C. Schumacher Brustzentrum St. Elisabeth-Krankenhaus Operatives Procedere bei Multizentrizität: Ist eine Ablatio immer erforderlich? C. Schumacher Brustzentrum St. Elisabeth-Krankenhaus 1

Ziele der Mammakarzinomtherapie Optimale lokale Kontrolle (Einfluss auf das Gesamtüberleben: 4 Lokalrezidive führen zu einem brustkrebsbedingten Todesfall) Optimale lokoregionäre Kontrolle Fernmetastasenfreiheit

Lokale Kontrolle Multizentrizität? Lokalrezidivrate Ziel: max. 1% pro Jahr, um den negativen Effekt auf das Überleben zu limitieren Aktuelle Daten: ca. 2-3% Lokalrezidive nach 5 Jahren Wichtigste Einflussfaktoren: Tumorbiologie, Tumormasse, positive Ränder, junges Alter, nicht durchgeführte Strahlentherapie oder adjuvante medikamentöse Therapie Multizentrizität?

Multizentrizität: Häufigkeit Inzidenz lt. Literatur: 6 – 75% je nach Definition, Ein- oder Ausschluss von In-situ-Läsionen, pathologischer Aufarbeitung und bildgebender Diagnostik Holland et al: in > 60% der Mastekomiepräparate bei vermuteter Unifokalität Detektion weiterer Läsionen, 43% > 2 cm entfernt) klinische Relevanz??? Zunehmende Inzidenz durch Verbesserungen in der bildgebenden Diagnostik Houvenaeghel G et al, World Journal of Clinical Oncology

Diagnosestellung Multifokalität / Multizentrizität Sensitivity of MRI versus mammography for detecting foci of multifocal, multicentric breast cancer in Fatty and dense breasts using the whole-breast pathologic examination as a gold standard. Sardanelli F et al., Am J Roentgenol 2004 Mammographie: Sensitivität 60-75 % und PPV 73 -78 % je nach Gewebedichte MRT: Sensitivität 80 - 81% und PPV 65-71% je nach Gewebedichte Accuracy and surgical impact of magnetic resonance imaging in breast cancer staging: systematic review and meta-analysis in detection of multifocal and multicentric cancer. N Houssami Metaanalyse von 19 Studien, n=2610: bei median 16 % der Patientinnen zusätzliche Läsionen Increasing the diagnosis of multifocal primary breast cancer by the use of bilateral whole-breast ultrasound. Wilkinson LS et al., Clin Radiol 2005 BBUS increased the preoperative diagnosis of multiple tumours in women presenting with primary breast cancer, resulting in a management change in 8% of cases.

MRT und Multizentrizität: eigene Daten MRI – result n = 209 No. of patients (%) No. of patients with malignant lesions (%) Additional lesions 87 (41,6) 34 (16,3) Additional lesions close to the tumor (Influence on resection volume) 45 (21,5) 26 (12,4) Additional lesions outside the resection volume 64 (30,6) 12 ( 5,7) Here you can see our results starting with the MRI resultsI: In 87 (41,8%) of the 209 patients additional suspicious lesions were seen with MRI. We divided these lesions into 2 categories: lesions close to the tumor and lesions outside the resection volume, that means at least 3-4 cm away from the tumor. In 22 patients we found lesions in both categories so that we have double entries of patients within the table. A total of 34 patients (39% of MRI marked patients) had additional malignant lesions. In most of these patients the lesions were localized close to the tumor (76,5%) showing multifocality or intraductal components with enlargement of the resection volume. In 35,3% of these patients and 5,7% of all study patients respectively additional malignant lesions were found outside the resection volume indicating extensive multifocality or multicentricity resulting in the decision made against using the IORT-boost.

Characteristics of Multifocal and Multicentric Breast Cancers Kanumuri P et al., Ann Surg Oncol. 2015 Of 1495 invasive cancers, 1231 (82.3 %) were UF, 169 (11.3 %) were MF, and 95 (6.4 %) were MC cancers. MC but not MF cancers were associated with young age at diagnosis, larger tumor size, lymphovascular invasion, and node positivity. MF but not MC tumors were more likely to be ER/PR+Her2+ tumors and less likely to be triple-negative cancers compared with UF tumors. MF tumors were more likely to be infiltrating ductal carcinomas with an extensive intraductal component, and MC tumors were more likely to be infiltrating lobular carcinomas. Concordance of histology and receptor status between primary and secondary foci was high and was similar for both MF and MC cancers. Multicentricity remained an independent predictor of lymph node positivity on multivariate analysis.

