Neues aus San Antonio 2013 Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe KLINIKUM DER UNIVERSITÄT MÜNCHEN® NEUES AUS SAN ANTONIO 2013: PRIMÄRES MAMMAKARZINOM Lokaltherapie

Campus Innenstadt | Campus Großhadern

Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe

Prof. Dr. Nadia HarbeckLeitung Brustzentrum der Universität München

Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe Ludwig-Maximilians-Universität München

Direktor: Prof. Dr. Klaus Friese

Neues aus San Antonio2013

BrustzentrumKlinik und Poliklinik für Frauenheilkunde und Geburtshilfe

KLINIKUM DER UNIVERSITÄT MÜNCHEN®

NEUES AUS SAN ANTONIO 2013: PRIMÄRES MAMMAKARZINOM

LokaltherapieAdjuvante Therapie

BisphosphonateHER2-positiv

…

26.01.20142

San Antonio 2013 | Prof. Harbeck





This presentation is the intellectual property of the EBCTCG.Contact [email protected] for permission to reprint and/or distribute.

San Antonio Breast Cancer Symposium – December 10-14, 2013Cancer Therapy and Research Center at UT Health Science Center

Effects Of Bisphosphonate Treatment OnRecurrence And Cause-specific Mortality

In Women With Early Breast Cancer:A Meta-analysis Of Individual Patient Data

From Randomised Trials

R Coleman, M Gnant, A Paterson, T Powles, G von Minckwitz,K Pritchard, J Bergh, J Bliss, J Gralow, S Anderson, D Cameron,

V Evans, H Pan, R Bradley, C Davies, R Gray.Early Breast Cancer Trialists’ Collaborative Group

(EBCTCG)’s Bisphosphonate Working Group.





15 Years of Adjuvant Bisphosphonate Trial Data

• Clodronate✓ Diel et al (GABG; n=302) ‐ NEJM 1998✗ Saarto et al (Finnish; n=299) ‐ JCO 2001

✓ Powles et al (RMH; n=1089) ‐ JCO 2002Paterson et al (NSABP‐B34; n=3323) ‐ Lancet Oncol 2012

• Zoledronic acidGnant et al (ABCSG‐12; n=1803) ‐ NEJM 2009

✗ Coleman et al (AZURE; n=3360) ‐ NEJM 2011✓ Coleman et (ZO‐FAST; n=1065) ‐ Ann Oncol 2013

✓ Improved outcomes on ITT analysis ✗ No improved outcomes on ITT analysis





Bisphosphonate Analysis Outcomes

Primary outcomesTime to recurrence: includes distant recurrence, localrecurrence and new second primary breast cancer (ipsilateralor contralateral).

Time to first distant recurrence: includes distant recurrenceand ignores any prior loco-regional or contralateralrecurrences.

Breast cancer mortality.





Planned Subgroup Analyses• Site of recurrence: distant metastasis, local recurrence or

contralateral breast cancer• Site of first distant metastasis: bone± other, not bone

• Menopausal status: pre, peri, postmenopausal (natural/induced)• Type of bisphosphonate: aminobisphosphonate, clodronate• Schedule of bisphosphonate: advanced cancer, bone protection• Age: <45, 45-54, 55-69, ≥70• ER status• Nodal status: negative, N = 1-3+, N = ≥4+• Histological grade

• Duration of bisphosphonate: <1 year, 1-2 years, ≥ 2years• Presence/ absence of chemotherapy

• Recurrence rates in years 0-1, 2-4, 5-9, & 10+ after randomisation



Number

trials

Numberpatients

Trialsreceived

Patientsreceived

Percentreceived

Trialsoforalclodronate 7 5174 5 5053 98%

Trialsofaminobisphosphonates* 29 17808 17 12738 72%

Alltrials 36 22982 22 17791 77%


Data Received And Included In Analyses

Aminobisphosphonates include:• Zoledronic acid (65% of patient data received),• Oral ibandronate (24%),• Oral pamidronate (8%),• Oral residronate (2%)• Oral alendronate (1%)




Breast Cancer Recurrence: All Women

All Recurrences

3408 events

Distant recurrences

2835 events



Distant Recurrence: All Patients

Bone Recurrence

888 events

Non-bone Recurrence

1947 events


Breast Cancer Recurrence: Postmenopausal Women*

Distant Recurrence

1564 events

Bone Recurrence

508 events

Non Bone Recurrence

1056 events

Significantly Greater Effect on Bone than Other Distant Recurrence

* Includes induced menopause and women aged >55 if unknownThis presentation is the intellectual property of the EBCTCG.Contact [email protected] for permission to reprint and/or distribute.


