ABC1 - F. Cardoso - HER-2+ advanced breast cancer - State-of-the-art management of HER-2+ disease

State-of-the-art management of HER-2+ disease

Fatima Cardoso, MD
ESO Breast Cancer Program Coordinator
Director Breast Cancer Unit & Breast Cancer Research Program
Champalimaud Cancer Center
Lisbon, Portugal

IMPORTANT LESSONS FROM HER-2 + MBC

• Crucial role of patient selection
• ABC: primary or metastatic HER-2 status?
•Importance of starting anti-HER-2 agent early on
•Several possible combinations with cytotoxic and
endocrine agents
•Continue HER-2 blockade beyond progression (change of
paradigm in ABC)

• The principle of dual blockade
• Problem of brain metastases
• Even with target/targeted drug resistance occurs

SHOULD WE BIOPSY METASTASES & REPEAT ER/PR/HER-2?

Current recommendation:
WHENEVER POSSIBLE A BIOPSY OF THE METASTATIC LESION
SHOULD BE PERFORMED

• WHY?
• BUT…

ASCO 2010: Significant Rate of Discordancy
Between Primary and Metastases
#1007 #CRA 1008 #1009
Studies Amir et al. Locatelli et al. Karlsson et al.
N = 271 N = 255 N = 477
prospective retrospective (liver) retrospective
ER+ primary with loss in 21/174 (12%) 22/197 (11%) 123/336 (36%)
recurrence
ER- primary with gain in 8/57 (14%) 15/58 (25%) 32/141 (22%)
recurrence
Overall ER discordance rate 12% 14.5% 32%
Overall PR discordance rate 34% 48% 43%
HER2- primary with gain in 9/197 (4.6%) 7/118 (5.9%) n.d.
recurrence
HER2+ primary with loss in 3/24 (12.5%) 17/54 (31.5%) n.d.
recurrence
Change in management from 15% 12% n.d.
results of recurrence biopsy

Richardson AL. Presented at: 2010 ASCO Annual Meeting; 4-8 June 2010: Chicago, Illinois, United States.

% « FALSE » RESULTS: IHC & FISH

• European central vs local lab in the ALTTO trial:
• ER 21 %
• PgR 22 %
• HER2 19 % IHC & 12 % FISH

• US central vs local lab in the ALTTO trial:
• ER 8 %
• PgR 13 %
• HER2 26 % IHC & 25 % FISH

Courtesy G. Viale

META-ANALYSIS OF DISCORDANCE BETWEEN
PRIMARY VS. METS: HER-2 STATUS

Houssami et al, Breast Cancer Res Treat, 2011, DOI 10.1007/s10549-011-1632-x

META-ANALYSIS OF DISCORDANCE BETWEEN PRIMARY
Houssami et al, Breast Cancer Res Treat, 2011 VS. METS: HER-2 STATUS

• The pooled proportion of HER2 discordance was modest (5.5%;
3.6–8.5%)
• Significant association between HER2 discordance and the type of
metastasis (distant metastases showed higher proportions of HER2
discordance (9.6%; 4.9–17.7%) than LN mets only (4.2%; 2.5–7.1%))
• Weak evidence (P = 0.074) discordance “primary HER2-neg” to
“paired mets HER-2+” more likely than the reverse

• Limitations: meta-analysis of published studies (heterogeneity), no
breakdown by exact site of distant metastasis (bone mets issue!)
• Strenghts: Looked very carefully at all covariates, all studies
(re)tested primary & mets at same time. If only due to technical
issues no consistent pattern should be seen!

AGAINST REBIOPSY IN FAVOR OF REBIOPSY

• No level 1 evidence • It is reasonable if it may
– No prospective study with influence treatment decision
survival gain – Old cases/from other
– Some prospective studies institution(s)
ongoing (but not with • It is a balance benefits/risks
survival as primary – Difficulty: Lymph nodes vs.
endpoint) bone or liver
• There is a risk for – Accuracy: Soft tissue vs.
misinterpretations bone
• In many countries, it is not
covered

SHOULD WE BIOPSY METASTASES & REPEAT ER/PR/HER2?

REASSESS BIOLOGY AT TIME OF RECURRENCE … but…

• Does the tumor biology change overtime?
• How is it influenced by the different therapies given?
• Neoadjuvant trials have shown important differences
in pre and post treatment biomarker status
• Emergency of resistance is a proof that biology
changes

ONGOING EVALUATION OF DISEASE STATUS & BIOLOGY

IMPORTANCE OF EARLY ADMINISTRATION

M77001 trial: estimated survival Trastuzumab + docetaxel (n=92)
Docetaxel alone/crossover (n=41)
1.0 Docetaxel alone (n=53)

