Prognostic value of EndoPredict test in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative primary breast cancer screened for the randomized, double-blind, phase III UNIRAD trial.

BACKGROUND: The purpose of this study was to evaluate the prognostic value of the multigene EndoPredict test in prospectively collected data of patients screened for the randomized, double-blind, phase III UNIRAD trial, which evaluated the addition of everolimus to adjuvant endocrine therapy in high-risk, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer. PATIENTS AND METHODS: Patients were classified into low or high risk according to the EPclin score, consisting of a 12-gene molecular score combined with tumor size and nodal status. Association of the EPclin score with disease-free survival (DFS) and distant metastasis-free survival (DMFS) was evaluated using Kaplan-Meier estimates. The independent prognostic added value of EPclin score was tested in a multivariate Cox model after adjusting on tumor characteristics. RESULTS: EndoPredict test results were available for 768 patients: 663 patients classified as EPclin high risk (EPCH) and 105 patients as EPclin low risk (EPCL). Median follow-up was 70 months (range 1-172 months). For the 429 EPCH randomized patients, there was no significant difference in DFS between treatment arms. The 60-month relapse rate for patients in the EPCL and EPCH groups was 0% and 7%, respectively. Hazard ratio (HR) supposing continuous EPclin score was 1.87 [95% confidence interval (CI) 1.4-2.5, P < 0.0001]. This prognostic effect remained significant when assessed in a Cox model adjusting on tumor size, number of positive nodes and tumor grade (HR 1.52, 95% CI 1.09-2.13, P = 0.0141). The 60-month DMFS for patients in the EPCL and EPCH groups was 100% and 94%, respectively (adjusted HR 8.10, 95% CI 1.1-59.1, P < 0.0001). CONCLUSIONS: The results confirm the value of EPclin score as an independent prognostic parameter in node-positive, hormone receptor-positive, HER2-negative early breast cancer patients receiving standard adjuvant treatment. EPclin score can be used to identify patients at higher risk of recurrence who may warrant additional systemic treatments.

Need for risk-adapted therapy for malignant ovarian germ cell tumors: A large multicenter analysis of germ cell tumors' patients from French TMRG network.

BACKGROUND: Malignant ovarian germ cell tumors are rare tumors, affecting young women with a generally favorable prognosis. The French reference network for Rare Malignant Gynecological Tumors (TMRG) aims to improve their management. The purpose of this study is to report clinicopathological features and long-term outcomes, to explore prognostic parameters and to help in considering adjuvant strategy for stage I patients. PATIENTS AND METHODS: Data from patients with MOGCT registered among 13 of the largest centers of the TMRG network were analyzed. We report clinicopathological features, estimated 5-year event-free survival (5y-EFS) and 5-year overall survival (5y-OS) of MOGCT patients. RESULTS: We collected data from 147 patients including 101 (68.7%) FIGO stage I patients. Histology identifies 40 dysgerminomas, 52 immature teratomas, 32 yolk sac tumors, 2 choriocarcinomas and 21 mixed tumors. Surgery was performed in 140 (95.2%) patients and 106 (72.1%) received first line chemotherapy. Twenty-two stage I patients did not receive chemotherapy. Relapse occurred in 24 patients: 13 were exclusively treated with upfront surgery and 11 received surgery and chemotherapy. 5y-EFS was 82% and 5y-OS was 92.4%. Stage I patients who underwent surgery alone had an estimated 5y-EFS of 54.6% and patients receiving adjuvant chemotherapy 94.4% (P < .001). However, no impact on estimated 5y-OS was observed: 96.3% versus 97.8% respectively (P = .62). FIGO stage, complete primary surgery and post-operative alpha fetoprotein level significantly correlated with survival. CONCLUSION: Adjuvant chemotherapy does not seem to improve survival in stage I patients. Active surveillance can be proposed for selected patients with a complete surgical staging.

Clinical validation of a prognostic tool in a population of outpatients treated for incurable cancer undergoing anticancer therapy: PRONOPALL study.