Pathological Characteristics of Both Tumors in Bifocal and Bicentric Breast Cancer. Mosbah R et al., Anticancer Res 2015 A total of 205 patients were included. The same histological type in 182 patients (89%) The same grade in 178 of the cases (96.7% and 100% for grade 3 lesions). Excellent immunohistochemical concordance with correlation coefficients of 0.98, 0.96 and 0.99 for ER, PR and Ki67, respectively. (HER2) status was available for both tumors in 177 cases (86%), with a perfect concordance. No differences in molecular sub-type between tumor foci.

Frage: Ist eine Ablatio immer erforderlich? Welche Rolle spielt die Multizentrizität für die lokale Sicherheit und das Gesamtüberleben? Profitiert die Patientin von einer intensiveren präoperativen Bildgebung mit einer erhöhten Nachweisrate multizentrischer Tumorherde? 3. Kann das operative Vorgehen bei Multizentrizität das Outcome beeinflussen?

Was sagen die Leitlinien?

S3 – Leitlinie 2012

St. Gallen Konsens 2015

ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up 2015 In some patients, mastectomy is still carried out due to: tumour size (relative to breast size), tumour multicentricity, inability to achieve negative surgical margins after multiple resections, prior radiation to the chest wall/breast or other contraindications to RT, or patient choice NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Version 2.2016 Lumpectomy is contraindicated for patients who are pregnant and would require radiation during pregnancy; have diffuse suspicious or malignant-appearing microcalcifications on mammography; have widespread disease that cannot be incorporated by local excision through a single incision with a satisfactory cosmetic result; or have diffusely positive pathologic margins

AGO-Leitlinie

Aktuelle Praxis

Multifocality and multicentricity in breast cancer and survival outcomes Lynch SP et al., Oncologist 2013 MD Anderson database 1997 - 2010 n = 3924, 695 (17,7%) MF 247 ( 6,3%) MC med. FU 51 mo

Erhebung in England M. Dixon, Edinburgh, BC3-Konferenz 2013

Metaanalysis: Impact of MRI on Initial Surgical Outcomes

Is the use if breast MRI predictive of mastectomy Is the use if breast MRI predictive of mastectomy? Killelea et al, World J Surg Oncol 2013 Yale database 2004-2009

Aktuelle Studienlage

Welche Rolle spielt die Multizentrizität für die lokale Sicherheit und das Gesamtübeleben?

Multifocality and multicentricity in breast cancer and survival outcomes Lynch SP et al., Oncologist 2013 MD Anderson database 1997 - 2010 n = 3924, 695 (17,7%) MF 247 ( 6,3%) MC med. FU 51 mo

Comparing the outcome between multicentric and multifocal breast cancer: what is the impact on survival, and is there a role for guideline-adherent adjuvant therapy? A retrospective multicenter cohort study of 8,935 patients. Wolters R et al., Breast Cancer Res Treat 2013 After Adjustment on age, tumor size, grade, nodal status and adjuvant therapy according to guidelines no difference between unifocal and MF / MC tumors: MC tumors: RFS 0,88, p = 0,35 OS 1,08, p = 0,54 MF tumors: RFS 1,05, P = 0,597 OS 0,92, p = 0,28

Effect of multifocality and multicentricity on outcome in early breast cancer: A systematic review and meta-analysis. Vera-Badillo FE et al, Breast Cancer Res Treat 2014

Profitiert die Patientin von einer intensiveren präoperativen Bildgebung mit der erhöhten Nachweisrate multizentrischer Tumorherde?

Comparative effectiveness of MRI in breast cancer (COMICE) trial: a randomized controlled trial Turnbull et al., The Lancet 2010

Relationship of breast magnetic resonance imaging to outcome after breast-conserving treatment with radiation for women with early-stage invasive breast carcinoma or ductal carcinoma in situ Solin LJ et al, J Clin Oncol 2008 Patients and methods: n = 756 during 1992-2001 215 patients with MRI, 541 without MRI, med. FU 4,6 y Results: 8-year local failure rate 3% vs 4% (p=0,51) 8-year overal survival rate 86% vs 87% (p=0,51)

Magnetic resonance imaging in the planning of initial lumpectomy for invasive breast carcinoma: its effect on ipsilateral breast tumor recurrence after breast-conservation therapy. Hwang N et al., Ann Surg Oncol. 2009 MRI was performed before 127 (27%) lumpectomies, while 345 (73%) patients did not have a preoperative breast MRI. At median follow-up of 54 months (range 4.8-111.6 months), there was no significant difference in actuarial 8-year IBTR rates between women with preoperative MRI evaluation and women without MRI (1.8% versus 2.5%, respectively; P=0.67). MRI visualization of tumors prior to lumpectomy did not influence the achievement of negative margins and was not associated with lower rates of re-excision (MRI: 11.8% versus no-MRI: 13.3%; P=0.50

