Peter Kern

The effect of EUSOMA certification on quality of breast cancer care

AIM OF THE STUDY The European Society of Breast Cancer Specialists (EUSOMA) has fostered a voluntary certification process for breast units to establish minimum standards and ensure specialist multidisciplinary care. In the present study we assess the impact of EUSOMA certification for all breast units for which sufficient information was available before and after certification. MATERIALS AND METHODS For 22 EUSOMA certified breast units data of 30,444 patients could be extracted from the EUSOMA database on the evolution of QIs before and after certification. RESULTS On the average of all units, the minimum standard of care was achieved for 12/13 QIs before and after EUSOMA certification (not met for DCIS receiving just one operation). There was a significant improvement of 5 QIs after certification. The proportion of patients with invasive cancer undergoing an axillary clearance containing >9 lymph nodes (91.5% vs 89.4%, p 0.003) and patients with invasive cancer having just 1 operation (83.1% vs 80.4%, p < 0.001) dropped, but remained above the minimum standard. The targeted standard of breast care was reached for the same 4/13 QIs before and after EUSOMA certification. CONCLUSION Although the absolute effect of EUSOMA certification was modest it further increases standards of care and should be regarded as part of a process aiming for excellence. Dedicated units already provide a high level of care before certification, but continuous monitoring and audit remains of paramount importance as complete adherence to guidelines is difficult to achieve.

Neoadjuvant, anthracycline-free chemotherapy with carboplatin and docetaxel in triple-negative, early-stage breast cancer: a multicentric analysis of feasibility and rates of pathologic complete response.

Background: Triple-negative breast cancer (TNBC) attracts a disproportionate share of intensive research because of its poor prognosis. Standard anthracycline- and taxane-based regimens still yield an unsatisfactorily low rate of pathologic complete response (pCR). The pCR rate is a recognized surrogate marker for good long-term survival. Methods: A multicentric, retrospective study was conducted including all patients not willing to undergo or not suitable for an anthracycline-based regimen. Six cycles of docetaxel 75 mg/m2 and carboplatin AUC 6 q3w were administered. The primary endpoint was pCR (ypT0/ypTis + ypN0) and near-pCR (≤5 mm residual disease). The secondary endpoint was feasibility (CTCAE version 4.03 criteria) and adherence to treatment. Results: Six cycles of carboplatin AUC 6 and docetaxel 75 mg/m2 resulted in a high pCR rate of 50% and a combined pCR/near-pCR rate of 70%. Grade 3 and 4 toxicities were rare events and 28 of 30 (93%) patients completed all 6 cycles. No toxicity-related treatment discontinuation and no febrile neutropenia were registered. Conclusion: This chemotherapy regimen provides a highly effective and feasible strategy for patients not willing to receive or not suitable for an anthracycline-based treatment (cardiac ejection fraction <65% or age >65 years). Combinations of platinum compounds with taxanes and anthracyclines may be also desirable in TNBC.

Breast conservative surgery and local recurrence

INTRODUCTION Breast conservation is a legacy of Umberto Veronesi who laid the groundwork for the preservation of the body image of women affected by breast cancer (BC) with the Milan I study in the late 70ies of the last millennium. Breast conservative surgery (BCS) has two aspects: oncological safety of tumour resection with free margins and aesthetic preservation of the breast. Determinants of local control used to be T-size, nodal status and receptor status until biologically driven concepts defined risk of recurrence on the basis of molecular portraits. We explored whether these concepts of intrinsic subtypes prove at a large scale in the context of BCS and which surgical techniques procure best oncological and aesthetic outcomes, avoiding re-excision and necessity of conversion to mastectomy. PATIENTS AND METHODS We analyzed 1035 BCS patients with primary unilateral breast cancer (2004-2009) with regards to the local recurrence as a function of tumour location, surgical technique, resection volume, T-size, nodal status, grading, histopathological and intrinsic subtype and margins. RESULTS Five surgical techniques were applied to 944 eligible patients at a median follow-up of 5.2 years with the following frequency: Glandular rotation mammoplasty (63.8%), tumour-adapted rotation mammoplasty (20.9%), dermoglandular rotation mammoplasty (6.7%), 4.4% (lateral thoracic wall advancement), 0.7% latissimus dorsi flap (0.7%) and others (13.5%). Tumour-free margins were achieved in 88.6% of all patients at first surgery. Recurrence was independent of the surgical technique used, resection volume, T-size (in a T1/T2-cohort), nodal status (in low N-stages: NO/N1) and histopathology (inv.-ductal vs. lobular), however non-invasive subtype (DCIS), high grading (G3 vs. G1), non-luminal Her2 positive BC and triple-negative breast cancer (TNBC) were significantly associated with local recurrence. CONCLUSIONS Five defined oncoplastic principles presented in our nomogramme (targeted breast surgery) allow the reconstruction of major segmental resection defects during breast-conserving therapy with high clinical applicability and result in favorable oncological and aesthetic outcome. Recurrence was not a function of traditional prognostic factors like T-size or nodal status (in a T1/T2, N0/N1 cohort), but of grading, intrinsic subtypes and non-invasive breast cancer components. Lobular histology, multi-centricity and DCIS were predictive for breast preservation failure and conversion to mastectomy.

