Clinical and genomic analysis of a randomised phase II study evaluating anastrozole and fulvestrant in postmenopausal patients treated for large operable or locally advanced hormone-receptor-positive breast cancer.

BACKGROUND: The aim of this study was to assess the efficacy of neoadjuvant anastrozole and fulvestrant treatment of large operable or locally advanced hormone-receptor-positive breast cancer not eligible for initial breast-conserving surgery, and to identify genomic changes occurring after treatment. METHODS: One hundred and twenty post-menopausal patients were randomised to receive 1 mg anastrozole (61 patients) or 500 mg fulvestrant (59 patients) for 6 months. Genomic DNA copy number profiles were generated for a subgroup of 20 patients before and after treatment. RESULTS: A total of 108 patients were evaluable for efficacy and 118 for toxicity. The objective response rate determined by clinical palpation was 58.9% (95% CI=45.0-71.9) in the anastrozole arm and 53.8% (95% CI=39.5-67.8) in the fulvestrant arm. The breast-conserving surgery rate was 58.9% (95% CI=45.0-71.9) in the anastrozole arm and 50.0% (95% CI=35.8-64.2) in the fulvestrant arm. Pathological responses >50% occurred in 24 patients (42.9%) in the anastrozole arm and 13 (25.0%) in the fulvestrant arm. The Ki-67 score fell after treatment but there was no significant difference between the reduction in the two arms (anastrozole 16.7% (95% CI=13.3-21.0) before, 3.2% (95% CI=1.9-5.5) after, n=43; fulvestrant 17.1% (95%CI=13.1-22.5) before, 3.2% (95% CI=1.8-5.7) after, n=38) or between the reduction in Ki-67 in clinical responders and non-responders. Genomic analysis appeared to show a reduction of clonal diversity following treatment with selection of some clones with simpler copy number profiles. CONCLUSIONS: Both anastrozole and fulvestrant were effective and well-tolerated, enabling breast-conserving surgery in over 50% of patients. Clonal changes consistent with clonal selection by the treatment were seen in a subgroup of patients.

Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer.

BACKGROUND: The aromatase inhibitor letrozole, as compared with tamoxifen, improves disease-free survival among postmenopausal women with receptor-positive early breast cancer. It is unknown whether sequential treatment with tamoxifen and letrozole is superior to letrozole therapy alone. METHODS: In this randomized, phase 3, double-blind trial of the treatment of hormone-receptor-positive breast cancer in postmenopausal women, we randomly assigned women to receive 5 years of tamoxifen monotherapy, 5 years of letrozole monotherapy, or 2 years of treatment with one agent followed by 3 years of treatment with the other. We compared the sequential treatments with letrozole monotherapy among 6182 women and also report a protocol-specified updated analysis of letrozole versus tamoxifen monotherapy in 4922 women. RESULTS: At a median follow-up of 71 months after randomization, disease-free survival was not significantly improved with either sequential treatment as compared with letrozole alone (hazard ratio for tamoxifen followed by letrozole, 1.05; 99% confidence interval [CI], 0.84 to 1.32; hazard ratio for letrozole followed by tamoxifen, 0.96; 99% CI, 0.76 to 1.21). There were more early relapses among women who were assigned to tamoxifen followed by letrozole than among those who were assigned to letrozole alone. The updated analysis of monotherapy showed that there was a nonsignificant difference in overall survival between women assigned to treatment with letrozole and those assigned to treatment with tamoxifen (hazard ratio for letrozole, 0.87; 95% CI, 0.75 to 1.02; P=0.08). The rate of adverse events was as expected on the basis of previous reports of letrozole and tamoxifen therapy. CONCLUSIONS: Among postmenopausal women with endocrine-responsive breast cancer, sequential treatment with letrozole and tamoxifen, as compared with letrozole monotherapy, did not improve disease-free survival. The difference in overall survival with letrozole monotherapy and tamoxifen monotherapy was not statistically significant. (ClinicalTrials.gov number, NCT00004205.)