Bone Recurrence By Menopausal Status

‡

*

‡ includes women aged < 45 if unknown* Includes women aged 45-55 if menopausal status unknown

Significantly Reduced Bone Recurrence in Postmenopausal WomenThis presentation is the intellectual property of the EBCTCG.Contact [email protected] for permission to reprint and/or distribute.


Distant Recurrence At Sites Other Than Bone ByMenopausal Status

*

* May be an underestimate due to different competing risks

No Difference in Non-bone Recurrence in Postmenopausal WomenThis presentation is the intellectual property of the EBCTCG.Contact [email protected] for permission to reprint and/or distribute.


Bone Recurrence By Menopausal StatusAminobisphosphonates e.g. zoledronic acid

Clodronate

Bone Recurrence Irrespective Of Bisphosphonate TypeThis presentation is the

0.79 SE 0.092p = 0.01

0.74 SE 0.112p = 0.02



Bone Recurrence By Bisphosphonate Schedule:Postmenopausal Women



Mortality – All Women

Breast cancer mortality

2097 events

Non-breast cancer mortality

493 events


Breast Cancer Mortality By Menopausal Status

Significantly Improved Survival in Postmenopausal WomenThis presentation is the intellectual property of the EBCTCG.Contact [email protected] for permission to reprint and/or distribute.



Mortality In Post-menopausal Women

Breast cancer mortality

1146 events

All cause mortality

1524 events



Conclusions

• Adjuvant bisphosphonates reduce bone metastases andimprove survival in post-menopausal women.– 34% reduction in risk of bone recurrence (p=0.00001).

– 17% reduction in risk of breast cancer death (p=0.004).

– No significant reduction in first distant recurrence outside bone

– Risk reductions similar irrespective of ER, node status, use/non useof chemotherapy.

– Benefits similar for aminobisphosphonates and clodronate.

• No effects apparent on disease outcomes in pre-menopausalwomen.

• No significant effects on non breast cancer deaths,contralateral breast cancer or loco-regional recurrence.

Postneoadjuvant treatment with zoledronate in patients with tumor residuals

after anthracycline-taxane-based chemotherapy for primary breast cancer – the

phase III NATAN study (GBG 36/ABCSG 29)

Gunter von Minckwitz, Mahdi Rezai, Holger Eidtmann, Hans Tesch, Jens Huober, Bernd Gerber, Dirk Michael

Zahm, Jörn Hilfrich, Serban Costa, Michael Gnant, Jens Uwe Blohmer, Carsten Denkert, Claus Hanusch,

Christian Jackisch, Sherko Kümmel, Peter A. Fasching, Andreas Schneeweiß, Stefan Paepke, Michael Untch,

Valentina Nekljudova, Keyur Mehta, Sibylle Loibl

for the

GBG / AGO-B / ABCSG study groups

San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 10-14, 2013

This presentation is the intellectual property of GBG and AGO-B. Contact them at [email protected] for permission to reprint and/or distribute.