BACKGROUND: In 2008, a study of the characteristics of hospitalised patients led to the development of a prognostic tool that distinguished three populations with significantly different 2-month survival rates. The goal of our study aimed at validating prospectively this prognostic tool in outpatients treated for cancer in terminal stage, based on four factors: performance status (ECOG) (PS), number of metastatic sites, serum albumin and lactate dehydrogenase. PATIENTS AND METHODS: PRONOPALL is a multicentre study of current care. About 302 adult patients who met one or more of the following criteria: life expectancy under 6 months, performance status ≥ 2 and disease progression during the previous chemotherapy regimen were included across 16 institutions between October 2009 and October 2010. Afterwards, in order to validate the prognostic tool, the score was ciphered and correlated to patient survival. RESULTS: Totally 262 patients (87%) were evaluable (27 patients excluded and 13 unknown score). Median age was 66 years [37-88], and women accounted for 59%. ECOG PS 0-1 (46%), PS 2 (37%) and PS 3-4 (17%). The primary tumours were: breast (29%), colorectal (28%), lung (13%), pancreas (12%), ovary (11%) and other (8%). About 32% of patients presented one metastatic site, 35% had two and 31% had more than two. The median lactate dehydrogenase level was 398 IU/l [118-4314]; median serum albumin was 35 g/l [13-54]. According to the PRONOPALL prognostic tool, the 2-month survival rate was 92% and the median survival rate was 301 days [209-348] for the 130 patients in population C, 66% and 79 days [71-114] for the 111 patients in population B, and 24% and 35 days for [14-56] the 21 patients in population A. These three populations survival were statistically different (P <0.0001). CONCLUSION: PRONOPALL study confirms the three prognostic profiles defined by the combination of four factors. This PRONOPALL score is a useful decision-making tool in daily practice.

Circulating tumour cells and pathological complete response: independent prognostic factors in inflammatory breast cancer in a pooled analysis of two multicentre phase II trials (BEVERLY-1 and -2) of neoadjuvant chemotherapy combined with bevacizumab.

Background: We present a pooled analysis of predictive and prognostic values of circulating tumour cells (CTC) and circulating endothelial cells (CEC) in two prospective trials of patients with inflammatory breast cancer (IBC) treated with neoadjuvant chemotherapy combined with neoadjuvant and adjuvant bevacizumab. Patients and methods: Nonmetastatic T4d patients were enrolled in two phase II multicentre trials, evaluating bevacizumab in combination with sequential neoadjuvant chemotherapy of four cycles of FEC followed by four cycles of docetaxel in HER2-negative tumour (BEVERLY-1) or docetaxel and trastuzumab in HER2-positive tumour (BEVERLY-2). CTC and CEC were detected in 7.5 and 4 ml of blood, respectively, with the CellSearch System. Results: From October 2008 to September 2010, 152 patients were included and 137 were evaluable for CTC and CEC. At baseline, 55 patients had detectable CTC (39%). After four cycles of chemotherapy, a dramatic drop in CTC to a rate of 9% was observed (P < 0.01). Pathological complete response (pCR) rate was 40%. No correlation was found between CTC or CEC levels and pCR rate. Median follow-up was 43 months. CTC detection (≥1 CTC/7.5 ml) at baseline was associated with shorter 3-year disease-free survival (39% versus 70% for patients without CTC, P < 0.01, HR 2.80) and shorter 3-year overall survival (OS) (P < 0.01). In multivariate analysis, independent prognostic parameters for shorter survival were absence of hormonal receptors, no pCR and CTC detection at baseline. CEC level at baseline or variations during treatment had no prognostic value. Conclusion: In this pooled analysis of two prospective trials in nonmetastatic IBC, detection rate of CTC was 39% with a strong and independent prognostic value for survival. Combination of pCR after neoadjuvant treatment with no CTC detection at baseline isolated a subgroup of IBC with excellent OS (94% 3-year OS), suggesting that CTC count could be part of IBC stratification in prospective trials.

Combined oral topotecan plus carboplatin in relapsed or advanced cervical cancer: a GINECO phase I-II trial.