Translating the concept of intrinsic subtypes into an oncoplastic cohort of more than 1000 patients – predictors of recurrence and survival

INTRODUCTION A paradigm shift in breast cancer was introduced by Sørlies concept of intrinsic subtypes [1]. We validated this concept - which was originally based on 84 individuals - in a large cohort study of 1035 patients with oncoplastic surgery and analyzed if early and late recurrences are linked to a specific intrinsic tumor subtype or resection margins. MATERIALS AND METHODS 1035 patients with oncoplastic surgery (2004-2009) were analyzed with regard to treatment characteristics and patterns of early (<5 years) and late recurrence (>5 years) and survival related to the intrinsic subtypes. Data was retrieved from patients charts, customized patients questionnaires and cancer registries. RESULTS 944 patients with primary, unilateral breast cancer, median age 58 years, were eligible for analysis. At a median FU of 5.2 years, LRR was 4.0%, 5-year-OS 94.5% and DFS 90.9%. Intrinsic subtypes, but not T-size, nodal-status, resections margins nor histopathology, governed local control and survival. There was no signal for prevelance of unclear margins in any of intrinsic subgroups and no preference of any oncoplastic technique attributed to them. TNBC and Her2 non-luminal breast cancer had highest recurrence and lowest survival rates. Although sentinel involvement (SLN+) was prevailing in the Luminal-B-Her 2 negative subtype at 34.3%, this did not translate into a higher axillary dissection rate. CONCLUSION This study confirmed the intrinsic subtype concept on a large clinical basis and describes the patterns of early and late recurrence in oncoplastic surgery, concluding that bigger risk may not be overcome by bigger surgery.

Neoadjuvant, anthracycline-free chemotherapy with carboplatin and docetaxel in triple-negative, early-stage breast cancer: a multicentric analysis of rates of pathologic complete response and survival

Introduction: Triple-negative breast cancer (TNBC) has the highest mortality rates of all subtypes. Anthracycline and taxane regimens yield unsatisfactorily low rates of pathologic complete response (pCR) and are often not feasible in cardiac comorbidity. This study seeks to increase pCR and survival by introducing platin agents. Patients and Methods: In this multicentric, open-label study with six cycles of docetaxel (75 mg/m2) and carboplatin AUC 6 q3w, patients were unwilling or unsuitable for anthracycline-based regimens. Primary endpoint was pCR (ypT0/ypTis ypN0) and survival. Results: pCR rate was 50%. After 2 and 5 years, overall survival (OS) was 96.7 and 89.7%, disease-free-survival (DFS) 96.7 and 85.7%, DDFS 96.7 and 89.6%. Grade 3/4 toxicities were rare. Ninety-three per cent of patients completed six cycles. No toxicity-related treatment discontinuation or febrile neutropaenia was recorded. Conclusion: This regimen is highly effective and feasible in TNBC and may be combined with anthracyclines.

Oncoplastic Reduction Mammoplasty: Incision Patterns, Safety Issues, and Plasticity

Macromastia has been considered a contraindication to breast conservation therapy because of difficulties with radiation therapy. Bilateral reduction mammoplasty in conjunction with a tumor-directed and segmental oriented partial mastectomy is a surgical technique that can potentially improve the efficacy of radiation therapy in this setting, alleviate the neuropathic symptoms that can accompany macromastia, and increase rates of breast-preserving surgery for breast cancer patients. Many different and varied techniques for breast reduction have been described. In addition, many of these procedures have variably overlapping technical details, all of which can create confusion when attempting to evaluate published results. To achieve the aims and quality indicators of breast conservation therapy in conjunction with aesthetic results, a reduction technique with a modified inferior flap and superior pedicle was developed. This technique can be used as a standardized oncoplastic procedure in breast conservation therapy associated with macromastia and in aesthetic surgical treatment of macromastia, ptosis, and tubular breasts. The principles of the tumor-adapted reduction mammoplasty developed are described.