Effect of MRI on Local Recurrence After BCT

3. Kann das operative Vorgehen bei Multizentrizität das Outcome beeinflussen?

Lokalrezidivraten nach BET bei Multifokalität / Multizentrizität: retrospektive Studienergebnisse Houvenaeghel G et al, World Journal of Clinical Oncology

Woods et al: Lokalrezidivraten bei Multifokalität / Multizentrizität

Woods et al: Lokalrezidivraten bei Multifokalität / Multizentrizität

Is breast-conserving therapy a safe option for patients with tumor multicentricity and multifocality? Yerushalmi et al, 2012 Database Breast Cancer Agency Vancouver 1989-2005 n = 11983 BCT, 7771 mastectomies (11683 unifocal tumors, 300 MC/MF tumors) med. FU 7,9 years BCT in MF / MC: 50-69 years, no EIC, smaller tumors Cumulative incidence of local relapse by unifocal versus multicentric/multifocal disease for breast concerving therapy cases

Is breast-conserving therapy a safe option for patients with tumor multicentricity and multifocality? Yerushalmi et al, 2012 Database Breast Cancer Agency Vancouver 1989-2005 n = 11983 BCT, 7771 mastectomies (11683 unifocal tumors, 300 MC/MF tumors) med. FU 7,9 years BCT in MF / MC: 50-69 years, no EIC, smaller tumors Cumulative incidence of local relapse by unifocal versus multicentric/multifocal disease for mastectomy cases

Multifocality and multicentricity in breast cancer and survival outcomes Lynch SP et al., Oncologist 2013 MD Anderson database 1997 – 2010, n = 3924, med. FU 52 mo

Multifocality and multicentricity in breast cancer and survival outcomes Lynch SP et al., Oncologist 2013 MD Anderson database 1997 – 2010, n = 3924, med. FU 52 mo BET Mastektomie Mastektomie + RX

RFS in patients treated according to guidelines Comparing the outcome between multicentric and multifocal breast cancer: what is the impact on survival, and is there a role for guideline-adherent adjuvant therapy? A retrospective multicenter cohort study of 8,935 patients. Wolters R et al., Breast Cancer Res Treat 2013 RFS in patients treated according to guidelines MF tumors: BCT + RT vs Mastectomy HR 1,25, p= 0,284 MC tumors: BCT + RT vs Mastectomy HR 1,19, p= 0,7 BCT + RT vs Mastectomy + PMRT HR 1,23, p= 0,64

Preliminary results: double lumpectomies for multicentric breast carcinoma. Kapoor NS et al., Am Surg. 2012 Seven patients underwent double lumpectomies for multicentric carcinoma. Median age was 69 years (range, 61 to 80 years). In five patients, MRI identified ipsilateral second malignancies. All patients had two foci of invasive carcinoma, all tumors expressed estrogen receptor, and none showed HER-2 overexpression. Tumor sizes ranged from 0.7 to 2.9 cm. All patients had sentinel lymph node biopsies and none had nodal metastasis. Median follow-up was 26 months (range, 18 to 85 months). No patient developed locoregional recurrence.

Zusammen-fassung

Zusammenfassung 1 Zunehmende Inzidenz der Diagnose Multizentrizität durch Verbesserungen in der bildgebenden Diagnostik mit konsekutiver Steigerung der Mastektomierate weltweit. Die Diagnose Multizentrizität ist lt. Datenlage kein unabhängiger Prognosefaktor für die Lokalrezidivrate und das Gesamtüberleben. Eine intensivere präoperative Bildgebung insbesondere unter Einschluss der MRT-Mammographie ist bisher ohne nachweisbaren Effekt auf die Lokalrezidivrate und das Gesamtüberleben

Zusammenfassung 2 - multidisziplinäre Patientinnenselektion Steigende Evidenz, dass die BET in ausgesuchten Fällen eine onkologisch adäquate Therapie ist. Voraussetzungen: - multidisziplinäre Patientinnenselektion - präoperative onkologische und ästhetische Planung - freie Ränder - zufriedenstellende kosmetische Rekonstruktion - postoperative Strahlentherapie ( 2 Boostbestrahlungen?) - adäquate adjuvante medikamentöse Therapie Fehlen eindeutiger aktueller Leitlinien für das Management

Vielen Dank für Ihre Aufmerksamkeit! 43