Michael Knauer

Morbidity of Breast Cancer Patients Following Complete Axillary Dissection or Sentinel Node Biopsy Only: A Comparative Evaluation

AbstractIntroduction The usefulness of routine axillary dissection (AD) at levels I–II in breast cancer patients has been questioned for years because of the high postoperative morbidity in the shoulder and arm region, and the increasing number of patients with negative nodes. Sentinel node biopsy (SNB) was hoped both to reduce morbidity and to improve the reliability of staging. This study was designed to provide more evidence in this matter by comparing the follow-up data of patients with AD and those with SNB only. Method One hundred forty patients who had undergone AD between 1993 and 1996 were questioned for their subjective and objective symptoms using a questionnaire and subsequently subjected to a clinical examination. Their data were compared with those of 57 patients who had undergone SNB only between 1998 and 2000. Results Local recurrences have not been seen to date. The difference between the two groups in terms of a loss of quality of life was negligible. The differences in overall complaints, number of symptoms, pain, limited range of motion of the operated upper extremity, numbness, paresthesias, and arm swelling as well as perceived disability in activities of daily living were significantly in favor of SNB. The length of hospital stay was significantly shorter for SNB patients. Conclusion SNB appears to be an accurate procedure for axillary nodal staging in breast cancer patients and is associated with reduced postoperative morbidity and length of hospital stay. But it is still investigational and should not be implemented as therapeutical standard before results of randomized trials are published.

Cost-effectiveness of the 70-gene signature versus St. Gallen guidelines and Adjuvant Online for early breast cancer

BACKGROUND The 70-gene signature (MammaPrint) is a prognostic test used to guide adjuvant treatment decisions in patients with node-negative breast cancer. In order to decide upon its use, a systematic comparative analysis of the effects of the 70-gene signature, the Sankt Gallen guidelines and the Adjuvant Online Software for these patients on survival, quality of life and costs is warranted. METHODS A Markov decision model was used to simulate the 20-year costs and outcomes (survival and quality-of-life adjusted survival (QALYs)) in a hypothetical cohort of node-negative, estrogen receptor positive breast cancer patients. Sensitivity and specificity of the three prognostic tools were based on 5 and 10 years breast cancer specific survival and distant metastasis as first event, derived from a pooled analysis consisting of 305 tumour samples from 3 previously reported validation studies concerning the 70-gene signature. RESULTS Small differences in survival, but substantial differences in quality-adjusted survival between the prognostic tools were observed. Quality-adjusted survival was highest when using the 70-gene signature. Based on costs per QALY, the 70-gene has the highest probability of being cost-effective for a willingness to pay for a QALY higher than euro12.000. Sankt Gallen showed the highest survival rates compared to the 70-gene signature, but leads to a substantial larger amount of adjuvant chemotherapy and lower cost-effectiveness, thus demanding a high willingness to pay to save a life year. CONCLUSIONS When deciding upon the cost-effectiveness of the prognostic tests, the 70-gene signature improves quality-adjusted survival and has the highest probability of being cost-effective.

Multicentric Breast Cancer: A New Indication for Sentinel Node Biopsy—A Multi-Institutional Validation Study

PURPOSE Multicentric breast cancer has been considered to be a contraindication for sentinel node (SN) biopsy (SNB). In this prospective multi-institutional trial, SNB-feasibility and accuracy was evaluated in 142 patients with multicentric cancer from the Austrian Sentinel Node Study Group (ASNSG) and compared with data from 3,216 patients with unicentric cancer. PATIENTS AND METHODS Between 1996 and 2004, 3,730 patients underwent SNB at 15 ASNSG-affiliated hospitals. Patient data were entered in a multicenter database. One hundred forty-two patients presented with multicentric invasive breast cancer and underwent SNB. RESULTS Intraoperatively, a mean number of 1.67 SNs were excised (identification-rate, 91.5%). The incidence of SN metastases was 60.8% (79 of 130). This was confirmed by axillary lymph node dissection (ALND) in 125 patients. Of patients with positive SNs, 60.8% (48 of 79) showed involvement of nonsentinel nodes (NSNs), as did three patients with negative SNs (false-negative rate, 4.0). Sensitivity, negative predictive value, and overall accuracy were 96.0%, 93.3%, and 97.3%, respectively. Ninety-one percent of the patients underwent mastectomy, and 9% were treated with breast conserving surgery. None of the patients have shown axillary recurrence so far (mean follow-up, 28.8 months). Compared with 3,216 patients with unicentric cancer, there was a significantly higher rate of SN metastases as well as in NSNs, whereas there was no difference in detection and false-negative rates. CONCLUSION Multicentric breast cancer is a new indication for SNB without routine ALND in controlled trials. Given adequate quality control and an interdisciplinary teamwork of surgical, nuclear medicine, and pathology units, SNB is both feasible and accurate in this disease entity.

