Immunohistochemical subtypes predict the clinical outcome in high-risk node-negative breast cancer patients treated with adjuvant FEC regimen: results of a single-center retrospective study.

BACKGROUND: Anthracycline-based adjuvant chemotherapy improves survival in patients with high-risk node-negative breast cancer (BC). In this setting, prognostic factors predicting for treatment failure might help selecting among the different available cytotoxic combinations. METHODS: Between 1998 and 2008, 757 consecutive patients with node-negative BC treated in our institution with adjuvant FEC (5FU, epirubicin, cyclophosphamide) chemotherapy were identified. Data collection included demographic, clinico-pathological characteristics and treatment information. Molecular subtypes were derived from estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) status and Scarff-Bloom-Richardson (SBR) grade. Disease-free survival (DFS), distant disease-free survival (DDFS) and overall survival (OS) were estimated using the Kaplan-Meier Method, and prognostic factors were examined by multivariate Cox analysis. RESULTS: After a median follow-up of 70 months, the 5-year DFS, DDFS and OS were 90.6 % (95 % confidence interval (CI): 88.2-93.1), 92.8 % (95 % CI: 90.7-95) and 95.1 % (95 % CI, 93.3-96.9), respectively. In the multivariate analysis including classical clinico-pathological parameters, only grade 3 maintained a significant and independent adverse prognostic impact. In an alternative multivariate model where ER, PR and grade were replaced by molecular subtypes, only luminal B/HER2-negative and triple-negative subtypes were associated with reduced DFS and DDFS. CONCLUSIONS: Node-negative BC patients receiving adjuvant FEC regimen have a favorable outcome. Luminal B/HER2-negative and triple-negative subtypes identify patients with a higher risk of treatment failure, which might warrant more aggressive systemic treatment.

Long-term survival of advanced triple-negative breast cancers with a dose-intense cyclophosphamide/anthracycline neoadjuvant regimen.

BACKGROUND: Triple-negative (TN) breast cancers exhibit major initial responses to neoadjuvant chemotherapy, but generally have a poor outcome. Because of the lack of validated drug targets, chemotherapy remains an important therapeutic tool in these cancers. METHODS: We report the survival of two consecutive series of 267 locally advanced breast cancers (LABC) treated with two different neoadjuvant regimens, either a dose-dense and dose-intense cyclophosphamide-anthracycline (AC) association (historically called SIM) or a conventional sequential association of cyclophosphamide and anthracycline, followed by taxanes (EC-T). We compared pathological responses and survival rates of these two groups and studied their association with tumours features. RESULTS: Although the two regimens showed equivalent pathological complete response (pCR) in the whole population (16 and 12%), the SIM regimen yielded a non-statistically higher pCR rate than EC-T (48% vs 24%, P=0.087) in TN tumours. In the SIM protocol, DFS was statistically higher for TN than for non-TN patients (P=0.019), although we showed that the TN status was associated with an increased initial risk of recurrence in both regimens. This effect gradually decreased and after 2 years, TN was associated with a significantly decreased likelihood of relapse in SIM-treated LABC (hazard ratio (HR)=0.25 (95% CI: 0.07-0.86), P=0.028). CONCLUSIONS: AC dose intensification treatment is associated with a very favourable long-term survival rate in TN breast cancers. These observations call for a prospective assessment of such dose-intense AC-based regimens in locally advanced TN tumours.

Tailored chemotherapy based on tumour gene expression analysis: breast cancer patients' misinterpretations and positive attitudes.

