Andrew Kramar

Trastuzumab for Patients With Axillary-Node–Positive Breast Cancer: Results of the FNCLCC-PACS 04 Trial

PURPOSE To evaluate the efficacy of trastuzumab in patients with node-positive breast cancer treated with surgery, adjuvant chemotherapy, radiotherapy, and hormone therapy if applicable. PATIENTS AND METHODS Three thousand ten patients with operable node-positive breast cancer were randomly assigned to receive adjuvant anthracycline-based chemotherapy with or without docetaxel. Patients who presented human epidermal growth factor receptor 2 (HER2) -overexpressing tumors were secondary randomly assigned to either a sequential regimen of trastuzumab (6 mg/kg every 3 weeks) for 1 year or observation. The primary end point was disease-free survival (DFS). RESULTS Overall 528 patients were randomly assigned between trastuzumab (n = 260) and observation (n = 268) arm. Of the 234 patients (90%) who received at least one administration of trastuzumab, 196 (84%) received at least 6 months of treatment, and 41 (18%) discontinued treatment due to cardiac events (any grade). At the date of analysis (October 2007), 129 DFS events were recorded. Random assignment to the trastuzumab arm was associated with a nonsignificant 14% reduction in the risk of relapse (hazard ratio, 0.86; 95% CI, 0.61 to 1.22; P = .41, log-rank stratified on pathologic node involvement). Three-year DFS rates were 78% (95% CI, 72.3 to 82.5) and 81% (95% CI, 75.3 to 85.4) in the observation and trastuzumab arms, respectively. CONCLUSION After a 47-month median follow-up, 1 year of trastuzumab given sequentially after adjuvant chemotherapy was not associated with a statistically significant decrease in the risk of relapse.

Adequate locoregional treatment for early breast cancer may prevent secondary dissemination.

PURPOSE To analyze different events that determine event-free survival (EFS) in a randomized trial on adjuvant radiotherapy in early breast cancer patients with more than 15 years of follow-up evaluation. PATIENTS AND METHODS The trial included 960 patients with a unilateral, operable breast cancer. Surgery consisted of a modified radical mastectomy. The trial compared three arms, as follows: preoperative radiotherapy, postoperative radiotherapy, and no adjuvant treatment. Events were analyzed by a competing-risk approach. A proportional hazards multiple regression model was used to analyze the effects of radiotherapy on the risk of distant metastasis. Similar analyses were performed separately for node-negative [N(-)] and node-positive [N(+)] patients in the two groups that did not include preoperative radiotherapy. RESULTS Radiotherapy produced a fivefold decrease of the risk of local recurrence (P < .0001). In N(+) patients, postoperative radiotherapy decreased the risk of distant dissemination (relative risk, 0.63). When local recurrence was introduced in the model as a time-dependent covariate, this factor was predictive of distant dissemination (P < .0001) and nullified the effect of postoperative radiotherapy. This finding suggests that the decrease of distant metastases was related to the prevention of local recurrence. A similar effect was found in models that used overall survival as an end point. CONCLUSION This study shows that postmastectomy radiotherapy in N(+) breast cancer patients may decrease the distant metastasis rate by preventing local recurrences and thus avoiding secondary dissemination.

CD4 and CD8 T-lymphocyte apoptosis can predict radiation-induced late toxicity: a prospective study in 399 patients.

Purpose: Predicting late effects in patients treated with radiation therapy by assessing in vitro radiation-induced CD4 and CD8 T-lymphocyte apoptosis can be useful in individualizing treatment. Experimental Design: In a prospective study, 399 curatively irradiated patients were tested using a rapid assay where fresh blood samples were in vitro irradiated with 8 Gy X-rays. Lymphocytes were collected and prepared for flow cytometric analysis. Apoptosis was assessed by associated condensation of DNA. The incidences of late toxicities were compared for CD4 and CD8 T-lymphocyte apoptoses using receiver-operating characteristic curves and cumulative incidence. Results: No association was found between early toxicity and T-lymphocyte apoptosis. Grade 2 and 3 late toxicities were observed in 31% and 7% of patients, respectively. More radiation-induced T-lymphocyte apoptosis was significantly associated with less grade 2 and 3 late toxicity (Grays test, P < 0.0001). CD8 (area under the curve = 0.83) was more sensitive and specific than CD4. No grade 3 late toxicity was observed for patients with CD4 and CD8 values greater than 15% and 24%, respectively. The 2-year cumulative incidence for grade 2 or 3 late toxicity was 70%, 32%, and 12% for patients with absolute change in CD8 T-lymphocyte apoptosis of ≤16, 16 to 24, and >24, respectively. Conclusions: Radiation-induced T-lymphocyte apoptosis can significantly predict differences in late toxicity between individuals. It could be used as a rapid screen for hypersensitive patients to radiotherapy. In future dose escalation studies, patients could be selected using the apoptosis assay.