Radiofrequency ablation as a substitute for surgery in elderly patients with nonresected breast cancer: pilot study with long-term outcomes.

PURPOSE: To determine the efficacy and tolerance of ultrasonography (US)-guided percutaneous radiofrequency (RF) ablation with endocrine therapy in elderly patients with breast cancer who decline or are not candidates for surgery. MATERIALS AND METHODS: Internal ethics committee approval was obtained, and patients gave informed written consent. Women older than 70 years with breast carcinoma, who had undergone neoadjuvant endocrine therapy within the past 6 months, underwent US-guided RF ablation while under local anesthesia and sedation. Only tumors measuring 3 cm or smaller and situated at least 1 cm from the skin, nipple, and chest wall were selected. Multitine electrodes were used. Endocrine therapy was continued for a total of 5 years, and breast irradiation was not performed. Clinical follow-up included US, mammography, and dynamic contrast material-enhanced (DCE) magnetic resonance (MR) imaging every 2 months for 6 months and then every 6 months until 5 years. Primary end points were RF ablation efficacy at 1 year on the basis of DCE MR imaging follow-up and procedural tolerance. The secondary end point was delayed local efficacy at the end of endocrine therapy (5 years) on the basis of DCE MR imaging follow-up. RESULTS: Twenty-one women were treated from December 2004 to April 2010 (median age, 79 years; age range, 70-88 years). Efficacy was demonstrated at 1 year, with only one patient presenting with a local relapse. No general complications were noted. Skin burn occurred in four patients, with spontaneous healing after a maximum of 2 months. Ten patients were followed up for 5 years, with three additional patients presenting with cancer recurrence outside the ablation zone at 30, 48, and 60 months-including two with lobular carcinoma. Four patients died during the full follow-up, two of breast cancer-related causes and two of unrelated causes. CONCLUSION: RF ablation in elderly patients with nonresected breast cancer is well tolerated and efficient at 1-year follow-up. The technique is not recommended for lobular carcinoma.

Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up.