The aim of this study was to document how breast cancer patients perceive their prognosis and a tailored treatment based on tumour gene expression analysis, and to identify the features of this approach that may impact its clinical application. In-depth interviews were conducted at three French cancer centres with 37 women (35-69 years of age) with node-positive breast cancer undergoing an adjuvant chemotherapy regimen defined on the basis of the genomic signature predicting the outcome after chemotherapy. Several concerns were identified. First, some misconceptions about these methods were identified due to semantic confusions between the terms 'genomic' and 'genetic', which generated anxiety and uncertainty about the future. Second, the 'not done' and 'not interpretable' signatures were misinterpreted by the women and associated with highly negative connotations. However, the use of tumour genomic analysis to adapt the treatment to each patient received most of the patients' approval because it was perceived as an approach facilitating personalised medicine. In conclusion, improving the quality of provider/patient communications should enable patients to play a more active part in the decision making about their treatment. This will ensure that those who agree to have tumour gene analysis have realistic expectations and sound deductions about the final result disclosure process.

A phase II trial to evaluate gefitinib as second- or third-line treatment in patients with recurring locoregionally advanced or metastatic cervical cancer.

BACKGROUND: Cancer of the cervix occurs in approximately 500,000 women worldwide each year, with prognosis highly dependent on disease stage at diagnosis. Survival times are poor and therapy options are limited for patients who relapse following radiotherapy and chemotherapy regimens, suggesting alternative treatments are required. Evidence suggests the epidermal growth factor receptor (EGFR) is expressed at moderate to high levels in cervical carcinomas. We investigated whether gefitinib (IRESSA), an EGFR tyrosine kinase inhibitor, is a potential second- or third-line treatment option for women with recurrent cervical cancer. METHODS: This was a multicenter, open-label, non-comparative, phase II trial (study 1839IL/0075) evaluating the clinical outcomes of 500 mg/day gefitinib. An exploratory objective was to investigate the correlation of baseline EGFR expression with tumor response and disease control. RESULTS: Thirty patients with squamous-cell carcinoma or adenocarcinoma were recruited from six centers in France. Of these, 28 patients were evaluable for efficacy. Although there were no objective responses, six (20%) patients experienced stable disease with a median duration of 111.5 days. Median time to progression was 37 days and median overall survival was 107 days. Disease control did not appear to correlate with levels of EGFR expression. Gefitinib was well tolerated, with the most common drug-related adverse events being skin and gastrointestinal toxicities. CONCLUSIONS: In recurrent disease resistant to standard treatment, gefitinib has only minimal monotherapy activity. However, the observation that 20% of patients treated with gefitinib had stable disease may warrant further investigation.

Patients' preference of trastuzumab administration (subcutaneous versus intravenous) in HER2-positive metastatic breast cancer: Results of the randomised MetaspHer study.

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 < 0.001), 13/92 preferred H-i.v. (14.1%, 95% CI [7.0-21.3]). HCPs were most satisfied with H-s.c. (56/88 available data, 63.6%, [53.6-73.7]). On the safety population, adverse events occurred in 73 (67.6%) and 49 (44.1%) patients during the H-s.c. and H-i.v. periods, respectively; 7 (6.5%) and 4 (3.6%) were grade ≥ III, 3 (2.8%) and 2 (1.8%) were serious. 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.

Post-operative sequential high-dose chemotherapy with haematopoietic stem cell support as front-line treatment in advanced ovarian cancer: a phase II multicentre study.

In spite of multimodal management including aggressive surgery and chemotherapy, the prognosis of advanced ovarian cancer (AOC) remains poor. Multicycle high-dose chemotherapy (HDC) with haematopoietic stem cell (HSC) support has been shown to be a promising procedure in various cancers including AOC. We conducted a phase II multicentre study to evaluate feasibility, toxicity and efficacy of post-operative front-line sequential HDC with HSC support in AOC. Thirty four patients with stage IIIC/IV received a post-operative sequential combination of high-dose cyclophosphamide/epirubicin (D1, D21) with HSC harvesting, high-dose carboplatin (D42, D98) followed by HSC infusion, and dose-dense paclitaxel (D63, D77, D119, D133). Rh-G-CSF (filgrastim) was administered following all cycles. Primary endpoint was pathological complete response rate (pCR). Thirty patients received at least 7 of the scheduled 8 cycles. Haematological toxicity was significant but manageable. Grade 3/4 extra-haematopoietic toxicities were relatively uncommon and reversible. No toxicity-related death was observed. The observed pCR was 37% and did not reach the initial endpoint. Post-operative front-line sequential HDC in AOC is feasible and safe in a multicentre setting. The observed pCR does not support a clear advantage over conventional treatment. This approach remains an experimental strategy to further optimise and validate.