Development and Validation of a Prognostic Model to Predict the Length of Survival in Patients With Carcinomas of an Unknown Primary Site

PURPOSE To identify clinical and biologic variables with significant impact on survival in patients with carcinomas of an unknown primary site and to develop a simple prognostic model for the selection of patients in prospective clinical trials. PATIENTS AND METHODS Univariate and multivariate prognostic factor analyses were conducted in a population of 150 unselected patients and led to the construction of two successive classification schemes. An external data set of 116 patients enrolled onto two prospective trials was used for validation. RESULTS When studying clinical variables only, poor performance status (2 or 3) and presence of liver metastases were retained in the multivariate analysis. The first classification scheme consisted of three subgroups of patients with median survivals of 10.8, 6.0, and 2.4 months, according to the number of adverse prognostic factors. With the introduction of serum lactate dehydrogenase (LDH) levels in a further step, liver metastases were no longer significant. The second classification scheme therefore included poor performance status (relative risk [RR], 2.1) and elevated serum LDH level (RR, 2.1). Good-risk and poor-risk patients were identified, with median survivals of 11.7 months and 3.9 months, respectively (P <.0001). The 1-year survival rates were 45% and 11%, respectively. This second classification scheme was validated in an external data set: the median survival rates of patients assigned to the good-risk group and the poor-risk group were 12 months and 7 months, respectively (P =.0089). The 1-year survival rates were 53% and 23%, respectively. CONCLUSION A simple prognostic model using performance status and serum LDH levels was developed and validated. It allows the assignment of patients into two subgroups with divergent outcome. Further prospective trials will be designed using this prognostic model.

6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial

BACKGROUND Since 2005, 12 months of adjuvant trastuzumab has been the standard treatment for patients with HER2-positive early-stage breast cancer. However, the optimum duration of treatment has been debated. We did a non-inferiority trial of a shorter exposure of 6 months versus the standard 12 months of trastuzumab for patients with early breast cancer. METHODS We did an open-label, randomised, phase 3 trial in 156 centres in France. Patients with HER2-positive early breast cancer who had received at least four cycles of chemotherapy, had breast-axillary surgery, and had received up to 6 months of trastuzumab (administered by intravenous infusions over 30-90 min every 3 weeks; initial loading dose 8 mg/kg; 6 mg/kg thereafter) before randomisation were eligible. Patients were randomly assigned via central randomisation procedure with web-based software to continue trastuzumab for another 6 months (12 months total duration; control group) or to discontinue trastuzumab at 6 months (6 months total duration; experimental group). Randomisation was stratified by concomitant or sequential administration of trastuzumab with chemotherapy, oestrogen-receptor status, and centre using a minimisation algorithm. The primary endpoint was disease-free survival, with a prespecified non-inferiority margin of 1·15. Analyses were done in the intention-to-treat population. This study is registered at ClinicalTrials.gov, number NCT00381901. FINDINGS 1691 patients were randomly assigned to receive 12 months of trastuzumab and 1693 to receive 6 months of trastuzumab; 1690 patients in each group were included in the intention-to-treat analyses. After a median follow-up of 42·5 months (IQR 30·1-51·6), 175 disease-free survival events were noted in the 12-month group and 219 in the 6-month group. 2-year disease-free survival was 93·8% (95% CI 92·6-94·9) in the 12-month group and 91·1% (89·7-92·4) in the 6-month group (hazard ratio 1·28, 95% CI 1·05-1·56; p=0·29). 119 (93%) of the 128 cardiac events (clinical or based on assessment of left ventricular ejection fraction) occurred while patients were receiving trastuzumab. Significantly more patients in the 12-month group experienced a cardiac event than did those in the 6-month group (96 [5·7%] of 1690 patients vs 32 [1·9%] of 1690 patients, p<0·0001). INTERPRETATION After 3·5 years follow-up, we failed to show that 6 months of treatment with trastuzumab was non-inferior to 12 months of trastuzumab. Despite the higher rates of cardiac events, 12 months of adjuvant trastuzmab should remain the standard of care. FUNDING French National Cancer Institute.

