Bernard Asselain

Sequential Adjuvant Epirubicin-Based and Docetaxel Chemotherapy for Node-Positive Breast Cancer Patients: The FNCLCC PACS 01 Trial

PURPOSE The PACS 01 trial compared six cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) with a sequential regimen of three cycles of FEC followed by three cycles of docetaxel (FEC-D) as adjuvant treatment for women with node-positive early breast cancer. PATIENTS AND METHODS Between June 1997 and March 2000, 1,999 patients with operable node-positive breast cancer were randomly assigned to either FEC every 21 days for six cycles, or three cycles of FEC followed by three cycles of docetaxel, both given every 21 days. Hormone-receptor-positive patients received tamoxifen for 5 years after chemotherapy. The primary end point was 5-year disease-free survival (DFS). RESULTS Median follow-up was 60 months. Five-year DFS rates were 73.2% with FEC and 78.4% with FEC-D (unadjusted P = .011; adjusted P = .012). Multivariate analysis adjusted for prognostic factors showed an 18% reduction in the relative risk of relapse with FEC-D. Five-year overall survival rates were 86.7% with FEC and 90.7% with FEC-D, demonstrating a 27% reduction in the relative risk of death (unadjusted P = .014; adjusted P = .017). The incidence of grade 3 to 4 neutropenia, the need for hematopoietic growth factor, and incidence of nausea/vomiting were higher with FEC. Docetaxel was associated with more febrile neutropenia in the fourth cycle, stomatitis, edema, and nail disorders. Though rare overall, there were fewer cardiac events after FEC-D (P = .03), attributable mainly to the lower anthracycline cumulative dose. CONCLUSION Sequential adjuvant chemotherapy with FEC followed by docetaxel significantly improves disease-free and overall survival in node-positive breast cancer patients and has a favorable safety profile.

Age as prognostic factor in premenopausal breast carcinoma

Whether or not young age at diagnosis is an adverse prognostic factor in breast cancer has long been controversial, in part because much previous work has not taken due account of menopausal status and confounding factors. We have analysed the influence of age on prognosis in a consecutive series of 1703 patients with stage I-III breast cancer. All were premenopausal and all were treated in one centre (Institut Curie, Paris) between 1981 and 1985. Mean age was 44 years (range 23-55) and median follow-up was 82 months. Younger patients had significantly lower survival rates and higher local and distant relapse rates than older patients. The hazard rate of relapse decreased over time in the youngest age group (< or = 33) to reach that of older patients after 5 years. The relation between the hazard of recurrence and age was a continuous one, best fitted by a log-linear function and indicating a 4% decrease in recurrence for every year of age. Multivariate analysis of both survival and disease-free interval demonstrated that the worse prognosis of young age was independent of other factors such as clinical tumour size, clinical node status, histological grade, hormone receptor status, locoregional treatment procedure, and adjuvant systemic therapy. This difference in outlook has yet to be explained biologically but it does suggest the need for a closer look at the natural history of breast cancer in young women.

Neoadjuvant versus adjuvant chemotherapy in premenopausal patients with tumours considered too large for breast conserving surgery: Preliminary results of a randomised trial: S6

The aim of this study was to assess a potential advantage in survival by neoadjuvant as compared to adjuvant chemotherapy. 414 premenopausal patients with T2-T3 N0-N1 M0 breast cancer were randomised to receive either four cycles of neoadjuvant chemotherapy (cyclophosphamide, doxorubicin, 5-fluorouracil), followed by local-regional treatment (group I) or four cycles of adjuvant chemotherapy after primary irradiation +/- surgery (group II). Surgery was limited to those patients with a persisting mass after irradiation, and aimed to be as conservative as possible. 390 patients were evaluable. With a median follow-up of 54 months, we observed a statistically significant difference (P = 0.039) in survival in favour of the neoadjuvant chemotherapy group. A similar trend was seen when the time to metastatic recurrence was evaluated (P = 0.09). At this stage, no difference in disease-free interval or local recurrence between these two groups could be observed. The mean total dose of chemotherapy administered was similar in both groups. On average, group I had more intensive chemotherapy regimes (doxorubicin P = 0.02) but fewer treatment courses (P = 0.008) as compared to the treated patients in group II. Haematological tolerance was reduced when chemotherapy succeeded to exclusive irradiation. Breast conservation was identical for both groups at the end of primary treatment (82 and 77% for groups I and II, respectively). Of the 191 evaluable patients in the neoadjuvant treatment arm, 65% had an objective response (> 50% regression) following four cycles of chemotherapy. The objective response rate to primary irradiation (55 Gy) was 85%. Improved survival figures in the neoadjuvant treatment arm could be the result of the early initiation of chemotherapy, but we cannot exclude that this difference might be attributable to a slightly more aggressive treatment. So far, the trend in favour of decreased metastases was not statistically significant. The local control appeared similar in both subgroups.