Updated results of neoadjuvant chemotherapy with carboplatin AUC 6 and docetaxel 75 mg/m2 in triple-negative breast cancer (TNBC).

149 Background: Triple-negative breast cancer (TNBC) is associated with a poor prognosis unless a pathological complete response (pCR) is achieved or almost achieved (near-pCR). Treatment of TNBC remains a challenge as some patients fail to respond to the use of standard anthracyclin-based chemotherapy regimens. Phenotypic and molecular similarities between TNBC and BRCA1-associated breast cancer suggest that TNBC may share the same sensitivity to platinum analogues as tumors associated with BRCA1. METHODS 30 patients with primary, unilateral, non-metastasized TNBC (majority of them cT1 or cT2, two cT4) had to be unsuitable for standard anthracycline-based chemotherapy. They received 6 cycles, respectively in two case sonly 5 cycles, of carboplatin AUC 6 and docetaxel 75 mg/m² q3w. Adverse effects were recorded according to CTCAE V4.07. Primary endpoint was pathological complete response (pCR) and near-pCR, secondary endpoint toxicity. RESULTS 70% (21/30) of patients had either a pathological complete response (55%; 15/27) or a near-complete response (20%; 6/30) - defined as pT1mic and ypT1a - both being associated with a good prognosis. Eight remaining patients had still good partial response, leaving only low residual cancer burden, which was specified as ypT1, in contrast only one ypT4 tumor. Treatment was well tolerated - grade IV toxicities were predominantly hematological side effects (especially concerning neutropenia) and in 2 cases grade IV edema and joint pain. Carboplatin dose reduction (to an AUC of 5) was required in 5 cases (because of limited renal function, hematological side effects or patients age). CONCLUSIONS Our results demonstrate a high-anti-tumour activity of docetaxel 75mg/m² in combination with carboplatin AUC 6, promising high rates of tumour regression and pathological complete remission. The omission of exposure to anthracyclines in patients with considerable heart disease risks seems to be feasible with a good pCR-rate, the latter being a surrogate-marker for long-term survival. Survival data of this trial are currently being updated and will be presented on the Breast Cancer Symposium.

Onkoplastische Brustchirurgie – Zielgerichtete Brustchirurgie angepasst an Tumorsitz und Tumor-Brust-Relation

Basierend auf einer individuellen Charakterisierung der Tumorbiologie des Mammakarzinoms werden zunehmend zielgerichtete Behandlungsstrategien eingesetzt. In einer uber 1000 Patienten mit Brusterhaltender Therapie (BET) umfassenden Studie haben wir die Systematik einfach zu beherrschender Techniken, angepasst an den Tumorsitz und an die Tumor-Brust-Relation, validieren konnen. Uber 60 % aller Tumoren liesen sich hierbei mit glandularer Rotationstechnik und uber 30 % mit dermo-glandularer Rotationsmastopexie, tumorlager-adaptierter Reduktionsplastik und lateralem Thoraxwand-Advancement-Lappen- (n. Rezai), bei hoher Patientenzufriedenheit, beherrschen. Nur in seltenen Fallen waren Volumen-Ersatz-Techniken aus anderen Donor-Regionen (Thorakoepigastrischer Lappen, Latissimus-dorsi-Lappen) erforderlich 4 5 8 .

Abstract P2-13-01: Stage-related risk categorization and influence of free margins on survival in triple negative early breast cancer - a population-based study of 2037 TNBC patients with adjuvant chemotherapy