AIM: Combined cisplatin-topotecan therapy is standard care for advanced cervical cancer, however it is associated with haematotoxicity and nephrotoxicity. This trial was designed to assess the combination of carboplatin which is less nephrotoxic, and oral topotecan. PATIENTS AND METHODS: Patients with advanced/recurrent squamous cervical cancer received carboplatin (AUC5) on day 1, with escalating oral topotecan (3.0 mg/m(2) starting dose) on days 1, 8 and 15, every 4 weeks. Endpoints were the maximal tolerated dose for the phase I part and safety profiles and response rates for the phase II part of the study. RESULTS: Two dose levels were evaluated. A total of 18 patients (6 phase I, 12 phase II) were treated. The maximal tolerated dose was 3.0 mg/m(2) topotecan with carboplatin AUC5. Phase II accrual was interrupted following unacceptable toxicity, with 10 therapy-related related serious events in 9 out of 12 patients: grade 3-4 pancytopenia (7), febrile neutropenia (1), grade 3 haemorrhage (1) and grade 3 vomiting (1). CONCLUSION: Weekly oral topotecan combined with carboplatin is associated with unmanageable toxicity and is not recommended. Future studies are warranted to better understand the toxicity of such a combination and explore alternative combinations for advanced cervical cancer.

Docetaxel and pegylated liposomal doxorubicin combination as first-line therapy for metastatic breast cancer patients: results of the phase II GINECO trial CAPYTTOLE.

BACKGROUND: This phase II study evaluated the clinical benefit of pegylated liposomal doxorubicin (PLD) and docetaxel (Taxotere) as first-line therapy for metastatic breast cancer (MBC). PATIENTS AND METHODS: MBC patients were enrolled to receive six cycles of PLD 35 mg/m2 (day 1) and docetaxel 40 mg/m2 (days 1 and 15), every 28 days (group A). Because of unacceptable toxic effects, doses were modified to PLD 30 mg/m2 (day 1) and docetaxel 75 mg/m2 (day 2), every 3 weeks (group B). The primary end point was clinical benefit. RESULTS: Sixty-seven patients were included (group A, 53; group B, 14). In both groups, the median number of cycles delivered was 4 and the overall dose intensity was 82% for docetaxel and 71% for PLD. In group A, main toxic effects were hematologic, palmar-plantar erythrodysesthesia (PPE), and stomatitis. In group B, higher rates of grade 3-4 PPE, febrile neutropenia, and hematologic toxic effects were reported. The rate of clinical benefit was 47%. Among patients with a measurable disease, 49% achieved a partial response, 27% had a stable disease, and 13% progressed, according to RECIST criteria. CONCLUSION: The combination of PLD and docetaxel delivered at planned doses in this study yields unacceptable toxicity and should not be used routinely in patients with MBC.

Cetuximab, topotecan and cisplatin for the treatment of advanced cervical cancer: A phase II GINECO trial.

OBJECTIVE: Cisplatin (Cp) plus topotecan (Tc) is the first combination chemotherapy to demonstrate a survival advantage over cisplatin alone in advanced cervical cancer. Combining Cp and Tc with an epidermal growth factor receptor (EGFR) inhibitor such as cetuximab (Ce) may increase the activity of chemotherapy. METHODS: Patients with advanced cervical squamous cell cancer or adenocarcinoma and at least one measurable target received intravenous Cp 50 mg/m(2) on day 1 plus Tc 0.75 mg/m(2)/day from days 1 to 3 every 3 weeks combined with Ce (initial dose of 400 mg/m(2) followed by subsequent weekly dose of 250 mg/m(2)). Objective response rate according to RECIST criteria was the primary end point; safety, progression free survival (PFS) and overall survival (OS) were secondary end points. RESULTS: Between April and July 2007, 19 out of the 44 planned patients were accrued before the study was stopped early due to excessive toxicity. The most frequent adverse event was severe myelosuppression with grades 3-4 neutropenia (72%), grades 3-4 thrombocytopenia (61%), and grade 3 anemia (44.5%). The main grades 3-4 non-hematologic toxicities were infection (39%) and febrile neutropenia (28%), skin reactions (22%), renal toxicity (11%), and pulmonary embolism (11%). Five (28%) patients died during the treatment including 3 deaths related to treatment toxicity. Six (32%) evaluable patients achieved a partial response. The median times of PFS and OS were 172 and 220 days, respectively. CONCLUSION: In this phase II trial, the combination Cp-Tc-Ce induced a high rate of serious adverse and/or fatal events at standard dose and schedule. Cetuximab plus platinum-based combination chemotherapy should be further explored with caution in the future in advanced cervix cancer.