Phase I and pharmacokinetic study of Taxotere (RP 56976; NSC 628503) given as a short intravenous infusion.

Taxotere (N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl Taxol; RP 56976; NSC 628503) is a semisynthetic analogue of Taxol. It is twice as active in inhibiting tubuline depolymerization and has a better in vivo activity on B16 melanoma, with responses in advanced colon 38 and PO3 adenocarcinoma. Sixty-five patients (49 women, 16 men), with a median age of 57 years, received 248 courses of Taxotere given as a 1-2-h i.v. infusion every 2 or 3 weeks. Ten distinct dose levels from 5 to 115 mg/m2 were studied. Dose-dependent, reversible neutropenia was the limiting toxicity. Delayed and cumulative skin reactions occurred beyond 70 mg/m2. Alopecia was observed in the majority of patients beyond 70 mg/m2. Four partial responses were achieved in patients with ovarian carcinoma, breast carcinoma, small cell lung cancer, and carcinoma with unknown primary. The pharmacokinetics of Taxotere, determined in 23 patients receiving 20 to 115 mg/m2, was linear. At the highest doses, the Taxotere plasma profile was typically triphasic, with a terminal half-life of 13.5 +/- 7.5 (SD) h, a plasma clearance of 21.1 +/- 5.3 liters/h/m2, and a distribution volume of 72 +/- 40 liters/m2. AUC correlated with the percentage decrease of neutrophils in a sigmoid Emax model. The renal excretion of unchanged Taxotere was very low (< 5% of the dose). The recommended dose for phase II trials with this schedule is 100 mg/m2 every 3 weeks.

Phase I and pharmacokinetic study of the camptothecin derivative irinotecan, administered on a weekly schedule in cancer patients.

Irinotecan (CPT-11) is a novel water-soluble, semisynthetic derivative of camptothecin, with inhibitory effects on mammalian DNA topoisomerase I, high cytotoxic activity in vitro and anticancer activity in animal models. Fifty-nine patients, with cancer refractory to conventional therapy, were entered in this phase I study, using a weekly schedule administration. A total of 304 weekly doses were administered at dose levels ranging from 50 to 145 mg/m2 (30-90 min i.v. infusion). Leukoneutropenia and diarrhea were the dose-limiting toxicities and appeared to be dose related, reversible and noncumulative. However, interpatient variability of toxic effects was substantial. Prolongation of the infusion time from 30 min to 90 min appeared to decrease the diarrhea. Other toxicities included moderate emesis, asthenia, alopecia, abdominal pain, and anemia. CPT-11 plasma disposition was bi- or triphasic with a terminal half-life of 9.3 h. CPT-11 area under the plasma concentration versus time curves increased linearly with dose (r = 0.47, P < 0.01). The active metabolite area under the plasma concentration versus time curve correlated significantly with that of CPT-11, but not with that of CPT-11 dose. Both CPT-11 and 7-ethyl-10-hydroxycamptothecin areas under the plasma concentration versus time curve correlated significantly with leukoneutropenia and diarrhea. One partial and 4 minor responses were observed at dose levels of 130 and 145 mg/m2. Using this weekly schedule, recommended doses for phase II studies are 100 mg/m2 in high risk patients and 115 mg/m2 in others.

Highly favorable outcome in BRCA-mutated metastatic breast cancer patients receiving high-dose chemotherapy and autologous hematopoietic stem cell transplantation.