Study design

Observation

RANDOMIZATION

Prior and/or simultaneous endocrine/trastuzumab treatment or radiotherapy

Stratification factorsCenterHormon receptor status

(<10 or ≥ 10 % ER or PgR)Age (<50 / ≥50 years) Time since surgery

(within 3 months, 1 year, 2 years, or 3 years)

Zoledronic acid 4 mg iv.• Every 4 weeks for the first 6 doses (year 0- 0.5)• Every 3 months for 8 doses (year 0.5-2.5)• Every 6 months for 5 doses (year 2.5- 5.0)

Primary objective• To determine disease-free survival (DFS) after

zoledronic acid for 5 years vs. observation in patients with chemo-insensitive breast cancer after preoperative anthracycline/taxane containing chemotherapy

Event definition: any invasive or non-invasive ipsilateral locoregional, contralateral, distant recurrence, secondary primaries or death due to any cause (corresponding to DFS-DCIS1)

1 Hudis C, JCO 2007

Baseline Characteristics

Age Median 50 years Range 28-80

ypT0/N+ypT1-3ypT4

3 %93 %4 %

ypN0N+

27 %73 %

Her2 posHer2 neg

17%83%

HR posHR neg

80%20%

Ductal Lobular Other

71%17%12%

N = 693 patients

Event rate

• Observed event rate only 50% of expected rate• Interim analysis was therefore supported by a non-protocolled Bayesian futility

analysis• Futility boundary was set to 15% for the likelihood that results would become

statistically significant if follow up continued until 316 events (approximately 8 additional years)

Disease‐free survival

HR=1.042 (observation to ZA)95% CI 0.771 – 1.41

Conclusions• Postneoadjuvant treatment of zoledronate does not

improve outcome in patients without pCR after neoadjuvant anthracycline-taxane-based chemotherapy for early breast cancer.

• No subgroup effect observed• No new safety signal for zoledronate observed• Other options are currently investigated in this setting,

e.g. – Rucaparib (PARP-inh.) in TNBC (BRE09-146)– Trastuzumab emtansine in HER2+ disease (Katherine) – palbociclib in HR+/HER2- disease (Penelope)

BETH: A Randomized Phase III Study Evaluating Adjuvant Bevacizumab Added

to Trastuzumab/Chemotherapy for Treatment of HER2+ Early Breast Cancer

TRIO -011 / NSABP B-44-1 / BO20906

D.Slamon, S.Swain, M.Buyse, M.Martin, C.Geyer, Y-H.Im, T.Pienkowski, S-B.Kim, N.Robert, G.Steger, J.Crown, S.Verma, W.Eiermann,

J.Costantino, SA.Im, E.Mamounas, L.Schwartzberg, A.Paterson, J.Mackey, L.Provencher, M.Press, M.Thirlwell, V.Bee-Munteanu,

V.Henschel, A.Crepelle-Flechais, N.Wolmark

Slamon et al, SABCS 2013

BETH Trial Design

STRATIFICATIONNumber of positive Nodes (0, 1-3 ,4+)

Hormone Receptor Status (+/-)Geographic Center

COHORT 1Non-anthracycline regimen

TCH H6 (T 75 / C AUC 6)

1 year H ( load 8mg/kgH 6 mg/kg q3w)

COHORT 2Anthracycline regimen

TH FEC H3 T 100 3 5Fu 600 / E 90 / C 600

1 year H (load 8mg/kg H 6 mg/kg q3w - not during FEC)

TCH HArm 1A

TCHB HBArm 1B

TCHB HBArm 1B

TH FEC HArm 2A

THB FEC HBArm 2B

THB FEC HBArm 2B

N=3509

N=3231 N=278

N=1617 N=1614 N=140 N=138

STRATIFICATIONNumber of positive Nodes (0, 1-3 ,4+)

Hormone Receptor Status (+/-)Geographic Center

Node-Positive or High Risk Node-Negative Breast Cancer HER2 Positive by Central Testing

Node-Positive or High Risk Node-Negative Breast Cancer HER2 Positive by Central Testing


BETH Assumptions

BETH: Assumptions based on results of BCIRG-006 (AC→T vs AC→TH vs TCH) at 3-year follow-up:

• 86% DFS on TCH arm

• 87% DFS on AC→TH arm


Primary Endpoint: IDFS for overall study population

1.0

0.8

0.6

0.4

0.2

0

No. at risk:CTxHB-HB 1752 1692 1672 1648 1601 1510 1108 641 287 62 3CTxH-H 1757 1717 1690 1657 1607 1518 1106 642 282 57 1