Association of p53 mutations with short survival in colorectal cancer

BACKGROUND/AIMS Mutations in p53, a tumor suppressor gene located on chromosome 17p, are the most frequent genetic alterations found in human cancers. Increased intracellular concentration of p53, which is frequently but not systematically related to p53 mutation, has been proposed to be associated with poor prognosis in some tumor types. In colorectal cancer, this significance is still a matter of debate. To directly investigate the relationship between prognosis and p53 mutation, this study screened a series of 85 colorectal carcinomas for mutations in exons 5-8 of this gene. METHODS Polymerase chain reaction-amplified products from tumor DNA were analyzed by denaturing gradient gel electrophoresis and direct DNA sequencing. RESULTS Forty-four tumors were found to be mutated (52%). A strong correlation between the presence of a mutation and short survival was observed (P = 0.003). When tumors were classified according to their histological stage, a multivariate Cox model analysis showed that p53 mutation, rather than 17p allelic loss (previously proposed to convey prognostic information), was retained as the only independent prognostic factor (relative risk, 2.25; 95% confidence interval, 1.06-4.80; P < 0.029). CONCLUSIONS Combined with staging, direct monitoring of p53 mutation improves prognostic accuracy for colorectal cancer.

Value of axillary dissection in addition to lumpectomy and radiotherapy in early breast cancer

Axillary dissection in early breast cancer remains controversial because of its substantial side-effects and because its value with respect to recurrence or survival has not been unequivocally proven. Between 1982 and 1987, 658 patients were included in a prospective randomised comparison of lumpectomy alone with lumpectomy plus axillary dissection. All patients had a unilateral breast tumour not exceeding 3 cm in diameter and lymph-node involvement or metastases. Radiation therapy was given to both groups. The two groups of patients were similar with respect to mean age, TNM stage, and presence of hormonal receptors. Median follow-up was 54 months. 5-year survival of the patients was 94.2% (95% Cl: 92.1-96.4). There was a significant advantage in survival in the axillary dissection group (p = 0.014). Recurrence of tumour in the breast was similar in the two groups but visceral metastases, supraclavicular metastases, and lymph-node recurrences were less frequent in the axillary dissection group. Survival was related to the age of the patients (p = 0.005), the presence of positive nodes (p = 0.006), the histological grading (p less than 0.0001), and the presence of hormonal receptors (progesterone p = 0.0008, oestrogen p less than 0.0001). Treatment-adjusted relative risk was 2.4 (95% Cl: 1.3-4.2). The findings show that axillary dissection is justified for treatment of small breast cancers, although whether the better survival is due to axillary clearance itself or to adjuvant treatment for lymph-node involvement is unclear.

Incidence and Prognostic Significance of Complete Axillary Downstaging After Primary Chemotherapy in Breast Cancer Patients With T1 to T3 Tumors and Cytologically Proven Axillary Metastatic Lymph Nodes

PURPOSE To determine the incidence and prognostic significance of eradication of cytologically proven axillary lymph node metastases in breast cancer patients treated with primary chemotherapy. PATIENTS AND METHODS Between January 1985 and December 1994, 152 breast cancer patients with invasive T1 to T3 tumors and axillary metastases cytologically proven by fine-needle sampling underwent primary chemotherapy followed by lumpectomy or mastectomy, level I and II axillary lymph node dissection, and irradiation. We studied pathologic complete responses (pCRs) of axillary nodes and breast tumors, as well as predictors of distant metastases. RESULTS Thirty-five patients (23%) had axillary pCRs, and 20 patients (13.2%) had pCRs of primary breast tumors. Scarff-Bloom-Richardson grade 3 tumors (P =.04) and a clinical response to chemotherapy > or = 50% (P =.003) were associated with negative axillary status at dissection. An initial tumor size < or = 3 cm (63 patients) was associated with pCR of the primary tumor (P =.02) but not with complete histologic clearance of axillary lymph nodes. The median length of follow-up was 75 months. In the univariate analysis, age greater than 40 years (P =.003), absence of residual nodal disease (P =.01), and pCR of the tumor (P =.05) were associated with better distant disease-free survival. Five-year distant disease-free survival rates were 73.5% +/- 14.9% among patients with no involved nodes at the time of surgery and 48.7% +/- 9.2% among patients with residual nodal disease. In the multivariate Cox regression analysis, parameters associated with poor distant disease-free survival were age < or = 40 years (P =.002), persistence of nodal involvement (P =.03), and S-phase fraction greater than 4% (P =.02). CONCLUSION Our results suggest that axillary status is a better prognostic factor than response of the primary tumor to primary chemotherapy.

