Emiel J. Rutgers

Changes in Gene Expression Associated With Response to Neoadjuvant Chemotherapy in Breast Cancer

PURPOSE At present, clinically useful markers predicting response of primary breast carcinomas to either doxorubicin-cyclophosphamide (AC) or doxorubicin-docetaxel (AD) are lacking. We investigated whether gene expression profiles of the primary tumor could be used to predict treatment response to either of those chemotherapy regimens. PATIENTS AND METHODS Within a single-institution, randomized, phase II trial, patients with locally advanced breast cancer received six courses of either AC (n = 24) or AD (n = 24) neoadjuvant chemotherapy. Gene expression profiles were generated from core-needle biopsies obtained before treatment and correlated with the response of the primary tumor to the chemotherapy administered. Additionally, pretreatment gene expression profiles were compared with those in tumors remaining after chemotherapy. RESULTS Ten (20%) of 48 patients showed a (near) pathologic complete remission of the primary tumor after treatment. No gene expression pattern correlating with response could be identified for all patients or for the AC or AD groups separately. The comparison of the pretreatment biopsy and the tumor excised after chemotherapy revealed differences in gene expression in tumors that showed a partial remission but not in tumors that did not respond to chemotherapy. CONCLUSION No gene expression profile predicting the response of primary breast carcinomas to AC- or AD-based neoadjuvant chemotherapy could be detected in this interim analysis. More subtle differences in gene expression are likely to be present but can only be reliably identified by studying a larger group of patients. Response of a breast tumor to neoadjuvant chemotherapy results in alterations in gene expression.

Calibration and discriminatory accuracy of prognosis calculation for breast cancer with the online Adjuvant! program: a hospital-based retrospective cohort study

BACKGROUND Adjuvant! is a web-based program that calculates individualised 10-year survival probabilities and predicted benefit of adjuvant systemic therapy. The Adjuvant! model has not been validated in any large European series. The aim of our study was to validate Adjuvant! in Dutch patients, investigating both its calibration and discriminatory accuracy. METHODS Patients who were at least partly treated at the Netherlands Cancer Institute for breast cancer between 1987 and 1998 were included if they met the following criteria: tumour size T1 (< or =2 cm), T2 (2-5 cm), or T3 (>5 cm), invasive breast carcinoma, with information about involvement of axillary lymph nodes available, no distant metastases, primary surgery, axillary staging, and radiotherapy according to national guidelines. Clinicopathological characteristics and adjuvant treatment data were retrieved from hospital records and medical registries and were entered into the Adjuvant! (version 8.0) batch processor with blinding to outcome. Endpoints were overall survival and the proportion of patients that did not die from breast cancer (breast-cancer-specific survival [BCSS]). FINDINGS 5380 patients were included with median follow-up of 11.7 years (range 0.03-21.8). The 10-year observed overall survival (69.0%) and BCSS (78.6%) and Adjuvant! predicted overall survival (69.1%) and BCSS (77.8%) were not statistically different (p=0.87 and p=0.18, respectively). Moreover, differences between predicted and observed outcomes were within 2% for most relevant clinicopathological subgroups. In patients younger than 40 years, Adjuvant! overestimated overall survival by 4.2% (p=0.04) and BCSS by 4.7% (p=0.01). The concordance index, which indicates discriminatory accuracy at the individual level, was 0.71 for BCSS in the entire cohort. INTERPRETATION Adjuvant! accurately predicted 10-year outcomes in this large-scale Dutch validation study and is of use for adjuvant treatment decision making, although the results may be less reliable in some subgroups.

Clear cell sarcoma (malignant melanoma) of soft parts

Clear cell sarcoma, or malignant melanoma of soft parts, is a rare tumor that occurs predominantly in the extremities of young adults. The importance of surgery has been well established. However, the role of adjuvant radiotherapy has yet to be determined.

Photodynamic therapy as adjuvant therapy in surgically treated pleural malignancies.

