role of anthracycline-based therapy in the adjuvant treatment … · 2019-10-04 · role of...
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Role of Anthracycline-Based Therapy in the Adjuvant Treatment of Breast Cancer:
Efficacy Analyses Determined by HER2 Molecular Subtype
Cancer International Research Group (CIRG)
Global Project Coordinators
Valerie Bee - BCIRG 006 StudyHenry Taupin - BCIRG 005 Study
The HER2 AlterationThe HER2 Alteration
IHC
Southern
Northern
Western
Slamon et al. Science 1987, 1989
The HER-2 Gene: encodes a 185kd protein that is a member of the type I receptor
tyrosine kinase family which also contains EGFR, HER-3 and HER-4
Functions When Altered:1.) Growth and proliferation - increased
2.) Differentiation - decreased3.) Cell survival - increased
4.) Motility - increased5.) Neoangiogenesis - increased
6.) Reduced dependency on estrogen and insensitivity to hormonalblockade
The Topoisomerase IIa Gene: encodes an enzyme which is critical in DNA
replication and function including RNA transcription
Functions:1.) Resolves topological problems in DNA
2.) Is critical in RNA transcription from DNA3.) Makes transient protein-bridged DNA breaks on one or both DNA strands during
replication4. Plays critical roles in segregation, condensation and superhelicity
The Topo IIa protein is a major target of the anthracyclines
The META-Analysis
How Did The Current Chapter Start ?
Attempts to explain the differential prognosis of HER2 positive breast cancers
CALGB 8541
Paik, JNCI 92:1991, 2000 (NSABP B-15)
NSABP-B15
Pritchard, NEJM 354:2103, 2006
HER-2 neg MA-5 TRIAL HER-2 pos
Overall SurvivalOverall Survival
heterogeneity c25 = 5.2, p = 0.39heterogeneity c25 = 5.5, p = 0.36
Test for interaction chi2 = 12.0, p < 0.001
Study HR 95% CI0.47 - 0.92
0.69 - 1.180.66 0.90 NSABP B11
0.63 - 1.060.88 - 1.30
0.821.07 NSABP B15
0.27 - 2.690.85 - 3.15
0.85 1.64 GUN 3
0.32 - 1.160.89 - 1.79
0.611.26 Milan
0.50 - 1.050.59 - 1.13
0.730.82DBCG-89-D
0.42 - 1.010.80 - 1.40
0.651.06 NCIC MA-5
0.62 - 0.850.92 - 1.16
0.73 1.03
Overall
HER2 positiveHER2 negative
non anthra betteranthra better
0.6 1 2 50.4
p < 0.0001p = 0.86
0.9
A. GennariSABCS 2006
0.83 - 1.000.91Total p = 0.056
Is this due to a unique and/or inherent sensitivity to anthracycline caused by
HER-2 overexpression?
Human Breast Cancer Cells
MCF-7
Single copyLow Expressor
Transfect
HER-2/neuMCF-7*
Multiple copyHigh Expressor
Additional Human Breast Cancer Cells
Single copyLow Expressor
Transfect
HER-2/neu
MDA-435
MDA-231
BT-20Multiple copyHigh Expressor
*Consistent results in 9 additional Breast Cancer Cell Lines
MDA-435
MDA-231
BT-20
Effect of HER-2/neu overexpression on sensitivity of human breast cells to
doxorubicin in vitro
5.6
0.17±0.030.15±0.02
0.3±0.030.2±0.05
0.6±0.090.6±0.07
0.39±0.030.34±0.07
IC-50 for DOX (μM)
[Peak Plasma] -achievable in humans
BT-20/NEOBT-20/HER-2
MDA-MB-231/NEOMDA-MB-231/HER-2
MDA-MB-435/NEOMDA-MB-435/HER-2
MCF7/NEOMCF7/HER-2
These in vitro and in vivo studies demonstrated convincingly that the
increased anthracycline sensitivity was NOT due to HER-2 overexpression
Instead the current data indicate that it is the topo IIa gene amplification and not HER2 that
is responsible for improved anthracyclinesensitivity
HER2Core region
Normal Amplified Deletion
Example 1
Example 2
Example 3
Example 4
Example 5
Example 6
Example 7
HER2
Mapping the HER2 Amplicon
TOP2A
TOPO II region
HER-2/neu-telomeric BAC FISH signals/Chr. 17 cen. signalExample 1 : Breast ca. cell line BT-474
HER-2 Amp TOPO IIa Deleted
HER-2/neu-telomeric BAC FISH signals/Chr. 17 cen. signalExample 2 : Breast ca. cell line: SKBR-3
HER-2 Amp TOPO IIa co-Amp
