fluid of 24 patients treated with high-dose intrathecal methotrexate for breast cancer leptomeningeal meningitis (BLM). Cytologic response (CSF cytology without neoplastic cells after treatment) was observed in 11 patients (46%) and related to survival (P = 0.005). In addition, clinical symptoms improved in all 11 patients who had a cytologic response and in 7 patients (54%) without cytologic response (P = 0.02). The predictive value of cytologic response needs further confirmation. Cytologic response could be helpful in the management of intrathecal chemotherapy in patients with BLM.

A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer.

To better understand the relationship between tumor-host interactions and the efficacy of chemotherapy, we have developed an analytical approach to quantify several biological processes observed in gene expression data sets. We tested the approach on tumor biopsies from individuals with estrogen receptor-negative breast cancer treated with chemotherapy. We report that increased stromal gene expression predicts resistance to preoperative chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide (FEC) in subjects in the EORTC 10994/BIG 00-01 trial. The predictive value of the stromal signature was successfully validated in two independent cohorts of subjects who received chemotherapy but not in an untreated control group, indicating that the signature is predictive rather than prognostic. The genes in the signature are expressed in reactive stroma, according to reanalysis of data from microdissected breast tumor samples. These findings identify a previously undescribed resistance mechanism to FEC treatment and suggest that antistromal agents may offer new ways to overcome resistance to chemotherapy.

CXCR4 membrane expression in node-negative breast cancer.

CXC chemokine receptor 4 (CXCR4) has been reported to be involved in organ-specific homing of breast cancer-derived metastasis. We investigated CXCR4 expression by immunohistochemistry as a possible new prognostic factor for primary breast cancer. Two groups of women treated for breast cancer in 1991 at the Centre for the fight against cancer of Upper Normandy-France (Centre de Lutte contre le Cancer de Haute Normandie) were assessed retrospectively. CXCR4 expression was evaluated using standard immunohistochemistry. Usual prognostic factors were recorded in the computer database. Final date of follow-up was December 31, 2001. Tissues were available for 110 node-positive and 84 node-negative breast cancer patients treated in 1991. CXCR4 membrane staining was considered a strong prognostic factor for both 10-year metastasis-free- (p < 0.0001) and overall survival (p < 0.0001) in node-negative but not in node-positive breast cancer patients. CXCR4 cytoplasmic staining was not considered a significant prognostic factor. Our results suggest that CXCR4 membrane staining could be considered a new prognostic factor. Moreover, targeting CXCR4 in primary breast cancer patients may be a new therapeutic concept. However, these results warrant further investigation.

Anti-tumor activity of capecitabine and vinorelbine in patients with anthracycline- and taxane-pretreated metastatic breast cancer: findings from the EORTC 10001 randomized phase II trial.

The aim of this randomized phase II study was to evaluate the anti-tumor activity and safety of capecitabine and vinorelbine in patients with metastatic breast cancer pretreated with taxanes and anthracyclines. We planned to randomize 72 patients to capecitabine 1250 mg/m(2) orally bid days 1-14 or vinorelbine 30 mg/m(2) i.v. days 1 and 8, both given every 3 weeks. The study was stopped due to poor accrual with 47 patients enrolled. Responses were seen in 2/23 patients treated with capecitabine (8.7%; 95% CI 1.1-29.0) and 3/24 patients treated with vinorelbine (12.5%; 95% CI 2.7-32.4). Median progression-free survival was 2.8 and 2.6 months, and median overall survival was 9.3 and 11.0 months, in the capecitabine and vinorelbine arms, respectively. There was more hematologic toxicity, neurotoxicity, and nausea/vomiting with vinorelbine and more diarrhea and hand-foot syndrome with capecitabine. The anti-tumor activity of capecitabine and vinorelbine seems to be comparable, but the toxicity profiles are different.

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.