Breast cancer carrying BRCA mutation may be highly sensitive to DNA-damaging agents. We hypothesized a better outcome for BRCA-mutated (BRCA(mut)) metastatic breast cancer (MBC) patients receiving high-dose chemotherapy and autologous hematopoietic stem cell transplantation (HDC AHSCT) versus unaffected BRCA (BRCA wild type; (BRCA(wt))) or patients without documented BRCA mutation (BRCA untested (BRCA(ut))). All female patients treated for MBC with AHSCT at Institut Paoli-Calmettes between 2003 and 2012 were included. BRCA(mut) and BRCA(wt) patients were identified from our institutional genetic database. Overall survival (OS) was the primary end point. A total of 235 patients were included. In all, 15 patients were BRCA(mut), 62 BRCA(wt) and 149 BRCA(ut). In multivariate analyses, the BRCA(mut) status was an independent prognostic factor for OS (hazard ratio (HR): 3.08, 95% confidence interval (CI): 1.10-8.64, P=0.0326) and PFS (HR: 2.52, 95% CI :1.29-4.91, P=0.0069). In this large series of MBC receiving HDC AHSCT, we report a highly favorable survival outcome in the subset of patients with documented germline BRCA mutations.

Intensive and sequential combination chemotherapy for aggressive malignant lymphomas (protocol LNH-80).

Ninety-seven patients with aggressive malignant lymphoma (ML) were treated with an intensive and sequential chemotherapy (protocol LNH-80). There were 42 patients with intermediate grade ML, 53 patients with high-grade ML, and two patients with true histiocytic ML. Most of the patients were in advanced stage: 21 stage III and 61 stage IV. The LNH-80 protocol schedule comprised three phases: (1) induction with three courses of an intensified CHOP-Bleo (cyclophosphamide, doxorubicin, vindesine, methylprednisolone, and bleomycin); (2) consolidation with cytarabine, followed by high-dose methotrexate and folinic acid rescue, then asparaginase; and (3) final intensification with two courses of CVAP-Bleo (cyclophosphamide, teniposide, cytarabine, methylprednisolone, and bleomycin). CNS prophylaxis included one injection of methotrexate during each induction course and the drugs of the consolidation phase. In cases of initial CNS localization, cranial radiotherapy was added. Eighty-four patients (87%) went into complete remission (CR), 18 (21%) of whom relapsed, usually during the phase of treatment or within 6 months of completing chemotherapy. Sixty-three patients are alive with an overall median follow-up of 24 months. The median survival time and the median disease-free survival have not been reached, and the survival curve seems to have plateaued at above 60%. There was no statistical difference between intermediate-grade ML (CR 90%, relapse 18%) and high-grade ML (CR 84%, relapse 24%). The toxicity of this treatment is mainly encountered during the induction phase: almost all patients had short-term neutropenia, less than 0.500 g/L in 57, with a documented infection in 25. Overall treatment-related mortality was 6%, with four patients dying during the induction phase.

Efficacy and tolerance of vinorelbine and fluorouracil combination as first-line chemotherapy of advanced breast cancer: results of a phase II study using a sequential group method.

PURPOSE: To assess the antitumor efficacy and safety profile of the combination of Fluorouracil (5FU) and vinorelbine given as first-line therapy to patients with advanced breast cancer. PATIENTS AND METHODS: As defined in the seven consecutive steps of a phase II group sequential design, 63 patients received 5FU 750 mg/m2/d for 5 consecutive days as a continuous infusion and vinorelbine 30 mg/ m2 on days 1 and 5 as a short intravenous (I/V) infusion every 3 weeks. RESULTS: Forty-one of 63 patients achieved an objective response, which allowed us to discontinue the study and reject a response rate less than 50% with a statistical power of 90%. The unbiased estimate of the response rate was 61.6%. Response rate did not differ significantly according to the following: (1) type of prior adjuvant therapy (none, n = 23; without anthracycline, n = 6; with anthracyline, n = 34); (2) site of metastatic disease; and (3) number of metastatic sites. The median time to progression was 8.4 months. The median response duration was 12.3 months, and the median duration of complete response (CR), from the first assessment of CR, was 7.3 months. The median overall survival time was 23 months (28.1 months for patients with a CR). The main toxicities (grades 3 and 4) were neutropenia (90% of patients), infection (12.7%), mucositis (37%), and constipation (9.5%). Nevertheless, treatment could be given on an outpatient basis to the majority of patients, and the median relative dose-intensity was 86%. CONCLUSION: This phase II study, which used a group-sequential design, shows that the combination of 5FU and vinorelbine is an active and tolerable regimen for the treatment of first metastatic progression of breast cancer. It provides an alternative regimen for patients who have previously received anthracycline-based adjuvant chemotherapy or in whom anthracyclines cannot be used.