Identification of a low-risk subgroup of HER-2-positive breast cancer by the 70-gene prognosis signature

Background:Overexpression of HER-2 is observed in 15–25% of breast cancers, and is associated with increased risk of recurrence. Current guidelines recommend trastuzumab and chemotherapy for most HER-2-positive patients. However, the majority of patients does not recur and might thus be overtreated with adjuvant systemic therapy. We investigated whether the 70-gene MammaPrint signature identifies HER-2-positive patients with favourable outcome.Methods:In all, 168 T1–3, N0–1, HER-2-positive patients were identified from a pooled database, classified by the 70-gene signature as good or poor prognosis, and correlated with long-term outcome. A total of 89 of these patients did not receive adjuvant chemotherapy.Results:In the group of 89 chemotherapy-naive patients, after a median follow-up of 7.4 years, 35 (39%) distant recurrences and 29 (33%) breast cancer-specific deaths occurred. The 70-gene signature classified 20 (22%) patients as good prognosis, with 10-year distant disease-free survival (DDFS) of 84%, compared with 69 (78%) poor prognosis patients with 10-year DDFS of 55%. The estimated hazard ratios (HRs) were 4.5 (95% confidence interval (CI) 1.1–18.7, P=0.04) and 3.8 (95% CI 0.9–15.8, P=0.07) for DDFS and breast cancer-specific survival (BCSS), respectively. In multivariate analysis adjusted for known prognostic factors and hormonal therapy, HRs were 5.8 (95% CI 1.3–26.7, P=0.03) and 4.7 (95% CI 1.0–21.7, P=0.05) for DDFS and BCSS, respectively.Interpretation:The 70-gene prognosis signature is an independent prognostic indicator that identifies a subgroup of HER-2-positive early breast cancer with a favourable long-term outcome.

Prospective cost-effectiveness analysis of genomic profiling in breast cancer

BACKGROUND The cost-effectiveness of the 70-gene signature (70-GS) (MammaPrint®) has earlier been estimated using retrospective validation data. Based on the prospective 5-year survival data of the microarRAy-prognoSTics-in-breast-cancER (RASTER) study, the aim here was to evaluate the cost-effectiveness reflecting the actual use in clinical practice, including reality-based compliance rates. METHODS Costs and outcomes (quality-adjusted-life-years (QALYs)) were calculated in node-negative (N-) patients included in the RASTER study (n=427). Sensitivity and specificity of the 70-gene and Adjuvant! Online (AO) were based on 5-year distant-disease-free survival (DDFS). Subgroup analyses were performed for two groups for whom benefit of the 70-gene had earlier been reported: (1) ductal, oestrogen receptor-positive (ER+), tumour diameter 10-30 mm, grade II, age 40-70; (2) ductal, oestrogen receptor-positive, tumour diameter 5-30 mm, grade II/III and age 40-70. RESULTS Based on 5-year survival data, the cost-effectiveness of the 70-gene signature versus AO was prospectively confirmed. The total health care costs per patient were €26,786 for the 70-gene and €29,187 for AO. The quality adjusted life years yielded 12.49 and 11.88, respectively. The subgroups retrieved slightly higher life gains and higher costs, but all resulted finally in a favourable position for the 70-gene signature. CONCLUSIONS The use of the 70-gene signature, as judged appropriate by doctors and patients and supported by a low risk 70-gene signature as an oncological safe choice, was also found to be cost-effective.