Introduction: Triple negative breast cancer (TNBC) represents 10-20% of all breast cancer entities [1][2] and has a known aggressive behavior and poor outcome. Patients treated in the setting of randomized clinical trials often do not represent actual treatment characteristics in real-life scenarios. To determine the stage-related survival and effect of surgical performance in TNBC with current multimodal treatment, we set out to analyze data of a large population-based registry of primary breast cancers which covering >50% of all breast cancer cases in Germany. Patients and methods: We analyzed data from a prospectively collected cancer registry of >200 certified breast units of the West-German Breast Center (WBC) in Germany from 2009-2011. From a cohort of 39570 primary breast cancer patients treated in this period, 12759 underwent adjuvant systemic therapy, out of which 2037 were TNBC cases with adjuvant chemotherapy. Inclusion criteria were triple negative breast cancers (Her2-new1+/2+ (Fish negative) and estrogen receptor (ER) and progesterone receptor (PR) The use of first, second and third generation chemotherapy was analyzed as well as the effect of clear/unclear resection margins and its impact on survival data. Results: 2037 patients were eligible for this study. Overall survival rates were as follows: T1 a and T1b 100 %, T1c 90,7 %, T2 90,9 %, T3 68,1 % and T4 64,3 %. No statistical differences were detected in between stages T1 and T2, and also not in between T3 and T4. Combining T1/T2 and T3/T4 and performing group-wise comparisons, differences for combined stages were highly statistically significant (3,9 x E-09). Inflammatory TNBC was prognostically worst with a survival-rate of 33,3 % at 24-months. (p Unclear resection-margins versus clear margins in TNBC exerted a negative impact on DFS (87 vs. 73 %; p=0,00002) and DDFS (p=0,0004). Age was an independent risk factor for survival with a cut-off at 35 years.(p=0,044) Third-generation chemotherapies (anthracycline+taxanes) were associated with a significant improved overall-survival at 24-months compared to first generation chemotherapies (non-anthracycline, non-taxane) (95 % vs. 87 %; p=0,0029) Conclusion: Standard 3rd generation (anthracycline- and taxane-containing) chemotherapy and optimal surgical performance with clear margins is vital for patients with early, triple-negative breast cancer (TNBC). Within T1 and T2 stages, no stage-related deterioration of prognosis was detected, however these stages were markedly different from stages T3/T4, declining from 90-100% to 64-68 %. This analysis of a large database of a population-based study demonstrates that tumor size, margins and guideline-adapted chemotherapy matter in triple-negative, early breast cancer. [1] Schwentner et al. 2013 [2] Elsawaf et al. 2013. Citation Format: Peter Kern, Gunter von Minckwitz, Carolin Putter, Annika Flach, Sofia Pavlidou, Rainer Kimmig, Mahdi Rezai. Stage-related risk categorization and influence of free margins on survival in triple negative early breast cancer - a population-based study of 2037 TNBC patients with adjuvant chemotherapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-13-01.

Abstract P1-16-07: Translating the concept of intrinsic subtypes into an oncoplastic cohort of more than 1000 patients-predictors of recurrence and survival

Introduction: The concept of breast cancer experienced a paradigm shift by Sorlie T. et al. with intrinsic subtypes as prognostic classification of breast cancer [1]. We validated this concept in a large cohort study of oncoplastic surgery. Patients and methods: We analysed 1035 patients with oncoplastic surgery (2004-2009) and survival parameters related to histopathological approximated intrinsic subtypes. Data were retrieved from customized questionnaires and patients charts. Survival data were determined from cancer registries. Results: A total of 944 patients with primary unilateral breast cancer, median age 58 years, were eligible for analysis. At a median follow-up of 5.3 years, LRR was 4.1%, with 5-year-OS of 94.5% and DFS of 90.9%. Stage distribution was as follows: T1a 3%, T1b 12 %, T1c 44,2 % and T2 was 22,1%. 70,4 % of patients were nodal-negative and nodal involvement was predominantly low. Intrinsic subtypes, not T-size, nodal-status, resection margin width nor histopathology, governed the prognosis of this cohort. Triple-negative and Her2 non luminal breast cancer had the highest recurrence and the lowest survival rates compared to Luminal A: Recurrence TNBC 11,3 %, Her2pos non luminal 9,3 %, Luminal A 2,5 %; Overall survival: TNBC 91,3 %, Her2 non luminal 93,7 %; Luminal A: 96,3 %. Our data confirmed the intrinsic subtype concept on a large basis in oncoplastic surgery. (1) Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Lonning PE, Borresen-Dale AL: Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 2001; 98: 10869–10874. Citation Format: Mahdi Rezai, Stephanie Kellersmann, Sarah Knispel, Rainer Kimmig, Peter Kern. Translating the concept of intrinsic subtypes into an oncoplastic cohort of more than 1000 patients-predictors of recurrence and survival [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-16-07.