High dose-intensity of irinotecan administered every 3 weeks in advanced cancer patients: a feasibility study.

PURPOSE: To assess, on a multicenter basis, the feasibility of treating advanced cancer patients with high-dose irinotecan. PATIENTS AND METHODS: Thirty-five patients who met the usual phase I criteria (26 men and nine women) were included. Primary tumor sites were colon, head and neck, unknown primary, kidney, liver, and others. All had been previously treated. Irinotecan was given at the maximum-tolerated dose (MTD) (600 mg/m2) or the level below (500 mg/m2) as a 30-minute infusion once every 3 weeks. RESULTS: Eighteen patients were entered in the four participating centers at the MTD of 600 mg/m2. This dose level was clearly shown not to be feasible: 14 patients (78%) had grade 3 to 4 neutropenia, with febrile episodes in 11 patients; grade 3 to 4 diarrhea was observed in nine patients; and one toxic death occurred. Subsequently, 17 not heavily pretreated patients were included at 500 mg/m2 and carefully monitored. The safety of this dose level was considered acceptable: 41% of patients had grade 3 to 4 neutropenia, 24% experienced grade 3 to 4 diarrhea, and no febrile granulocytopenia or toxic death occurred. Six partial responses were documented in metastatic colorectal cancer, all in patients who had previously received conventional chemotherapy, four in patients who had exhibited progressive disease under fluorouracil (5FU)-based chemotherapy. CONCLUSION: We plan to study the higher dose-intensity 500-mg/m2 level on good-risk and carefully monitored patients. This could enlarge the spectrum of tumors sensitive to irinotecan and improve the already good results observed in colorectal cancers.

Primary chemotherapy for operable breast cancer: incidence and prognostic significance of ipsilateral breast tumor recurrence after breast-conserving surgery.

PURPOSE: To determine the incidence and the prognostic value of ipsilateral breast tumor recurrence (IBTR) in patients treated with primary chemotherapy and breast-conserving surgery. PATIENTS AND METHODS: Between January 1985 and December 1994, 257 patients with invasive T1 to T3 breast carcinoma were treated with primary chemotherapy, lumpectomy, and radiation therapy. The median follow-up time was 93 months. To evaluate the role of IBTR in metastase-free survival, a Cox regression multivariate analysis was performed using IBTR as a time-dependent covariate. RESULTS: The IBTR rates were 16% (+/- 2.4%) at 5 years and 21.5% (+/- 3.2%) at 10 years. Multivariate analysis showed that the probability of local control was decreased by the following independent factors: age < or = 40 years, excision margin < or = 2 mm, S-phase fraction more than 4%, and clinical tumor size more than 2 cm at the time of surgery. In patients with excision margins of more than 2 mm, the IBTR rates were 12.7% at 5 years and 17% at 10 years. Nodal status, age < or = 40 years, and negative estrogen receptor status were predictors of distant disease in the Cox multivariate model with fixed covariates. The contribution of IBTR was highly significant (relative risk = 5.34) when added to the model, whereas age < or = 40 years was no longer significant. After IBTR, 31.4% (+/- 7.0%) of patients developed metastases at 2 years and 59.7% (+/- 8.1%) at 5 years. Skin involvement, size at initial surgery, and estrogen receptor status were predictors of metastases after IBTR. CONCLUSION: IBTR is a strong predictor for distant metastases. There are implications for conservative surgery after downstaging of the tumor and therapy at the time of IBTR.

Concomitant chemoradiotherapy followed, where feasible, by surgery for cancer of the esophagus.