0.8
Estimated probability

0.6

0.4

0.2

15.3 21.9 27.7
0
0 3 6 9 12 15 18 21 24 27 30
Months

Marty M et al. JCO 2005;23:4265–74

TAnDEM Study: Randomized, Open-Label Trial of Anastrozole
± Trastuzumab in Advanced HER2+, HR+ Breast Cancer

Anastrozole
Anastrozole +
N = 207 Trastuzumab
Median age 55 years
Visceral disease 1/3
Prior chemo 1/2 Cross-over
70%
6.8% Response rate 20.3% P = .018
2.4 m Median PFS 4.8 m HR = 0.63; P = .0016
23.9 m Median OS 28.5 m P = .325
28.6 m Median OS 34.1 m
for patients with centrally P = .451
confirmed HR status

Trastuzumab added to anastrozole  RR, PFS, TTP and CBR
Mackey JR, et al. Breast Cancer Res Treat. 2006;100(Suppl 1): Abstract 3.
Kaufman B, et al. J Clin Oncol. 2009 Sept 28. [Epub ahead of print].

HERNATA Study Design and Treatment

Docetaxel 100 mg/m2 day 1
+
Trastuzumab (8) 6 mg/kg day 1
R
HER2+ Q 3 weeks*
A
M1 - LABC N
Naϊve to CT D
except adjuvant O
M Vinorelbine 30-35** mg/m2 days 1+8
I +
Trastuzumab (8) 6 mg/kg day 1
Z
E Q 3 weeks*
*Treatment duration to PD or unacceptable toxicity
**Vinorelbine dose per institutional preference

Andersson M, et al. J Clin Oncol. 2011;29(3):264-271.

Trastuzumab Beyond
Trastuzumab: GBG-26 Study
MBC HER2-positive
Progression under trastuzumab-based first-line therapy (TFI < 6 weeks)
with taxane (n = 114)
or monotherapy or nontaxane (n = 42)

R

Capecitabine 2500 mg/m2
bid d1-14 q21 days
+ Capecitabine 2500 mg/m2
continuation of bid d1-14 q21 days
trastuzumab 6 mg/kg q3 weeks (n = 78)
(n = 78)
R, randomization;
TFI, treatment-free interval;
MBD, metastatic breast cancer
Von Minckwitz G, et al. J Clin Oncol. 2009;27(12):1999-2006.

Continuation of Trastuzumab Prolongs
Time to Progression by Nearly 3 Months
Trastuzumab + Capecitabine (n = 78)
1.0
+ Capecitabine (n = 78)
+
++ HR = 0.69 (two-sided P = .0338;
0.8 +
one-sided P = .0169)
+
+
+
+
0.6
PFS Probability

+ +
0.4 +
+
+ ++
+ ++
+
0.2
5.6* 8.2* + + +
0.0
0 10 20 30 40
Time from 1st progression, months
74 40 15 8 5 3 2 1 1
77 55 29 12 4 3 1 1 1
*Median TTP in months
Von Minckwitz G, et al. J Clin Oncol. 2009;27(12):1999-2006. TTP, time to progression; HR hazard ratio

Lapatinib Beyond Trastuzumab:
EGF 100151 Study
• Progressive, HER2+ MBC R Lapatinib 1250 mg PO qd
or LABC A continuously +
• Previously treated with N capecitabine 2000 mg/m2/d
anthracycline, taxane, and po days 1-14 q 3 weeks
D
trastuzumab* O
• No prior capecitabine M
I
Z Capecitabine 2500 mg/m2/d PO days
E 1-14 q 3 weeks
Stratification:
• Disease sites Patients on treatment until
• Stage of disease progression or unacceptable toxicity,
then followed for survival

*Trastuzumab must have been administered for metastatic disease!!
LABC, locally advanced breast cancer; MBC, metastatic breast cancer

Cameron D, et al. Breast Cancer Res Treat. 2008;112(3):533-543.
Geyer C, et al. N Engl J Med. 2006;355(26):2733-2743.

Kaplan-Meier Estimates of Time to Progression in
ITT Population by Independent Review Committee

HR 0.57 (95% CI, 0.43–0.77; P = .00013)
Median TTP 6.2 months (lapatinib plus capecitabine)
4.3 months (capecitabine monotherapy)

Cameron D, et al. Breast Cancer Res Treat. 2008;112(3):533-543.