BACKGROUND: Postmenopausal women with hormone receptor-positive early breast cancer have persistent, long-term risk of breast-cancer recurrence and death. Therefore, trials assessing endocrine therapies for this patient population need extended follow-up. We present an update of efficacy outcomes in the Breast International Group (BIG) 1-98 study at 8·1 years median follow-up. METHODS: BIG 1-98 is a randomised, phase 3, double-blind trial of postmenopausal women with hormone receptor-positive early breast cancer that compares 5 years of tamoxifen or letrozole monotherapy, or sequential treatment with 2 years of one of these drugs followed by 3 years of the other. Randomisation was done with permuted blocks, and stratified according to the two-arm or four-arm randomisation option, participating institution, and chemotherapy use. Patients, investigators, data managers, and medical reviewers were masked. The primary efficacy endpoint was disease-free survival (events were invasive breast cancer relapse, second primaries [contralateral breast and non-breast], or death without previous cancer event). Secondary endpoints were overall survival, distant recurrence-free interval (DRFI), and breast cancer-free interval (BCFI). The monotherapy comparison included patients randomly assigned to tamoxifen or letrozole for 5 years. In 2005, after a significant disease-free survival benefit was reported for letrozole as compared with tamoxifen, a protocol amendment facilitated the crossover to letrozole of patients who were still receiving tamoxifen alone; Cox models and Kaplan-Meier estimates with inverse probability of censoring weighting (IPCW) are used to account for selective crossover to letrozole of patients (n=619) in the tamoxifen arm. Comparison of sequential treatments to letrozole monotherapy included patients enrolled and randomly assigned to letrozole for 5 years, letrozole for 2 years followed by tamoxifen for 3 years, or tamoxifen for 2 years followed by letrozole for 3 years. Treatment has ended for all patients and detailed safety results for adverse events that occurred during the 5 years of treatment have been reported elsewhere. Follow-up is continuing for those enrolled in the four-arm option. BIG 1-98 is registered at clinicaltrials.govNCT00004205. FINDINGS: 8010 patients were included in the trial, with a median follow-up of 8·1 years (range 0-12·4). 2459 were randomly assigned to monotherapy with tamoxifen for 5 years and 2463 to monotherapy with letrozole for 5 years. In the four-arm option of the trial, 1546 were randomly assigned to letrozole for 5 years, 1548 to tamoxifen for 5 years, 1540 to letrozole for 2 years followed by tamoxifen for 3 years, and 1548 to tamoxifen for 2 years followed by letrozole for 3 years. At a median follow-up of 8·7 years from randomisation (range 0-12·4), letrozole monotherapy was significantly better than tamoxifen, whether by IPCW or intention-to-treat analysis (IPCW disease-free survival HR 0·82 [95% CI 0·74-0·92], overall survival HR 0·79 [0·69-0·90], DRFI HR 0·79 [0·68-0·92], BCFI HR 0·80 [0·70-0·92]; intention-to-treat disease-free survival HR 0·86 [0·78-0·96], overall survival HR 0·87 [0·77-0·999], DRFI HR 0·86 [0·74-0·998], BCFI HR 0·86 [0·76-0·98]). At a median follow-up of 8·0 years from randomisation (range 0-11·2) for the comparison of the sequential groups with letrozole monotherapy, there were no statistically significant differences in any of the four endpoints for either sequence. 8-year intention-to-treat estimates (each with SE ≤1·1%) for letrozole monotherapy, letrozole followed by tamoxifen, and tamoxifen followed by letrozole were 78·6%, 77·8%, 77·3% for disease-free survival; 87·5%, 87·7%, 85·9% for overall survival; 89·9%, 88·7%, 88·1% for DRFI; and 86·1%, 85·3%, 84·3% for BCFI. INTERPRETATION: For postmenopausal women with endocrine-responsive early breast cancer, a reduction in breast cancer recurrence and mortality is obtained by letrozole monotherapy when compared with tamoxifen montherapy. Sequential treatments involving tamoxifen and letrozole do not improve outcome compared with letrozole monotherapy, but might be useful strategies when considering an individual patient's risk of recurrence and treatment tolerability. FUNDING: Novartis, United States National Cancer Institute, International Breast Cancer Study Group.

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.

Ductal carcinoma in situ of the breast: influence of age on diagnostic, therapeutic, and prognostic features. Retrospective study of 812 patients.

BACKGROUND: The objective of this retrospective study was to identify prognostic, diagnostic, and therapeutic disparities between younger (≤ 40 years) and older (> 40 years) women with ductal carcinoma in situ (DCIS) of the breast. METHODS: From 1971 to 2001, all patients treated for DCIS at Institut Bergonié were included in our analyses. Follow-up data was collected over 10 years. We used univariate and multivariate analyses to investigate patient-, disease-, and treatment-related factors predictive of diagnostic, histological, therapeutic, and prognostic DCIS criteria. RESULTS: A total of 812 patients were eligible including 731 women aged >40 years and 81 women ≤40 years. Younger women with DCIS were more likely to receive a mastectomy and less likely to receive radiotherapy. Young age and initial surgical treatment (lumpectomy and especially nonfree margins) were revealed as predictive of recurrence in multivariate analyses. CONCLUSIONS: Young age represents a recurrence risk independent of histological and clinical characteristics of the tumor. Initial treatment, especially for nonfree margins, is also a predictive factor. Appropriate initial surgery with particularly wide margins appears essential for the treatment of young women with DCIS.

Efficacy of trastuzumab in routine clinical practice and after progression for metastatic breast cancer patients: the observational Hermine study.