PURPOSE: To conduct a multicenter phase II study of a concomitant combination of chemotherapy and radiotherapy followed by surgery, where feasible, in patients with nonmetastatic esophageal tumor, stratified on operability at diagnosis. METHODS: Each cycle consisted of fluorouracil (5FU) 800 mg/m2/d by continuous intravenous (IV) infusion on days 1 to 5, cisplatin (CDDP) 50 mg/m2/d IV bolus on days 1 and 8, hydroxyurea (HU) 1.5 or 2 g/d orally on days 8 to 12 and concomitant radiotherapy 20 Gy in 10 fractions over 12 days. All patients were to receive two cycles on days 1 and 22. If feasible, surgery was performed 3 to 6 weeks after cycle two completion. Otherwise, a third cycle was administered. RESULTS: Eighty-eight patients were included between September 1990 and September 1993. Of the 47 operable patients, 41 (87%) underwent surgery and 38 (81%) had a complete resection. No residual primary tumor was found in the surgical specimen in 17 cases (36%), and only microscopic foci in 13 (28%). Two-year overall and disease-free survival probabilities were 51% (95% confidence interval [CI]; 37 to 65) and 43% (95% CI, 28 to 57), respectively. Among the 41 inoperable patients, 12 (29%) became operable. Seven (17%) had complete resection, two incomplete resection, and three exploratory surgery. Two-year overall and disease-free survival probabilities were 29% (95% CI, 15 to 43) and 27% (95% CI, 13 to 40), respectively. Five deaths occurred during chemoradiotherapy, six postoperatively and four in patients with evidence of cancer. Five late complications (one myelopathy) were observed. CONCLUSION: Despite a high histologic response rate in initially operable patients, overall survival was similar to that observed in other preoperative chemoradiation series because of substantial toxicity.

Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy.

PURPOSE: To assess the efficacy of irinotecan (CPT-11) in the treatment of advanced colorectal cancer in both chemotherapy-naive and pretreated patients. PATIENTS AND METHODS: Two hundred thirteen patients (aged 18 to 75 years) with metastatic colorectal cancer, World Health Organization (WHO) performance status < or = 2, and life expectancy > or = 3 months were treated with CPT-11 350 mg/m2 every 3 weeks. All 178 patients eligible for efficacy analysis had not received more than one prior fluorouracil (5-FU)-based chemotherapy regimen (adjuvant or palliative) and had adequate hematologic, renal, and hepatic function. RESULTS: Primary tumor sites were the colon (71%) and rectum (28%). Sixty-six percent of the patients had > or = two metastatic sites. Ninety-eight percent of the patients had undergone previous surgery, and 77.5% had received prior chemotherapy. Thirty-two of 178 eligible patients achieved on objective response (four complete responses [CRs] and 28 partial responses [PRs]; response rate, 18%; 95% confidence interval, 12.6% to 24.4%), 65 were stable, and 59 progressed. The response rate was 17.7% in the pretreated group and 18.8% in the chemotherapy-naive group. Within the former subgroup, response rates of 16.1% were reported in patients who were progressive on prior 5-FU chemotherapy and 19.1% in patients who were progressive off such treatment. The median duration of objective response (9.1 months) and median time to achievement of a response (9.3 weeks) did not differ between chemotherapy-naive and pretreated patients. The most frequent adverse events were neutropenia, which developed in 80% of the patients, delayed diarrhea (87%), alopecia (88%), fatigue (81%), and nausea/vomiting (77%). All these adverse events were manageable. Severe (WHO grade 3 or 4) neutropenia was only observed in 18% of the cycles, leukopenia in 11%, delayed diarrhea in 11%, and nausea and vomiting in 3%. Development of simultaneous grade 3 or 4 neutropenia and delayed diarrhea during 4% of the cycles was the safety issue of greatest concern. CONCLUSION: CPT-11 has definite activity in the treatment of advanced metastatic colorectal cancer both in chemotherapy-naive and in pretreated patients who experienced disease progression on 5-FU, which suggests a lack of cross-resistance between CPT-11 and 5-FU. Diarrhea and neutropenia, the major toxicities of CPT-11, contribute to the risk to develop febrile neutropenic sepsis.