Stochastic Models of Tumor Latency and Their Biostatistical Applications

Statistical inference from censored data mathematical description of tumour latency regression analysis of tumour recurrence data threshold models of tumor growth statistical analysis of discrete cancer surveillance optimal strategies of cancer surveillance - minimum delay time approach, minimum cost approach.

Ki67 Expression and Docetaxel Efficacy in Patients With Estrogen Receptor–Positive Breast Cancer

PURPOSE The indications of adjuvant chemotherapy for patients with estrogen receptor (ER) -positive breast cancer are controversial. We analyzed the predictive value of Ki67, HER2, and progesterone receptor (PR) expression for the efficacy of docetaxel in patients with ER-positive, node-positive breast cancer. PATIENTS AND METHODS Expression of Ki67, HER2, and PR was measured by immunohistochemistry in tumor samples from 798 patients with ER-positive breast cancer who participated in PACS01, a randomized trial that evaluated the efficacy of docetaxel. Risk reduction was evaluated using a Cox model adjusted for age, tumor size, nodal involvement, treatment arm, and biomarkers. The predictive value of biomarkers was assessed by an interaction test. Disease-free survival (DFS) was the primary end point. Results Ki67, HER2, and PR were expressed in 21%, 9%, and 62% of samples, respectively. Hazard ratios for relapse associated with docetaxel were 0.51 (95% CI, 0.26 to 1.01) in ER-positive/Ki67-positive tumors and 1.03 (95% CI, 0.69 to 1.55) in ER-positive/Ki67-negative tumors (ratio for interaction: 0.53; 95% CI, 0.24 to 1.16; P = .11). Five-year DFS rates were 81% (95% CI, 76% to 86%) and 84% (95% CI, 75% to 93%) in patients with ER-positive/Ki67-negative and ER-positive/Ki67-positive tumors treated with docetaxel and 81% (95% CI, 76% to 86%) and 62% (95% CI, 52% to 72%) in patients with ER-positive/Ki67-negative and ER-positive/Ki67-positive tumors treated with fluorouracil, epirubicin, and cisplatin. No trend for interaction was observed between docetaxel and HER2 (ratio for interaction: 0.83; 95% CI, 0.35 to 1.94; P = .66), nor between docetaxel and PR (ratio for interaction: 0.89; 95% CI, 0.47 to 1.66; P = .71). CONCLUSION Ki67 expression identifies a subset of patients with ER-positive breast cancer who could be sensitive to docetaxel treatment in the adjuvant setting.

Axillary Treatment in Conservative Management of Operable Breast Cancer: Dissection or Radiotherapy? Results of a Randomized Study With 15 Years of Follow-Up

PURPOSE Axillary dissection is the standard management of the axilla in invasive breast carcinoma. This surgery is responsible for functional sequelae and some options are considered, including axillary radiotherapy. In 1992, we published the initial results of a prospective randomized trial comparing lumpectomy plus axillary radiotherapy versus lumpectomy plus axillary dissection. We present an update of this study with a median follow-up of 180 months (range, 12 to 221 months). PATIENTS AND METHODS Between 1982 and 1987, 658 patients with a breast carcinoma less than 3 cm in diameter and clinically uninvolved lymph nodes were randomly assigned to axillary dissection or axillary radiotherapy. All patients underwent wide excision of the tumor and breast irradiation. RESULTS The two groups were similar for age, tumor-node-metastasis system stage, and presence of hormonal receptors; 21% of the patients in the axillary dissection group were node-positive. Our initial results showed an increased survival rate in the axillary dissection group at 5 years (P =.009). At 10 and 15 years, however, survival rates were identical in both groups (73.8% v 75.5% at 15 years). Recurrences in the axillary node were less frequent in the axillary dissection group at 15 years (1% v 3%; P =.04). There was no difference in recurrence rates in the breast or supraclavicular and distant metastases between the two groups. CONCLUSION In early breast cancers with clinically uninvolved lymph nodes, our findings show that long-term survival does not differ after axillary radiotherapy and axillary dissection. The only difference is a better axillary control in the group with axillary dissection.

Regional copy number–independent deregulation of transcription in cancer

Genetic and epigenetic alterations have been identified that lead to transcriptional deregulation in cancers. Genetic mechanisms may affect single genes or regions containing several neighboring genes, as has been shown for DNA copy number changes. It was recently reported that epigenetic suppression of gene expression can also extend to a whole region; this is known as long-range epigenetic silencing. Various techniques are available for identifying regional genetic alterations, but no large-scale analysis has yet been carried out to obtain an overview of regional epigenetic alterations. We carried out an exhaustive search for regions susceptible to such mechanisms using a combination of transcriptome correlation map analysis and array CGH data for a series of bladder carcinomas. We validated one candidate region experimentally, demonstrating histone methylation leading to the loss of expression of neighboring genes without DNA methylation.