Late Recurrences in Early Breast Cancer: For Whom and How Long Is Endocrine Therapy Beneficial?

During the last decade, besides the well-established clinical-pathological predictors for the risk of late recurrence in breast cancer, such as estrogen receptor status, and T and N stage, a variety of multigene assays have been shown to improve prognostication and prediction in this setting. Several clinical trials have evaluated the role of extended endocrine therapy with tamoxifen (ATLAS) or aromatase inhibitors (MA.17, NSABP-B33 and ABCSG 6a), and other randomized studies are still ongoing. However, among this patient population, it is still not clear who could benefit from extended therapy and what the optimal treatment duration should be. New multigene assays such as EndoPredict, PAM50 ROR-score, HOXB13/IL17BR ratio and Breast Cancer Index provide significant and relevant prognostic information concerning the likelihood of recurrence beyond 5 years after surgery. The identified low-risk subgroups not only show a very favorable prognosis, they also seem to have only little benefit from extended aromatase inhibitor therapy. Many of these reverse transcriptase/polymerase chain reaction-based techniques have been validated in archived tumor material from large phase III trials, and will soon be available to routine pathology laboratories as an aid in clinical decision-making for patients.

Gene expression profiling in breast cancer - design of a pooled database to address open questions

ZusammenfassungGRUNDLAGEN: Das Netherlands Cancer Institute hat DNA-microarrays zur Identifizierung eines 70-Gen-Expressionsprofils verwendet, welches ein signifikant kürzeres Intervall bis zur Fernmetastasierung beim Mammakarzinom voraussagen kann. Für Patientinnen mit kleinen Tumoren ist das 70-Genprofil noch nicht ausreichend validiert. Außerdem werden 95 % aller Patienten mit triple-negativen Tumoren in die Hochrisikogruppe eingeteilt, obwohl 50 % keine Metastasen entwickeln werden. METHODIK: Eine Datenbank mit klinischen, pathologischen und microarray-Daten von 1696 Patientinnen wurde konstruiert, um die folgenden wissenschaftlichen Fragestellungen zu beantworten: 1. Validierung des 70-Genprofils bei kleinen T1-Tumoren und 2. Identifizierung von triple-negativen Tumoren und Durchführung von DNA-mircoarrays, um ein neues Genexpressionsprofil für diese Subgruppe zu finden. ERGEBNISSE UND SCHLUSSFOLGERUNGEN: Falls das 70-Genprofil für kleine Tumoren prädiktiv ist, könnten diese Patientinnen einer adjuvanten Therapie zugeführt werden. Das neue Profil für triple-negative Tumoren könnte Patientinnen identifizieren, bei denen sicher auf adjuvante Therapie verzichtet werden kann.SummaryBACKGROUND: The Netherlands Cancer Institute used DNA microarray analyses to identify a 70-gene expression profile strongly predictive of a short interval to distant metastases in breast cancer. For patients with small tumors, the signature is not yet adequately validated. Furthermore, 95% of estrogen-receptor or triple-negative tumors are assigned to poor prognosis by the profile. METHODS: A pooled database was constructed containing clinical, pathological and microarray data of 1696 patients. The database will be used to study the performance of the 70-gene profile in patients with small-sized T1 tumors. In addition, patients with triple-negative tumors will be identified and whole genome microarray analysis will be performed of these tumors to develop a new prognostic gene expression profile for this subgroup. RESULTS AND CONCLUSIONS: If the 70-gene profile is accurate for small tumors, patients at risk may be assigned to adjuvant treatment. A new prognostic classifier for triple-negative tumors may help to identify women, in whom adjuvant treatment may safely be omitted.

Identification of a low risk subgroup in Her2-positive breast cancer by the 70-gene prognosis signature.