Detection of MUC1-expressing mammary carcinoma cells in the peripheral blood of breast cancer patients by real-time polymerase chain reaction.

We have prospectively analyzed blood samples of 122 patients with breast disease for the presence of circulating expressing MUC1 cells before and after treatment. Among them, 28 patients had histologically confirmed benign breast disease (group 1), 34 patients had operable breast cancer (group 2), and 60 patients had advanced breast cancer (group 3). Circulating epithelial cells were isolated with BerEP4-coated immunomagnetic beads. Total RNA was extracted and reverse transcribed before analysis by real-time PCR of a MUC1-specific cDNA sequence. The sensitivity of the reverse transcription-PCR tested with blood spiked with MCF7 cells was one cell in 5 ml of blood. The immunomagnetic separation step was mandatory to obtain the maximum specificity. Control samples from healthy donors never displayed cycle threshold (Ct) values for MUC1 lower than 38. Circulating cells (Ct, <38) were detected in 3 of 28 (11%) cases in group 1, in 8 of 34 (24%) cases in group 2, and in 27 of 60 cases (45%) in group 3. A semiquantitative estimate of blood-borne cells could be derived from the Ct value when below 32 (the lowest was 28) or by the number of positive aliquots of the same blood sample. Thus, immunomagnetic separation, followed by MUC1-specific RT-PCR, allows the semiquantitative detection of circulating mammary cells. A significant correlation between the presence of MUC1-positive cells and the group of breast tumors was observed. The clinical significance of blood-borne cells in breast cancer, especially at the operable stage, may be investigated by following these patients.

Prospects with docetaxel in the treatment of patients with breast cancer.

Docetaxel (Taxotere) has been shown to be one of the most active cytotoxic agents in patients with breast cancer, achieving response rates of 41% when used as second-line treatment for metastatic breast cancer (34% in anthracycline-refractory patients) and 50-72% when used as first-line therapy. In both situations meaningful response durations of 7-8 months have been obtained. Based on these results, docetaxel is a promising candidate for new therapeutic strategies in patients with breast cancer. Studies comparing docetaxel with paclitaxel or anthracyclines in first-line therapy are ongoing. These studies should allow for an unequivocal definition of activity of docetaxel, yet not alter--as such--therapeutic strategies. A number of regimens are currently being explored combining docetaxel with anthracyclines, vinorelbine, 5-fluorouracil, cyclophosphamide and cisplatin. The preliminary conclusions are as follows: the main side-effect is non-cumulative neutropenia of short duration, and response rates are > 75%. Further, no cumulative cardiotoxicity has been observed with doxorubicin. The duration of response and length of the progression-free survival cannot yet be defined. Another option for combination chemotherapy is sequential combinations, the value of which has been demonstrated in advanced breast cancer as well as in the adjuvant setting. The short duration and non-cumulative character of docetaxel-induced neutropenia are good rationales for the use of dose-densified docetaxel-containing regimens. A dose of 100 mg/m2/14 days can be used as single-agent therapy. A phase I trial combining cyclophosphamide at doses increased from 750 to 1200 mg/m2 and docetaxel at doses increased from 66 to 100 mg/m2 every 2 weeks, is ongoing; at the first dose-levels, the combination appears feasible although cumulative asthenia has been observed. Further, responses have been observed at all dose levels. The value of single-agent chemotherapy added to tamoxifen has been emphasised for stage I-II breast cancer in postmenopausal patients. A randomised phase III study comparing tamoxifen (20 mg/day for 5 years) and epirubicin (50 mg/m2 days 1 and 8/28 days for 6 cycles) with the same regimen with epirubicin for 3 months followed by docetaxel (100 mg/m2/21 days x 3) was initiated at the end of 1996. Thus, docetaxel is currently under study in most therapeutic situations to better define its impact on the prognosis and curability of patients with breast cancer.