BACKGROUND: The Hermine study observed the use of trastuzumab for metastatic breast cancer (MBC) in routine practice, including patients who received trastuzumab treatment beyond progression (TBP). PATIENTS AND METHODS: The study observed 623 patients for > or = 2 years. Treatment was given according to oncologists' normal clinical practices. Endpoints included duration of treatment, efficacy, and cardiac safety. The TBP subanalysis compared overall survival (OS) in 177 patients who received first-line trastuzumab and either continued trastuzumab for > or = 30 days following progression or stopped at or before progression. RESULTS: The median treatment duration was 13.3 months. In the first-, second-, and third-line or beyond treatment groups, the median time to progression (TTP) were 10.3 months, 9.0 months, and 6.3 months, and the median OS times were 30.3 months, 27.1 months, and 23.2 months, respectively. Heart failure was observed in 2.6% of patients, although no cardiac-associated deaths occurred. In the TBP subanalysis, the median OS duration from treatment initiation and time of disease progression were longer in patients who continued receiving trastuzumab TBP (>27.8 months and 21.3 months, respectively) than in those who stopped (16.8 months and 4.6 months, respectively). However, the groups were not completely comparable, because patients who continued trastuzumab TBP had better prognoses at treatment initiation. The median TTP was longer in patients who continued trastuzumab TBP (10.2 months) than in those who stopped (7.1 months). CONCLUSION: The Hermine findings confirm that the pivotal trials of first-line trastuzumab treatment in MBC patients are applicable in clinical practice. The subanalysis suggests that trastuzumab TBP offers a survival benefit to MBC patients treated with first-line trastuzumab.

Results of a phase II study comparing three dosing regimens of fulvestrant in postmenopausal women with advanced breast cancer (FINDER2).

The Faslodex Investigation of Dose evaluation in Estrogen Receptor-positive advanced breast cancer (FINDER)2 study evaluated the efficacy, safety, and pharmacokinetics (PK) of three fulvestrant dosing regimens. FINDER2 enrolled Western postmenopausal women recurring or progressing after prior endocrine therapy. Primary endpoint: objective response rate (ORR); secondary endpoints: time to progression (TTP), clinical benefit rate (CBR), tolerability, and PK parameters. Patients were randomized to receive fulvestrant: 250 mg/month (approved dose [AD]); 250 mg plus loading dose (loading dose [LD]; 500 mg on day 0, 250 mg on days 14, 28, and monthly thereafter); or 500 mg (high dose [HD]; 500 mg/month plus 500 mg on day 14 of Month 1). Treatment continued until disease progression or discontinuation. 144 patients were randomized: fulvestrant AD (n = 47); LD (n = 51); HD (n = 46). ORRs were: 8.5% (95% confidence interval [CI]: 2.4, 20.4%), 5.9% (1.2, 16.2%), and 15.2% (6.3, 28.9%) in the AD, LD, and HD arms, respectively. CBRs were: 31.9% (95% CI: 19.1, 47.1%), 47.1% (32.9, 61.5%), and 47.8% (32.9, 63.1%) for the AD, LD, and HD arms, respectively. Median TTP (months) was numerically longer for HD (6.0) and LD (6.1) versus AD (3.1). Tolerability was similar across dosing regimens. Steady-state plasma fulvestrant concentrations were predictable and achieved earlier with LD and HD. While there appeared to be a trend toward improved efficacy with HD and LD versus AD, no significant differences could be shown. A parallel study (FINDER1) has reported similar findings in Japanese patients.

Activity of fulvestrant versus exemestane in advanced breast cancer patients with or without visceral metastases: data from the EFECT trial.