Time (months)

Estim

ated

pro

babi

lity

92%

92%

Median Follow-up: 38 months

CTx+H(N=1757)

CTx+H+BEV

(N=1752)Events, n (%) 145 (8) 147 (8)

Stratified HR (95% CI)

Log-rank p-value

1.00(0.79–1.26)

0.9789

Unstratified HR (95% CI)

Log-rank p-value

1.02(0.81–1.28)

0.8791


AEs of Special Interest Grade 3/4

AEs, # of patients (%)

Chemo-Trastuzumab

(n=1750)

Chemo-TrastuzumabBevacizumab

(n=1722)

p value

All grade 3/4 AEs of special interest 143 (8%) 463 (27%) <0.0001

Hypertension 78 (4%) 329 (19%) <0.0001

Thromboembolic event 42 (2%) 50 (3%)

Bleeding 9 (<1%) 42 (2%) <0.0001

CHF 12 (<1%) 23 (2.1%) 0.0621

Wound healing complication 10 (<1%) 15 (<1%)

Proteinuria 1 (<1%) 21 (1%) <0.0001

Gastrointestinal perforations 1 (<1%) 11 (<1%) 0.0031

Fistula/Abscess 3 (<1%) 3 (<1%)



26.01.201453


Prognose

Stanz-biopsie

(RS, Ki-67)

EndokrineTherapie

3 weeks

Hohes Risiko

Mittleres Risiko

Niedriges Risiko

Endokrine Therapie

Ansprechen

OP / Stanz-Biopsie

(RS, Ki-67)

Gutes Proliferations-Ansprechen

Niedriges Proliferations-Ansprechen

Chemotherapie →Endokrine Therapie

Studienleitung: N. Harbeck (LKP), München; U. Nitz, Mönchengladbach

WSG-ADAPT Studie: HR+ Subprotokoll

26.01.2014 54

26.01.2014 WSG GmbH 55

20.01.2014

ADAPT Studie: Rekrutierung HR+ (HER2-)



ADAPT run-in phase(n=400) bestätigt:

Machbarkeit des Studiendesigns im klinischen Alltag

Annahmen im Protokoll: > 70% Ki67 Abfall nach endokriner Induktionstherapie

26.01.201456

Biomarkers in early breast cancer | Prof. Harbeck

Harbeck et al, SABCS 2013



26.01.201457




PRIMÄRES MAMMAKARZINOMNACH SAN ANTONIO 2013:

26.01.201458

Adjuvante Strahlentherapie: Strahlentherapie verbessert lokale Kontrolle nicht aber Gesamtüberleben bei älteren Patientinnen mit low riskhormonempfindlichen TumorenDifferenzierte Aufklärung auch über Alternativen (z.B. IORT, Hypofraktionierung) erforderlich




PRIMÄRES MAMMAKARZINOMNACH SAN ANTONIO 2013:

26.01.201459

Adjuvante Bisphosphonat-therapie: Signifikanter Effekt auf Knochenmetastasen und Brustkrebs-bedingte Mortalität nur bei POSTmenopausalen Frauen:unabhängig von ER Status oder Bisphosphonat-Regime (oral vs. i.v.)

HER2-positiv:Frühes Mammakarzinom (Stadium I):Exzellentes Outcome nach Paclitaxel und Trastuzumab (3 Jahres DFS 98,7%)Studie beantwortet nicht die Frage, welche Pat. KEINE Chemotherapie mit Trastuzumab benötigt

BETH-Studie: keine Rolle für Bevacizumab




26.01.201460

www.karger.com/brc

EVIDENZBASIERTE BRUSTKREBS-THERAPIE

AGO (DKG, DGGG) www.ago-online.de

Jährlich aktualisierte, evidenzbasierte Empfehlungen zur Diagnostik und Therapie



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26.01.201463


Documents

Neues aus San Antonio 2013 Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe KLINIKUM DER UNIVERSITÄT MÜNCHEN® NEUES AUS SAN ANTONIO 2013: PRIMÄRES MAMMAKARZINOM Lokaltherapie