A small GTP-binding protein is frequently overexpressed in peripheral blood mononuclear cells from patients with solid tumours.

ras oncoproteins and ras-related proteins constitute a large family of the small GTP-binding protein family. The rab branch of the ras superfamily is involved in the intracellular transport along the secretory and endocytic pathway in eukaryotic cells. We here demonstrate that a member of the rab branch, the rab2 protein, is frequently overexpressed in peripheral blood mononuclear cells from patients with solid neoplasms. Moreover, this expression is shown to be greatly modified during the course of therapy. Our results provide strong evidence for the implication of a small GTP-binding protein in immunological events associated with neoplastic diseases. The precise cellular population involved as well as the potential prognostic value of this process remains to be determined.

Predictive factors of response to first-line chemotherapy in 1426 women with metastatic breast cancer.

Since response to chemotherapy is a major determinant of survival in metastatic breast cancer, the purpose of our study was to analyse the predictive factors of response. 1426 patients enrolled into eight consecutive randomised trials of anthracycline-based first-line chemotherapy in metastatic breast cancer, between 1977 and 1992, were analysed. A forward stepwise logistic regression analysis was used. The objective response rate (ORR) to chemotherapy in the total population was 63.6% (95% confidence interval (CI): 61.5-67.7). The complete response rate was 17.5%. Multivariate analysis defined adjuvant chemotherapy, lactate dehydrogenase (LDH), Karnofsky index (KI), and pleural and lung metastases to be the five main variables correlated with ORR. A predictive score was calculated using the coefficient of these five variables, The score was established as follows: -1.32+0.54 (if prior adjuvant chemotherapy) +0.80 (low KI) +0.75 (raised LDH) +0.49 (lung metastases) +0.51 (pleural metastases). A low score (less than -0.78) was associated with an ORR greater than 70.0%, representing 41.2% of our population. An intermediate score (between -0.78 and 0) was associated with an ORR of 50 to 70%, representing 37.5% of our population and a positive score was associated with an ORR of less than 50%, representing 21.3% of our population. This score can be used to predict objective response rates to first-line anthracycline-based chemotherapy. This method now needs to be evaluated prospectively in phase II trials. Identification of various risk groups may also be useful for interpretation and design of clinical trials.

Pharmacokinetics and safety profile of oxaliplatin.

In early clinical trials, oxaliplatin has demonstrated significant activity against colorectal cancer, both as a single agent and in combination with 5-fluorouracil (5-FU) and folinic acid (FA). Oxaliplatin differs from cisplatin in its lack of nephrotoxicity and from carboplatin in its hematologic toxicity being mild. The most constant acute side effect of oxaliplatin observed in clinical trials was a transient peripheral neuropathy manifesting as paresthesia and dysesthesia in the extremities, triggered or enhanced by exposure to cold. The neurosensory phenomena, dependent on the cumulative dose of oxaliplatin, affect all patients who receive doses > or = 540 mg/m2 over four cycles or more of therapy. This neurologic toxicity is also highly reversible, with 82% of patients having their neuropathy regress within 4 to 6 months and 41% experiencing complete recovery within 6 to 8 months. With these considerations in mind, the currently recommended dosing schedules for oxaliplatin are 130 mg/m2/d as a 2- to 6-hour infusion or 175 mg/m2/d as a chronomodulated infusion over 5 days, both of which are administered every 3 weeks. Oxaliplatin rapidly disappears from the plasma and is rapidly transformed into putative active species. 5-Fluorouracil and folinic acid, often used in combination with oxaliplatin, do not affect its pharmacokinetics. The favorable pharmacokinetics and safety profile of oxaliplatin contribute to its tolerability, particularly in pretreated cancer patients with reduced renal function. The reversible nature of its dose-limiting neurotoxicity and its synergistic action with 5-FU/FA make oxaliplatin an interesting agent for the treatment of colorectal cancer and for other potential indications.