PURPOSE: Patients with visceral metastases (VM: lung and/or liver metastases) are generally regarded as being less responsive to hormonal therapy, and chemotherapy often becomes the default treatment. This paper reports a subgroup analysis from EFECT (The Evaluation of Faslodex versus Exemestane Clinical Trial) examining the efficacy of fulvestrant and exemestane in patients with or without VM. METHODS: EFECT is a randomised, double-blind, multicentre, Phase III trial in postmenopausal women with advanced breast cancer progressing or recurring after prior non-steroidal aromatase inhibitor therapy. RESULTS: Overall, approximately 57% of patients in EFECT had visceral involvement. Fulvestrant and exemestane demonstrated clinical benefit in 29.1% and 27.2% of patients with VM, respectively. Median duration of response was 13.5 vs 10.8 months and median duration of clinical benefit was 9.9 vs 8.1 months, respectively. CONCLUSIONS: These results encourage the use of endocrine agents such as fulvestrant in treating patients with advanced breast cancer and VM.

D2-40 in breast cancer: should we detect more vascular emboli?

Peritumoral emboli assessed on hematoxylin-eosin-stained slides are taken into account for treatment of patients with operable breast cancer. We assessed whether immunostaining with D2-40 improves the prognostic significance of emboli in a group of tumors with a large immunohistochemical sampling and a long-term follow-up. Topography, number, and extension of hematoxylin-eosin and D2-40 emboli were compared in 94 node-negative breast cancers (median number of immunostained slides per tumor: 3). Metastasis-free survival of patients with or without hematoxylin-eosin and/or D2-40 emboli were evaluated (median follow-up of 178 months). Hematoxylin-eosin emboli were detected in 14 (15%) tumors and were located at distance from the tumor. D2-40 emboli were detected in 39 (41%) tumors and was often multiple (n=30), extensive (n=23), located within (n=13), close to (n=10) or at distance from the tumor (n=16). The 12 distant hematoxylin-eosin and D2-40 emboli were located in the same vessels (seven missed at the first hematoxylin-eosin examination and secondarily diagnosed by D2-40 staining). A difference in metastasis-free survival was found only between patients with no D2-40 emboli and those with distant D2-40 emboli (P=0.02). D2-40 emboli located within or close to the tumor had no prognostic value. Comparing the metastasis-free survival of patients with or without hematoxylin-eosin emboli, the prognostically unfavorable significance of hematoxylin-eosin emboli was improved when taking into account the seven patients with missed emboli at the first examination and secondarily diagnosed by D2-40 staining (P=0.006 vs 0.003). To conclude, D2-40 increases the diagnostic sensitivity of emboli in breast carcinoma and the high incidence of D2-40 emboli might be related to the number of immunostained slides per case. Nevertheless, only distant D2-40+ emboli had a prognostic impact. In practice, D2-40 might be useful to detect missed hematoxylin-eosin emboli especially in cases without any other prognostically unfavorable criterion.

Prediction of HER2 gene status in Her2 2+ invasive breast cancer: a study of 108 cases comparing ASCO/CAP and FDA recommendations.

Most Her2 testing guidelines recommend that all cases scoring Her2 2+ by immunohistochemistry should be analyzed by fluorescent in situ hybridization (FISH) to determine HER2 status to confirm eligibility for Trastuzumab therapy in breast cancer. The aim of our study was to determine HER2 gene and chromosome 17 (CEN17) status in a series of 108 Her2 2+ consecutive cases and study the correlation between pathological characteristics of the tumors and HER2 amplification. Invasive breast cancers were tested by FISH using the Dako HER2 FISH pharmDx kit. The Her2 immunohistochemistry protocol was performed using the polyclonal AO485 antibody (Dako) diluted to 1:1500. HER2 and CEN17 status were correlated to tumor SBR grade, mitotic count, estrogen receptor, progesterone receptor status and percentage of Her2 immunohistochemistry-positive cells. Following Food and Drug Administration guidelines, ie, HER2/CEN17 ratio >or=2 and an HER2 copy number >4, amplified cases were observed in 36 (33%) and 49 (45%) cases, respectively, and following American Society of Clinical Oncology/College of American Pathologists guidelines, ie, HER2/CEN17 ratio >2.2 and an HER2 copy number >6, amplified cases represented 30 and 24% of the study population, respectively. Chromosome 17 polysomy (CEN17 >2.25) was observed in 39 (36%) tumors. Significant positive correlations were found between FISH HER2 amplified cases and Her2 immunostaining >60% (P=1.1.10(-5)), SBR grade 3 (P=0.0001), nuclear atypia (P=0.03) and mitotic count (P=0.008). By multivariate analysis, Her2 immunostaining >60% (P<10(-3)) and SBR grade 3 (P<10(-3)) were independent factors predicting HER2 amplification status irrespective to cutoff guidelines. All SBR grade 3 cases with more than 60% Her2+ cells had an HER2/CEN17 ratio >or=2, only one had a ratio