**Analysis performed in a total of 26 human breast cancer cell lines to determine correct “cut-offs”
Test Set
“Test Set” 0648 Registrational Trial: Trastuzumab in 1st Line HER2 Positive Metastatic Disease
Analysis of PFS Outcomes as Related to Topo IIa
Treatment Arm Topo IIa Status PFS p-value
AC Alone (n=77) Normal/deleted (n=50) 5.6 mo(median PFS) Topo co-Amplified (n=27) 7.1 mo p=0.11
AC + Tras (n=85) Normal/deleted (n=54) 7.3 mo
(median PFS) Topo co-Amplified (n=31) 8.6 mo p=0.31
“Test Set” 0648 Registrational Trial: Trastuzumab in 1st Line HER2 Positive Metastatic Disease
Analysis of Survival Outcomes as Related to Topo IIa
Treatment Arm Topo IIa Status Survival p-value
AC Alone (n=77) Normal/deleted (n=50) 18.2 mo (med survival) Topo co-Amplified (n=27) 38.5 mo p=0.004
AC + Tras (n=85) Normal/deleted (n=54) 29.3 mo
(med survival) Topo co-Amplified (n=31) 29.4 mo p=0.66
Validation Set
4 x AC60/600 mg/m2
4 x Docetaxel100 mg/m2
6 x Docetaxel and Carboplatin75 mg/m2 AUC 6
1 Year Trastuzumab
N=3,222
1 Year Trastuzumab
AC T
AC TH
TCH
Her 2+(Central FISH)
N+or highrisk N-
4 x AC60/600 mg/m2
4 x Docetaxel100 mg/m2
BCIRG 006
Stratified by Nodes and Hormonal Receptor Status
HER2 and TOPO II in BCIRG 0062120 of 3222 patients analyzed
HER2Core region
17 q 12 17 q 21.1 17 q 21.2
1285 pts (60%)
N=2120
91 pts (4%)
Topo IINonCo-Amplified
Normal Amplified Deletion
TOPO II region
744 pts (35%)Co-Amplified
first interim analysissecond interim analysis
N=2990
1788 pts (60%)
145 pts (5%)
1057 pts (35%)
2990 of 3222 patients analyzed
Disease Free Survival - 2nd AnalysisAbsolute DFS benefits
(from years 2 to 4):AC→TH vs AC→T: 6%
TCH vs AC→T: 5%
% D
isea
se F
ree
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5
Patients Events1073 192 AC->T1074 128 AC->TH1075 142 TCH
81%
87%
86%
77%
83%82%
87%
93%
92%
HR (AC->TH vs AC->T) = 0.61 [0.48;0.76] P<0.0001HR (TCH vs AC->T) = 0.67 [0.54;0.83] P=0.0003
Year from randomization
DFS Non Co-Amplified Topo II by Arm (2nd Analysis)
% D
isea
se F
ree
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5
Patients Events643 146 AC->T643 87 AC->TH618 92 TCH
83%
91%
90%
78%
85%
84%
71%
83%
81%
Year from randomization
P<0.001P<0.001
DFS Co-Amplified Topo II by Arm (2nd Analysis)
% D
isea
se F
ree
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5
Patients Events328 42 AC->T357 35 AC->TH359 42 TCH
92%
95%
94%
87%
89%87%
85%
83%83%
Year from randomization
P=0.336P=0.648
Therapeutic Index – Most Recent 006 Data
04*Leukemia
TCHAC-TH
420Grade 3 / 4 CHF
149161Total
4744Br Ca Deaths9893Br Ca Recurrence
* in both anthracycline-based arms.
In a recent analysis of >1600 pts from the BCIRG 005 (HER2 normal) study for Topo IIa
alterations there is not a single case of TopoIIa amplification. It does not appear to
occur without HER-2 amplification.
Implications for HER2 negative and HER2 positiveBreast Cancers
♦ The superior efficacy benefits for anthracyclines (when present) appears to derive from their effects on topo IIa amplification and/or overexpression
♦ Given that thus far topo IIa amplification occurs ONLY in 35% of the 25% of breast cancer patients with HER2 amplification, i.e. a subset of a subclass (tested in >4,500 patients tested at USC/UCLA)………
♦ What data supports their preferential use in a HER-2 negative breast cancer population which is ~ 75% of all breasts cancers
♦ Moreover, for HER-2 positive breast cancers we now have trastuzumab and lapatinib, one of which (thus far) appears to replace the gained efficacy of anthracyclines in the 1/3 of patients with co-amplification of HER2 and Topo IIa(which is ~8% of all breast cancers) without risking their known and well established toxicities
♦ What is the role of anthracyclines in the adjuvant treatment of breast cancer?