Five patients with a pleural malignancy (four malignant mesotheliomas and one localized low grade carcinoid) were treated with maximal surgical resection of the tumour followed by intraoperative adjuvant photodynamic therapy (PDT). The additional photodynamic treatment was performed with light of 652 nm from a high power diode laser, and meta-tetrahydroxy phenylchlorin as the photosensitizer. The light delivery to the thoracic cavity was monitored by in situ isotropic light detectors. The position of the light delivery fibre was adjusted to achieve optimal light distribution, taking account of reflected and scattered light in this hollow cavity. There was no 30-day post-operative mortality and only one patient suffered from a major complication (diaphragmatic rupture and haematopericardium). The operation time was increased by a maximum of 1 h to illuminate the total hemithoracic surface with 10 J cm(-2) (incident and scattered light). The effect of the adjuvant PDT was monitored by examination of biopsies taken 24 h after surgery under thoracoscopic guidance. Significant damage, including necrosis, was observed in the marker lesions with remaining malignancy compared with normal tissue samples, which showed only an infiltration with PMN cells and oedema of the striated muscles cells. Of the five patients treated, four are alive with no signs of recurrent tumour with a follow-up of 9-11 months. One patient was diagnosed as having a tumour dissemination in the skin around the thoracoscopy scar and died of abdominal tumour spread. Light delivery to large surfaces for adjuvant PDT is feasible in a relatively short period of time (< 1 h). In situ dosimetry ensures optimal light distribution and allows total doses (incident plus scattered light) to be monitored at different positions within the cavity. This combination of light delivery and dosimetry is well suited for adjuvant treatment with PDT in malignant pleural tumours.

Treatment of operable breast cancer in the elderly: a randomised clinical trial EORTC 10851 comparing tamoxifen alone with modified radical mastectomy

For treatment of early breast cancer in older women, little evidence is available from randomised trials. We conducted a randomised trial comparing modified radical mastectomy (MRM) with tamoxifen (TAM) as the sole initial therapy in 164 patients aged >/=70 years with operable breast cancer. 82 were treated by MRM and 82 with TAM. Survival curves were estimated using the Kaplan-Meier method: multivariate analyses were performed using the Coxs proportional hazards model. Endpoints included survival, time to first relapse or progression, loco-regional progression, time to distant progression and progression-free survival. After a median follow-up of approximately 10 years, there was a significantly decreased time to progression in the TAM only group (logrank P<0.0001) and significantly shorter time to local progression within the TAM group (logrank P<0.0001). Overall survival of the two groups was similar. The results indicate that tamoxifen alone leads to an unacceptably high rate of local progression or relapse.

Predictors of patients' choices for breast-conserving therapy or mastectomy: a prospective study.

A study was undertaken to describe the treatment preferences and choices of patients with breast cancer, and to identify predictors of undergoing breast-conserving therapy (BCT) or mastectomy (MT). Consecutive patients with stage I/II breast cancer were eligible. Information about predictor variables, including socio-demographics, quality of life, patients’ concerns, decision style, decisional conflict and perceived preference of the surgeon was collected at baseline, before decision making and surgery. Patients received standard information (n=88) or a decision aid (n=92) as a supplement to support decision making. A total of 180 patients participated in the study. In all, 72% decided to have BCT (n=123); 28% chose MT (n=49). Multivariate analysis showed that what patients perceived to be their surgeons’ preference and the patients’ concerns regarding breast loss and local tumour recurrence were the strongest predictors of treatment preference. Treatment preferences in itself were highly predictive of the treatment decision. The decision aid did not influence treatment choice. The results of this study demonstrate that patients’ concerns and their perceptions of the treatment preferences of the physicians are important factors in patients’ decision making. Adequate information and communication are essential to base treatment decisions on realistic concerns, and the treatment preferences of patients.

Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer patients: Final analysis of the EORTC AMAROS trial (10981/22023).

LBA1001 Background: Sentinel node biopsy (SNB) is standard in assessing axillary lymph node status for cN0 breast cancer patients. In case of a positive SNB, if treatment is advised, axillary lymph node dissection (ALND) is the current standard. Although ALND provides excellent regional control, it may give harmful side effects. Axillary radiotherapy (ART) instead of ALND was hypothesized to provide comparable regional control and less side effects. METHODS From 2001 to 2010, patients with cT1E2N0 primary breast cancer were enrolled in the EORTC phase III non-inferiority AMAROS trial. Patients were randomized between ALND and ART in case of a positive SNB. Primary endpoint was 5-year axillary recurrence rate. Secondary endpoints were overall survival (OS), disease-free survival (DFS), quality of life (QOL), shoulder movement and lymphedema at 1 and 5 years. RESULTS Of the 4,806 patients entered in the trial, 744 in the ALND-arm and 681 in the ART-arm had a positive SNB, 60% with a macrometastasis. The two treatment-arms were comparable regarding age, tumor size, grade, tumor type, and adjuvant systemic treatment. With a median follow up of 6.1 years, the 5-year axillary recurrence rate after a positive SNB was 0.54% (4/744) after ALND versus 1.03% (7/681) after ART. The planned non-inferiority test was underpowered because of the unexpectedly low number of events. The axillary recurrence rate after a negative SNB was 0.8% (25/3131). There were no significant differences between treatment arms regarding OS (5 yr estimates: 93.27% ALND, 92.52% ART, p=0.3386) and DFS (5 yr estimates: 86.90% ALND, 82.65% ART, p=0.1788). Lymphedema was found significantly more often after ALND (1yr: 40% ALND, 22% ART, p<0.0001 and 5yr: 28% ALND, 14% ART, p<0.0001). There was a nonsignificant trend toward more early shoulder movement impairment after ART. These findings were compatible with a trend in two QOL items in the arm symptom scale: swelling (ART better) and movement (ALND better). There were no other differences in QOL. CONCLUSION ALND and ART after a positive SNB provide excellent and comparable regional control. ART reduces the risk of short-term and long-term lymphedema compared to ALND. CLINICAL TRIAL INFORMATION NCT00014612.