First-line capecitabine monotherapy for slowly progressing metastatic breast cancer: do we need aggressive treatment?

BACKGROUND: Primary treatment goals in less aggressive metastatic breast cancer (MBC) are prolonged survival, good quality of life and control of the disease and its symptoms. High activity, oral administration and no alopecia make capecitabine monotherapy attractive in slowly evolving disease. METHODS: We retrospectively analysed 226 patients who had received single-agent capecitabine as 1st-line chemotherapy at our institution. RESULTS: The median interval between breast cancer diagnosis and MBC was 52 months (range 0-479); 76% had received endocrine therapy for MBC, 58% had visceral involvement and 30% had 3 or more metastatic sites. The median starting dose was 1,000 mg/m(2) twice daily. Disease was improved in 56% of the patients (median duration: 13.2 months) and stabilised in 20%. Median time to treatment failure was 8.8 months (95% CI: 7.1-10.5); median overall survival from initiating capecitabine was 23.6 months (95% CI: 19.7-27.4). Prior adjuvant chemotherapy, endocrine therapy for MBC, visceral disease, hormone receptor status and initial capecitabine dose did not influence time to treatment failure. Among 161 patients <75 years, 90% received further chemotherapy. CONCLUSION: Based on these findings, 1st-line capecitabine should be considered in slowly progressing disease, offering an active, well-tolerated oral treatment with minimal toxicity and no alopecia. More toxic treatments may be reserved for more aggressive disease.

A gene expression signature that can predict the recurrence of tamoxifen-treated primary breast cancer.

PURPOSE: The identification of a molecular signature predicting the relapse of tamoxifen-treated primary breast cancers should help the therapeutic management of estrogen receptor-positive cancers. EXPERIMENTAL DESIGN: A series of 132 primary tumors from patients who received adjuvant tamoxifen were analyzed for expression profiles at the whole-genome level by 70-mer oligonucleotide microarrays. A supervised analysis was done to identify an expression signature. RESULTS: We defined a 36-gene signature that correctly classified 78% of patients with relapse and 80% of relapse-free patients (79% accuracy). Using 23 independent tumors, we confirmed the accuracy of the signature (78%) whose relevance was further shown by using published microarray data from 60 tamoxifen-treated patients (63% accuracy). Univariate analysis using the validation set of 83 tumors showed that the 36-gene classifier is more efficient in predicting disease-free survival than the traditional histopathologic prognostic factors and is as effective as the Nottingham Prognostic Index or the "Adjuvant!" software. Multivariate analysis showed that the molecular signature is the only independent prognostic factor. A comparison with several already published signatures demonstrated that the 36-gene signature is among the best to classify tumors from both training and validation sets. Kaplan-Meier analyses emphasized its prognostic power both on the whole cohort of patients and on a subgroup with an intermediate risk of recurrence as defined by the St. Gallen criteria. CONCLUSION: This study identifies a molecular signature specifying a subgroup of patients who do not gain benefits from tamoxifen treatment. These patients may therefore be eligible for alternative endocrine therapies and/or chemotherapy.

A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer.