ARGENTINA Olver CANADA El Khodary Clemens Tessen ISRAELFein Ransom Cantin ESTONIA Conrad Von Minckwitz BarakGiacomi Richardson Dorreen Padrik Dall Weist Ben BaruchMartinez Schwarz Dufresne Valvere Dubois Winzer GeffenMickiewicz Stewart Klimo FRANCE Eiermann * Wolf GoldbergXynos Sullivan Latreille Achille Sussenbach Zedelius KaufmanAUSTRALIA/NZ Van Hazel * Lopez Bonneterre Gerber Zippel RizelAbdbi Walpole Provencher Bressac Hempel GREECE SafraBegbie White Roy Cals Henschen Georgoulias SteinerBeith Young Sehdev Carola Hilfrich HONG KONG ITALYByard AUSTRIA Smylie * Colin Jackisch Chow BaroneChan Dittrich Wilson Dalivoust Jackish HUNGARY BonettiChirgwin Sevelda Zibdawi Dutel Jager Baki BonsignoriClingan BELGIUM COLOMBIA Fumoleau Jonat Dank GamucciCraft Cocquyt Gomez Gligorov Kettner Pinter * GaspariniDalley Demol Sanchez Guastalla Klare Szanto GeminianiDavidson Dirix Vargas Jaubert Kretzschmar INDIA IaffaioliDewar Mebis CROATIA Khayat Kullmer Advani MarangoloGanju Verhoeven Grgic Levy Kunz Doval NardiGreen Vermorken Markulin-Grgic Namer Lichtenegger Gupta PolleraGrimes BOSNIA Mrsic-Krmpotic Priou Lürmann Julka RavaioliHarvey Beslija Vrdoljak Tournigand Meerpohl Ranade LEBANONIsaacs BRAZIL CYPRUS Valenza Meinerz IRELAND Abi GergesJameson Anelli Adamou Vannetzel Morack Breathnach ChahineKannourakis Ferrari CZECH REPUBLIC GERMANY Noschel Crown * GhosnKoczwara Lago Petruzelka Bastert Prell Grogan SaghirKotasek Schwartsmann Vodvarka Breitbach Scharl Keane MEXICOLewis BULGARIA Vyzula Brunnert Schmidt Kennedy * ChanLinks Timcheva EGYPT Carstensen Schweppe McCaffrey SilvaMcCarthy Tzekova Azim Christensen Souchon Mullins Valle
Principal Investigators involved in the study (I)
Principal Investigators involved in the study (II)POLAND SOUTH KOREA SWITZERLAND Carroll Laufman RinaldiBorowska Bang Aapro Chakrabarti Lewis Robert (USO)Karnicka Im TAIWAN Chap * Limentani RodriguesPawlicki * Kim Chao Chap (network) Lower RubinPienkowski * Lim Liu * Chen Mac Andrew RussellWojtukiewicz Ro TUNISIA Chitneni Malamud SchleiderZaluski SPAIN Benayed Chowhan Mc Croskey SchwatzbergROMANIA Adrover Frikha Chuu McKeen ShafferBadulescu Alba Conejo TURKEY Cobb Mena ShiftanGhilezan Alonso Romera Aydiner Dookeran Mills (network)Gutulescu Alvarez Baltali Dreisbach Modiano SparanoRoman Aranda UK Falkson Moore SylvesterRUSSIA Arcusa Carmichael Fesen Moroose TaiGarin Baena Canada Le Vay Forsthoff Moss TangGorbunova Barnadas Wardley Foulke Neel TansinoSemiglazov Calvo Martinez URUGUAY George Olopade TezcanSLOVAKIA Crespo Rodriguez Goodman Orlowski TouroutouglouKoza Dominguez Viola Greenwald Osborn ValeroSpanik Enrique Ales USA Hajdenberg Overmoyer VaughnSLOVENIA Estevez Garcia Abukabr Hotchner Page VogelCufer Florian Gerico Ansari Houston Patel WaintraubTakac Jara Arena Jhangiani Patton WaismanSOUTH AFRICA Martin Baltz Jones Petruska WalkerCallaghan Martin Lorente Beall Justice Pluard WitnizerJacobs Mel Lorenzo Bianco Juturi Polikoff YostMoodley Oltra Ferrando Boccia Kalman (network) YoungPienarr Pelegri Boros Kennedy Rahman YunusRapoport SWEDEN Brufsky Kerr Rangineni VENEZUELASlabber Fornander Burris Kincaid Reich De Joghn
Vera
Acknowledgements (con’t)♦Genentech:
Axel UllrichH. Michael Shepard, Hank Fuchs, Bob Mass, Mark Sliwkowski
♦Amgen:Frank CalzoneElena Cajulis
♦Nat. Br. Ca. Coalition
♦IDDI: Mark Buyse
♦USC:Michael Press
♦Revlon Foundation:Ronald Perlman James Conroy Lilly Tartikoff
♦Herceptin Clinical Investigators Network & BCIRG
♦Community-based/UCLA Clinical Research Network
♦UCLA: Giovanni Pauletti - Amplicon Characterization
♦The Group of 20