Prognostic Factors in Patients With Metastatic Germ Cell Tumors Who Experienced Treatment Failure With Cisplatin-Based First-Line Chemotherapy

PURPOSE To develop a prognostic model in patients with germ cell tumors (GCT) who experience treatment failure with cisplatin-based first-line chemotherapy. PATIENTS AND METHODS Data from 1,984 patients with GCT who progressed after at least three cisplatin-based cycles and were treated with cisplatin-based conventional-dose or carboplatin-based high-dose salvage chemotherapy was retrospectively collected from 38 centers/groups worldwide. One thousand five hundred ninety-four (80%) of 1,984 eligible patients were randomly divided into a training set of 1,067 patients (67%) and a validation set of 527 patients (33%). Seminomas were set aside for posthoc analyses. Primary end point was the 2-year progression-free survival after salvage treatment. RESULTS Overall, 990 patients (62%) relapsed and 604 patients (38%) remained relapse free. Histology, primary tumor location, response, and progression-free interval after first-line treatment, as well as levels of alpha fetoprotein, human chorionic gonadotrophin, and the presence of liver, bone, or brain metastases at salvage were identified as independent prognostic variables and used to build a prognostic model in the training set. Survival rates in the training and validation set were very similar. The estimated 2-year progression-free survival rates in patients not included in the training set was 75% in very low risk, 51% in low risk, 40% in intermediate risk, 26% in high risk, and only 6% in very high-risk patients. Due to missing values in individual variables, 69 patients could not reliably be classified into one of these categories. CONCLUSION Prognostic variables are important in patients with GCT who experienced treatment failure with cisplatin-based first-line chemotherapy and can be used to construct a prognostic model to guide salvage strategies.

Estrogen Receptor β (ERβ) Level but Not Its ERβcx Variant Helps to Predict Tamoxifen Resistance in Breast Cancer

The antiestrogen tamoxifen, a major endocrine therapy of estrogen receptor (ER)-positive breast cancer, is nevertheless inefficient in 30 to 40% of cases for unknown reasons. We retrospectively studied 50 ER-positive primary breast carcinomas. All of the patients had received tamoxifen as the only adjuvant therapy. They were divided into two groups depending on whether they relapsed within 5 years (16 tamoxifen-resistant cases) or did not relapse within 5 years (34 tamoxifen-sensitive cases). The expression of total ERβ protein, and of ERβcx protein, was estimated anonymously in formalin-fixed, paraffin-embedded tumor sections, by using specific antibodies and quantifiying nuclear immunostaining with a computer image analyzer. All of the tumors were found to be HER-2/neu-negative by immunohistochemistry. Univariate analysis showed that Scarff-Bloom-Richardsson grade modified by Elston (SBR grade; P < 0.001), tumor size (P = 0.042), and MIB-1 proliferation index (P = 0.02) were significantly higher in tamoxifen-resistant tumors. A low level of total ERβ, whether in percentage of positive cells or in quantitative immunocytochemical (QIC) score, was also associated with tamoxifen resistance (P = 0.004). ERβcx expression and lymph node status were similar between the two groups. The expression of ERβ in the total population was positively correlated with ERβcx (r = 0.63, P < 0.001), and was independent of the other parameters. In a multivariate analysis, ERβ expression was the most important variable (P = 0.001), followed by SBR grade (I+II versus III; P = 0.008), and MIB-1 (P = 0.016). To conclude, tamoxifen resistance is associated with classical variables of aggressive tumors (high SBR grade, proliferation index, and tumor size) but not with node invasiveness. Low ERβ level is an additional independent marker, better than ERα level, to predict tamoxifen resistance.