Independent Prognostic Value of Screen Detection in Invasive Breast Cancer

BACKGROUND Mammographic screening has led to a proportional shift toward earlier-stage breast cancers at presentation. We assessed whether the method of detection provides prognostic information above and beyond standard prognostic factors and investigated the accuracy of predicted overall and breast cancer-specific survival by the computer tool Adjuvant! among patients with screen-detected, interval, and nonscreening-related carcinomas. METHODS We studied 2592 patients with invasive breast cancer who were treated at the Netherlands Cancer Institute from January 1, 1990, through December 31, 2000. Overall and breast cancer-specific survival probabilities among patients with mammographically screen-detected (n = 958), interval (n = 417), and nonscreening-related (n = 1217) breast carcinomas were compared. Analyses were adjusted for clinicopathologic characteristics and adjuvant systemic therapy. Because of gradual implementation of population-based screening in the Netherlands, analyses were stratified a priori according to two periods of diagnosis. All statistical tests were two-sided. RESULTS Screen detection was associated with reduced mortality (adjusted hazard ratio for all-cause mortality = 0.74, 95% confidence interval = 0.63 to 0.87, P < .001, and adjusted hazard ratio for breast cancer-specific mortality = 0.62, 95% confidence interval = 0.50 to 0.78, P < .001, respectively) compared with nonscreening-related detection. The absolute adjusted reduction in breast cancer-specific mortality was 7% at 10 years. The prognostic value of the method of detection was independent of the period of diagnosis and was similar across tumor size and lymph node status categories, indicating its prognostic value beyond stage migration. Adjuvant! underestimated breast cancer-specific survival in patients with screen-detected (-3.2%) and interval carcinomas (-5.4%). CONCLUSIONS Screen detection was found to be independently associated with better prognosis for overall and breast cancer-specific survival and to provide prognostic information beyond stage migration among patients with invasive breast cancer. We propose that the method of detection should be taken into account when estimating individual prognosis.

The contribution of routine follow-up mammography to an early detection of asynchronous contralateral breast cancer.

The role of routine mammography was assessed in the early detection of asynchronous contralateral breast cancer (ACBC). The breast cancer patient populations of two cities, Nijmegen and Eindhoven, The Netherlands, which were subjected to a well‐defined follow‐up program, were compared. The program consisted of regular physical examination and annual mammography in Nijmegen and physical examination only in Eindhoven. From 1975 until 1987, 24 ACBC patients were detected within a group of 880 breast cancer patients in Nijmegen (3%) and, from 1971 until 1984, 14 ACBC patients within a group of 411 patients in Eindhoven (3%). In Nijmegen, eight of the 23 evaluable patients (35%) had a contralateral tumor with a histologic size smaller than 10 mm or an in situ carcinoma, compared with one of the 14 of the Eindhoven patients (7%), whereas 18 of the 24 (75%) versus eight of the 14 patients (57%) were node‐negative. Thus, annual mammography is very likely a contribution in the early detection of contralateral breast cancer as compared with follow‐up by regular physical examination only.

Outcome of thoracoscopic pulmonary metastasectomy evaluated by confirmatory thoracotomy.

BACKGROUND The aim of this study was to determine the feasibility, accuracy, and outcome of thoracoscopic resection of peripherally located pulmonary metastases. METHODS The 28 patients had three or fewer solitary metastases, located in the periphery of the lung, with a diameter 3 cm or less on computed tomography scan. A thoracoscopic resection was performed to remove all identified lesions evaluated by confirmatory thoracotomy. RESULTS A thoracoscopic resection was technically impossible in 10 patients. In 1 patient a confirmatory thoracotomy was not performed because the lesion was diagnosed as carcinoid. Among the 17 patients who underwent confirmatory thoracotomy, 12 patients had a complete thoracoscopic resection and 5 patients had residual disease. The success rate appeared to be higher (p = 0.01) in patients with one lesion (11 of 12 patients), than in patients with more than one lesion (1 of 5 patients) found by preoperative computed tomography scan. CONCLUSIONS Thoracoscopic resection can be considered a viable treatment option for patients who present with a solitary pulmonary metastasis with a diameter of 3 cm or less, when the lesion is located in the periphery of the lung.