BACKGROUND: The aromatase inhibitor letrozole is a more effective treatment for metastatic breast cancer and more effective in the neoadjuvant setting than tamoxifen. We compared letrozole with tamoxifen as adjuvant treatment for steroid-hormone-receptor-positive breast cancer in postmenopausal women. METHODS: The Breast International Group (BIG) 1-98 study is a randomized, phase 3, double-blind trial that compared five years of treatment with various adjuvant endocrine therapy regimens in postmenopausal women with hormone-receptor-positive breast cancer: letrozole, letrozole followed by tamoxifen, tamoxifen, and tamoxifen followed by letrozole. This analysis compares the two groups assigned to receive letrozole initially with the two groups assigned to receive tamoxifen initially; events and follow-up in the sequential-treatment groups were included up to the time that treatments were switched. RESULTS: A total of 8010 women with data that could be assessed were enrolled, 4003 in the letrozole group and 4007 in the tamoxifen group. After a median follow-up of 25.8 months, 351 events had occurred in the letrozole group and 428 events in the tamoxifen group, with five-year disease-free survival estimates of 84.0 percent and 81.4 percent, respectively. As compared with tamoxifen, letrozole significantly reduced the risk of an event ending a period of disease-free survival (hazard ratio, 0.81; 95 percent confidence interval, 0.70 to 0.93; P=0.003), especially the risk of distant recurrence (hazard ratio, 0.73; 95 percent confidence interval, 0.60 to 0.88; P=0.001). Thromboembolism, endometrial cancer, and vaginal bleeding were more common in the tamoxifen group. Women given letrozole had a higher incidence of skeletal and cardiac events and of hypercholesterolemia. CONCLUSIONS: In postmenopausal women with endocrine-responsive breast cancer, adjuvant treatment with letrozole, as compared with tamoxifen, reduced the risk of recurrent disease, especially at distant sites. (ClinicalTrials.gov number, NCT00004205.)

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.

Epithelial atypia in biopsies performed for microcalcifications. practical considerations about 2,833 serially sectioned surgical biopsies with a long follow-up.

This study analyzes the occurrence of epithelial atypia in 2,833 serially sectioned surgical breast biopsies (SB) performed for microcalcifications (median number of blocks per SB:26) and the occurrence of subsequent cancer after an initial diagnosis of epithelial atypia (median follow-up 160 months). Epithelial atypia (flat epithelial atypia, atypical ductal hyperplasia, and lobular neoplasia) were found in 971 SB, with and without a concomitant cancer in 301 (31%) and 670 (69%) SB, respectively. Thus, isolated epithelial atypia were found in 670 out of the 2,833 SB (23%). Concomitant cancers corresponded to ductal carcinomas in situ and micro-invasive (77%), invasive ductal carcinomas not otherwise specified (15%), invasive lobular carcinomas (4%), and tubular carcinomas (4%). Fifteen out of the 443 patients with isolated epithelial atypia developed a subsequent ipsilateral (n = 14) and contralateral (n = 1) invasive cancer. The high slide rating might explain the high percentages of epithelial atypia and concomitant cancers and the low percentage of subsequent cancer after a diagnosis of epithelial atypia as a single lesion. Epithelial atypia could be more a risk marker of concomitant than subsequent cancer.

Exemestane as neoadjuvant hormonotherapy for locally advanced breast cancer: results of a phase II trial.

BACKGROUND: Neoadjuvant hormonotherapy has recently been used for downstaging large or locally advanced (LA) breast cancer in postmenopausal women. PATIENTS AND METHODS: A phase II study was conducted in postmenopausal, hormone-receptor (HR) positive, T2-T4 patients, receiving 25 mg/day exemestane for 16 weeks. RESULTS: Among 42 patients, 57.1% underwent conservative surgery. The clinical objective response rate (ORR) was 73.3%, without progression. A pathological partial response was achieved in 16.7% of the patients. Exemestane significantly reduced the expression of Ki-67 and progesterone receptors (PgR) (p<0.001). A significant decrease in PgR was correlated with clinical ORR (p=0.028). The responders presented higher baseline PgR levels (p=0.017). No relationship was found between ORR and mRNA expression of aromatase or oestrogen receptors beta (ER-beta). CONCLUSION: Neoadjuvant exemestane provided satisfactory efficacy and safety profiles in LA breast cancer. The main biological effects consisted of a reduction in PgR expression for responders and a decrease in Ki-67 expression.

Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group.

PURPOSE: This randomized, multicenter trial compared first-line trastuzumab plus docetaxel versus docetaxel alone in patients with human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer (MBC). PATIENTS AND METHODS: Patients were randomly assigned to six cycles of docetaxel 100 mg/m2 every 3 weeks, with or without trastuzumab 4 mg/kg loading dose followed by 2 mg/kg weekly until disease progression. RESULTS: A total of 186 patients received at least one dose of the study drug. Trastuzumab plus docetaxel was significantly superior to docetaxel alone in terms of overall response rate (61% v 34%; P = .0002), overall survival (median, 31.2 v 22.7 months; P = .0325), time to disease progression (median, 11.7 v 6.1 months; P = .0001), time to treatment failure (median, 9.8 v 5.3 months; P = .0001), and duration of response (median, 11.7 v 5.7 months; P = .009). There was little difference in the number and severity of adverse events between the arms. Grade 3 to 4 neutropenia was seen more commonly with the combination (32%) than with docetaxel alone (22%), and there was a slightly higher incidence of febrile neutropenia in the combination arm (23% v 17%). One patient in the combination arm experienced symptomatic heart failure (1%). Another patient experienced symptomatic heart failure 5 months after discontinuation of trastuzumab because of disease progression, while being treated with an investigational anthracycline for 4 months. CONCLUSION: Trastuzumab combined with docetaxel is superior to docetaxel alone as first-line treatment of patients with HER2-positive MBC in terms of overall survival, response rate, response duration, time to progression, and time to treatment failure, with little additional toxicity.

Letrozole inhibits tumor proliferation more effectively than tamoxifen independent of HER1/2 expression status.

BACKGROUND: The biological basis for the superior efficacy of neoadjuvant letrozole versus tamoxifen for postmenopausal women with estrogen receptor (ER)-positive locally advanced breast cancer was investigated by analyzing tumor proliferation and expression of estrogen-regulated genes before and after the initiation of therapy. METHODS: Tumor samples were obtained at baseline and at the end of treatment from 185 patients participating in a double blind randomized Phase III study of neoadjuvant endocrine therapy. These paired specimens were simultaneously analyzed for Ki67, ER, progesterone receptor (PgR), trefoil factor 1 (PS2), HER1 (epidermal growth factor receptor), and HER2 (ErbB2 or neu) by semiquantitative immunohistochemistry. RESULTS: The treatment-induced reduction in geometric mean Ki67 was significantly greater with letrozole (87%) than tamoxifen (75%; analysis of covariance P = 0.0009). Differences in the average Ki67 reduction were particularly marked for ER-positive tumors that overexpressed HER1 and/or HER2 (88 versus 45%, respectively; P = 0.0018). Twenty-three of 92 tumors (25%) on tamoxifen and 14 of 93 on letrozole (15%) showed a paradoxical increase in Ki67 with treatment, and the majority of these cases was HER1/2 negative. Letrozole, but not tamoxifen, significantly reduced expression of the estrogen-regulated proteins PgR and trefoil factor 1, regardless of HER1/2 status (P < 0.0001). ER down-regulation occurred with both agents, although levels decreased more with tamoxifen (P < 0.0001). CONCLUSION: Letrozole inhibited tumor proliferation to a greater extent than tamoxifen. The molecular basis for this advantage appears complex but includes possible tamoxifen agonist effects on the cell cycle in both HER1/2+ and HER1/2- tumors. A pattern of continued proliferation despite appropriate down-regulation of PgR expression with estrogen deprivation or tamoxifen was also documented. This observation suggests the estrogenic regulation of proliferation and PgR expression may be dissociated in endocrine therapy resistant cells.