Conventional-Dose Versus High-Dose Chemotherapy As First Salvage Treatment in Male Patients With Metastatic Germ Cell Tumors: Evidence From a Large International Database

PURPOSE Conventional-dose chemotherapy (CDCT) and high-dose chemotherapy (HDCT) may both be successfully used as salvage treatment for patients with metastatic germ cell tumors (GCTs) who experience progression with first-line treatment. PATIENTS AND METHODS Data on 1,984 patients with GCTs who experienced progression after at least three cisplatin-based cycles and were treated with either cisplatin-based CDCT or carboplatin-based HDCT chemotherapy were collected from 38 centers or groups worldwide. Of 1,984 patients, 1,594 (80%) were eligible, and among the eligible patients, 1,435 (90%) could reliably be classified into one of the following five prognostic categories based on prior prognostic classification: very low (n = 76), low (n = 257), intermediate (n = 646), high (n = 351), and very high risk (n = 105). Within each of the five categories, the progression-free survival (PFS) and overall survival (OS) after CDCT and HDCT were compared using the Cox model adjusted for significant distributional differences between important variables. RESULTS Overall, 773 patients received CDCT, and 821 patients received HDCT. Both treatment modalities were used with similar frequencies within each prognostic category. The hazard ratio for PFS was 0.44 (95% CI, 0.39 to 0.51) stratified on prognostic category, and the hazard ratio for OS was 0.65 (95% CI, 0.56 to 0.75), favoring HDCT. These results were consistent within each prognostic category except among low-risk patients, for whom similar OS was observed between the two treatment groups. CONCLUSION This retrospective analysis suggests a benefit from HDCT given as intensification of first salvage treatment in male patients with GCTs and emphasizes the need for another prospective randomized trial comparing CDCT to HDCT in this patient population.

Single nucleotide polymorphisms, apoptosis, and the development of severe late adverse effects after radiotherapy.

Purpose: Evidence has accumulated in recent years suggestive of a genetic basis for a susceptibility to the development of radiation injury after cancer radiotherapy. The purpose of this study was to assess whether patients with severe radiation-induced sequelae (RIS; i.e., National Cancer Institute/CTCv3.0 grade, ≥3) display both a low capacity of radiation-induced CD8 lymphocyte apoptosis (RILA) in vitro and possess certain single nucleotide polymorphisms (SNP) located in candidate genes associated with the response of cells to radiation. Experimental Design: DNA was isolated from blood samples obtained from patients (n = 399) included in the Swiss prospective study evaluating the predictive effect of in vitro RILA and RIS. SNPs in the ATM, SOD2, XRCC1, XRCC3, TGFB1, and RAD21 genes were screened in patients who experienced severe RIS (group A, n = 16) and control subjects who did not manifest any evidence of RIS (group B, n = 18). Results: Overall, 13 and 21 patients were found to possess a total of <4 and ≥4 SNPs in the candidate genes. The median (range) RILA in group A was 9.4% (5.3-16.5) and 94% (95% confidence interval, 70-100) of the patients (15 of 16) had ≥4 SNPs. In group B, median (range) RILA was 25.7% (20.2-43.2) and 33% (95% confidence interval, 13-59) of patients (6 of 18) had ≥4 SNPs (P < 0.001). Conclusions: The results of this study suggest that patients with severe RIS possess 4 or more SNPs in candidate genes and low radiation-induced CD8 lymphocyte apoptosis in vitro.

Gene Expression Signature in Advanced Colorectal Cancer Patients Select Drugs and Response for the Use of Leucovorin, Fluorouracil, and Irinotecan

PURPOSE In patients with advanced colorectal cancer, leucovorin, fluorouracil, and irinotecan (FOLFIRI) is considered as one of the reference first-line treatments. However, only about half of treated patients respond to this regimen, and there is no clinically useful marker that predicts response. A major clinical challenge is to identify the subset of patients who could benefit from this chemotherapy. We aimed to identify a gene expression profile in primary colon cancer tissue that could predict chemotherapy response. PATIENTS AND METHODS Tumor colon samples from 21 patients with advanced colorectal cancer were analyzed for gene expression profiling using Human Genome GeneChip arrays U133. At the end of the first-line treatment, the best observed response, according to WHO criteria, was used to define the responders and nonresponders. Discriminatory genes were first selected by the significance analysis of microarrays algorithm and the area under the receiver operating characteristic curve. A predictor classifier was then constructed using support vector machines. Finally, leave-one-out cross validation was used to estimate the performance and the accuracy of the output class prediction rule. RESULTS We determined a set of 14 predictor genes of response to FOLFIRI. Nine of nine responders (100% specificity) and 11 of 12 nonresponders (92% sensitivity) were classified correctly, for an overall accuracy of 95%. CONCLUSION After validation in an independent cohort of patients, our gene signature could be used as a decision tool to assist oncologists in selecting colorectal cancer patients who could benefit from FOLFIRI chemotherapy, both in the adjuvant and the first-line metastatic setting.