Gemcitabine-oxaliplatin combination for ovarian cancer resistant to taxane-platinum treatment: a phase II study from the GINECO group.

Advanced ovarian carcinoma in early progression (<6 months) (AOCEP) is considered resistant to most cytotoxic drugs. Gemcitabine (GE) and oxaliplatin (OXA) have shown single-agent activity in relapsed ovarian cancer. Their combination was tested in patients with AOCEP in phase II study. Fifty patients pre-treated with platinum-taxane received q3w administration of OXA (100 mg m(-2), d1) and GE (1000 mg m(-2), d1, d8, 100-min infusion). Patient characteristics were a : median age 64 years (range 46-79),and 1 (84%) or 2 (16%) earlier lines of treatment. Haematological toxicity included grade 3-4 neutropaenia (33%), anaemia (8%), and thrombocytopaenia (19%). Febrile neutropaenia occurred in 3%. Non-haematological toxicity included grade 2-3 nausea or vomiting (34%), grade 3 fatigue (25%),and grade 2 alopecia (24%). Eighteen (37%) patients experienced response. Median progression-free (PF) and overall survivals (OS) were 4.6 and 11.4 months, respectively. The OXA-GE combination has high activity and acceptable toxicity in AOCEP patients. A comparison of the doublet OXA-GE with single-agent treatment is warranted.

HER-2 overexpression is an independent marker of poor prognosis of advanced primary ovarian carcinoma: a multicenter study of the GINECO group.

BACKGROUND: Despite numerous studies, no biological marker has been identified that accurately predicts prognosis of advanced ovarian cancer. Tumors from a homogeneous population of 117 patients with a stage III/IV ovarian cancer, enrolled in a multicenter prospective GINECO clinical trial were analyzed retrospectively. PATIENTS AND METHODS: All patients received the same platinum-based combination therapy and were followed-up for a median of 68 months. Tumor expression of Ki67, BCL-2, BAX, P53 or c-erbB-2 proteins was evaluated immunohistochemically on paraffin-embedded tissues and their prognostic impact analyzed. RESULTS: The median rate of Ki67-positive nuclear area was 30%. BCL-2, BAX and P53 proteins were expressed in 52, 54 and 71% of the tumors, respectively, while HER-2 protein was overexpressed in 16%. Only HER-2 overexpression was significantly associated with shorter progression-free survival and overall survival. According to our multivariate analysis, the HER-2 prognostic impact was independent of classical clinical prognostic factors. CONCLUSION: HER-2 appeared to influence the outcome of advanced ovarian cancer patients included in a clinical trial with prolonged follow-up, thereby suggesting that HER-2 is a potential target for treatment of this cancer.

6-Day continuous infusion of high-dose ifosfamide with bone marrow growth factors in advanced refractory malignancies.

Ifosfamide is an analogue of cyclophosphamide active in the treatment of numerous tumours. Although its use by continuous infusion seems to be responsible for less toxicity, differences of efficacy and toxicity, observed according to its doses and schedules of administration, still remain debated. The objective of this study was to assess the toxicity of high-dose ifosfamide given by continuous infusion over 6 days and its therapeutic activity in various advanced tumours. Twenty-six patients were treated with 14 g/m2 ifosfamide, an equal dose of MESNA, and routine granulocyte- or granulocyte/macrophage-colony-stimulating factor during the intercycle. Courses were repeated every 3 weeks until disease progression or unacceptable toxicity occurred; 75 cycles were administered. The mean number of cycles per patient was 3 (range 1-11). Extrahaematological toxicity was manageable in most patients, WHO grade II or more neurological (5 patients) and renal (5 patients) toxicities occurring in those heavily pretreated with platinum compounds and presenting peritoneal disease. WHO grade III or more neutropenia occurred in 60% of cycles, while grade III-IV thrombocytopenia and anaemia were observed in 19% of them. Three partial responses (germ-cell tumour, chondrosarcoma, soft-tissue sarcoma) and one complete response (metastatic osteosarcoma) were assessed, all in patients with tumours refractory or resistant to standard-dose ifosfamide, which underlines the possibility of circumventing the resistance to ifosfamide given in conventional schedules. The present results confirm previous reports of changes in the therapeutic index of ifosfamide according to its dose and administration schedule.