Abstract #4171 Introduction:
 Her2/neu-overexpression is observed in 15-20% of invasive breast cancers and considered a negative prognostic factor. Most Her2-positive patients are classified as high risk by current treatment guidelines and thus allocated to adjuvant trastuzumab and chemotherapy. However, 74% of patients remained distant recurrence-free at 3 years without trastuzumab in the HERA-trial (HERceptin Adjuvant). In the present study the 70-gene prognosis signature (MammaPrint™), validated as an independent prognostic indicator for patients with up to three positive lymph nodes, was used to identify a subgroup of patients with low risk and favorable outcome.
 Methods:
 One-hundred-sixty-nine patients with Her2-positive breast cancer were selected from a pooled dataset of 1280 patients with known Her2-status. Patients had a unilateral T1-3, N0-1 tumor and were treated with either breast-conserving therapy or mastectomy. Samples were analyzed and classified by the 70-gene signature as good or poor prognosis by Agendia Laboratories.
 Results:
 After a median follow-up of 65 months (range 4-303) 49 (29%) distant recurrences and 41 (24%) breast cancer-specific deaths occurred. The 70-gene signature classified 27 (16%) patients as good prognosis, with a 10-year distant disease-free survival (DDFS) of 89% (25/27), compared to 142 (84%) patients classified as poor prognosis, who had a DDFS of 64%. The estimated hazard ratios (HR) for genomic risk were 4.9 (95%CI 1.2-20.1,p=0.029) and 4.4 (95%CI 1.1-18.4,p=0.040) for DDFS and breast cancer-specific survival at 10 years, respectively. In multivariate analysis, adjusted for known prognostic factors and adjuvant therapy, only the 70-gene signature and tumor size were independent predictors for 10-year-DDFS with HRs of 5.4 (95%CI 1.3-23.4,p=0.024) and 1.05 (95%CI 1.02-1.08,p=0.001), respectively. The good prognosis group had positive hormone-receptors in 85%, and fewer patients received adjuvant therapy: 16 patients (59%) received no adjuvant treatment, 6 (22%) received adjuvant chemotherapy, 8 (30%) hormonal therapy and 1 (4%) received trastuzumab. For the subgroup of 90 patients who were not treated with adjuvant chemotherapy or trastuzumab, the HR for low versus high 70-gene signature for 10-year DDFS was 4.75 (1.13-19.92,p=0.033).
 Discussion:
 The 70-gene signature is a strong independent prognostic indicator that can identify a subgroup with good clinical outcome in Her2-positive early breast cancer even in the absence of adjuvant chemotherapy and trastuzumab. This subgroup will be further studied in the ongoing MINDACT-trial (MIcroarray for Node-negative and 1-3 positive node Disease may Avoid ChemoTherapy) and beyond. The MINDACT-trial will prospectively evaluate if it is acceptable to withhold chemotherapy and/or trastuzumab in Her2-positive, genomic low risk patients. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4171.

The 70-Gene Profile (MammaPrintTM) Is an Independent Predictor of Breast Cancer Specific Survival for Women 65 Years of Age or Older.

Background: One-half of all new breast cancer diagnoses occur in women age 65 years or older. In this age group, the use of adjuvant chemotherapy is largely influenced by co-morbidity and little is known about the applicability of prognostic multi-gene assays. The 70-gene profile (MammaPrint) is an independent prognostic indicator in early breast cancer, however, its performance in women with breast cancer 65 years or older has not been systematically studied.Methods: Women 65 years or older who were diagnosed at the Jules Bordet Institute and the Netherlands Cancer Institute between 1987 and 2003 with primary breast cancer with 0-3 involved lymph nodes who received either no adjuvant systemic therapy or adjuvant hormonal therapy alone were selected. MammaPrint test results were compared with clinical-pathological risk assessment using Adjuvant!Online.Results: Of 204 women aged 65 years or older (median age 70 years), 129 (63.2%) were classified as genomic low risk and 75 (36.8%) as genomic high risk. After a median follow-up of 8.6 years (range 0.3-17.9), the 5- and 10-year breast cancer specific survival (BCSS) for the genomic low risk group was 96% (SE 2%) and 86% (SE 4%) versus 82% (SE 4%) and 66% (SE 6%) for the genomic high risk group (log-rank p=0.001). In univariate analysis, MammaPrint was prognostic for 5-year BCSS (HR=5.0, 95%CI 1.8-14.1, p=0.002) and 10-year BCSS (HR=3.1, 95%CI 1.6-6.0, p=0.001). In a multivariate model adjusted for 10-year risk predicted by Adjuvant!Online, MammaPrint was independently prognostic for 5-year BCSS (HR=4.4, 95%CI 1.6-12.7, p=0.005) and 10-year BCSS (HR=2.5, 95%CI 1.3-5.0, p=0.009). As in prior validation series, the performance of MammaPrint was time dependent, with improved prognostication for early BCSS (≤5 years).Conclusion: Although a smaller proportion of breast cancers diagnosed in women 65 years or older are classified as high-risk by MammaPrint, it is an independent prognostic indicator that may be useful to select patients that can safely forego adjuvant chemotherapy. Additional data from patients over 70 years of age will be available at the time of the meeting. If these data are confirmatory, the ongoing prospective MINDACT trial will be amended to include older women. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4049.

Standardization of pathologic complete response rates in breast cancer treatment

Dear Sir, Over the last decade neoadjuvant chemotherapy (NAC) has been used for locally advanced inoperable breast cancer as standard treatment. It is also being investigated for operable cancer to reduce tumor size and the extent of surgery as well as to treat occult metastatic disease. During the last years pathologic complete response rates (pCR) have become a focal point of interest, especially because subgroup analyses of recent clinical studies including NSABP protocol B-18 and B-27 have shown improved disease free and overall survival after pCR and neoadjuvant therapy. A current major problem for the comparison of study results are the several definitions of the outcome parameter pCR. Several ways of classification for the pathologic response to NAC have been described. Kuroi et al. [1] found seven different terms for pathologic complete response such as near pCR, quasi pCR, comprehensive pCR, strict pCR, pCRinv, and comprehensive and strict pCRbr + n. In the trials of McGuire [2], Huang [3], Dieras [4] and Buzdar [5] the term pCR has been restricted to the complete response of both tumor and axillary lymph nodes whereas in the NSABP-B18 [6] and B27 trials [7] and the studies by Semiglazov [8] and Steger [9] for example pCR was defined as complete response only in the tumor without respect to axillary staging. E.g. in the B27 study patients with pCR of the tumor, 16% (65/407) of the patients were found to have lymph node involvement with significant differences in survival. In a 2005 meta-analysis by Mauri et al. [10] with nine elegible trials pCR rates ranged from 4% (van der Hage et al.) [11] to 29% (Semiglazov et al.) [12] with a considerable heterogeneity between the studies and only five trials reporting pCR rates. This clearly shows that in the last years the comparison of results even in large randomized trials was not possible and is truly a dilemma. In our experience of 135 patients treated with neoadjuvant chemotherapy between January 1998 and June 2007 a pCR (yT0 + yN0) was restricted to 14 patients (10.4%) whereas it would have been 11.1% if the nodal status was not considered. The downstaging rate in our patients was 34.8%. In our patient population the difference was not significant, but in the NSABP-B27 trial including 2411 women the different pCR rates were 17.0 or 14.2%. In the trial of Limentani et al. both pCR rates were given with a difference of 6% [13]. These differences as a result of different assessment are within the same range as the sometimes reported differences between treatment arms in clinical trials. At the 2007 meeting of the American Society of Clinical Oncology one of the most important statements for breast cancer specialists was the justified claim of standardized reporting of pCR rates in clinical trials by Sandra Swain, Professor of Medicine at Georgetown University. At a National Cancer Institute meeting in Bethesda this march William Symmans, Professor of Pathology at the MD Anderson Cancer Center claimed that the term pCR should be restricted to patients with no residual invasive cancer M. Knauer (&) E. Wenzl A. Haid Department of General and Thoracic Surgery, Academic Teaching Hospital Feldkirch, Carinagasse 47, Feldkirch A-6800, Austria e-mail: michael.knauer@lkhf.at