CEREBEL Study: A Phase III Randomized Open-Label Study
of Lapatinib plus Capecitabine vs Trastuzumab +
Capecitabine in HER2-Positive Metastatic Breast Cancer
Inclusion Criteria:
• Stage IV HER2+ breast cancer
• Prior anthracycline and a R Capecitabine 2500 mg/m2 bid d1-14 q21
taxane days
• Prior treatment with CT, A +
trastuzumab, HT, RT is Trastuzumab loading dose 8 mg/kg→
permitted N
6 mg/kg q3 weeks
• LVEF ≥50%, normal organ D
function
O
M
Main Exclusion Criteria: I Lapatinib 1250 mg PO qd continuously
• History and/or current +
evidence of CNS metastases Z
capecitabine 2000 mg/m2/d
• Prior therapy with lapatinib or E PO days 1-14 q3 weeks
ErbB2 inhibitor other than
trastuzumab
• Primary endpoint: Incidence of CNS metastases at site
of first relapse
• Secondary endpoints: Incidence of CNS progression at
any time, time to first CNS progression, PFS, OS, ORR,
CBR, duration of response, toxicity, pharmacogenetics,
and biomarker analysis

EGF104900: Phase III Study Evaluated
Dual HER2 Blockade
Lapatinib 1500 mg/d PO
• HER2 (FISH+/IHC3+) (n = 148)
metastatic breast Primary endpoint:
R
cancer • Progression-free
• Progression on
A survival
– Anthracycline N
D Secondary endpoints:
– Taxane Crossover allowed to lapatinib +
• Overall survival
– Trastuzumab O trastuzumab if progression after at
M • Overall response
• Progression on least 4 weeks on therapy
rate
most recent I
Z • Clinical benefit rate
trastuzumab
regimen E

Lapatinib 1000 mg/d PO +
trastuzumab 4→2 mg/kg IV weekly
(n = 148)

• Staging occurred at 4, 8, 12, 16 weeks, and then every 8 weeks
• Steady state of single-agent lapatinib occurs at approximately 7 days

Blackwell KL, J Clin Oncol 2010;28(7):1124-1130.
Blackwell KL, et al. Cancer Res. 2009;69(24 Suppl): Abstract 61.

EGF104900: Significant Overall Survival (OS) Benefit
With Trastuzumab + Lapatinib Following Disease
100 Progression
L L+T
N = 148 N = 148
80%
80 Died, N (%) 113 (78) 105 (72)

Median, months 9.5 14.0
Survival, %

60 70% 56%
Hazard ratio (95% CI) .74 (.57-.97)
Log-rank P-value .026
6 Month OS
40
41%

20 12 Month OS

0
0 5 10 15 20 25 30 35
Time from Randomization, months
Patients at risk:
L 148 121 88 64 43 25 1
L+T 148 102 65 47 28 13

Blackwell KL, et al. Cancer Res. 2009;69(Suppl 2): Abstract 61.

Incidence of CNS Metastases in
Trastuzumab-Treated Patients
Case Series Patient Population # Overall %

Bendell et al, 2003 Trastuzumab-treated 42 123 34
Clayton et al, 2004 Trastuzumab-treated 23 93 25
Lai et al, 2004 Trastuzumab-treated 38 79 48.1
Lower et al, 2003 Trastuzumab-treated 22 87 26
Non-trastuzumab-treated 58 190 31
Pinder et al, 2007 Trastuzumab-treated first-line 95 231 41
Non-trastuzumab-treated 12 61 20
Shmueli et al, 2004 Trastuzumab-treated 10 41 21

Stemmler et al, 2006 Trastuzumab-treated 42 136 30.9
Yardley et al, 2007 HER2-positive MBC 236 768 30.7
Yau et al, 2006 Trastuzumab-treated 23 87 26.4

Leyland-Jones B. J Clin Oncol . 2009;27(31):5278-5286.

Trastuzumab Improves Survival in Patients With
mCNS Disease: U S Retrospective Analysis
Survival (%)
100 HER2 positive, trastuzumab (n = 36)
HER2 positive, no trastuzumab (n = 11)
80 HER2 negative (n = 48)

60
P<.0001

40

20
Time from
diagnosis of
0 mCNS disease
0 10 20 30 40 (months)

Kirsch DG, et al. J Clin Oncol. 2005;23(9):2114-2116.

LANDSCAPE STUDY: a FNCLCC phase II study with lapatinib and
capecitabine in pts with brain metastases from HER-2+ MBC before
whole brain RT

Primary endpoint: CNS volumetric response
CNS-OR: 29/43 = 67.4% (95% CI: 52-81)

CNS volumetric change N = 43 (%)
≥ 80% reduction 9 (20.9)

50-<80% reduction 20 (46.5)
20- <50% reduction 6 (14)
> 0- <20% reduction 2 (4.7)
Progression* 6 (14)
* 2 patients had extra-CNS disease progression

NSS improvement: 14/24 = 58.3% (95% CI: 36.6-77.9)

Bachelot et al, ASCO 2011

IMPORTANT LESSONS FROM HER-2 + BC

• Crucial role of patient selection
• ABC: primary or metastatic HER-2 status?
•Importance of starting anti-HER-2 agent early on
•Continue HER-2 blockade beyond progression (change of
paradigm in ABC)

• The principle of dual blockade
• Problem of brain metastases
• Even with target/targeted drug resistance occurs

COULD BLOCKAGE OF GRF PATHWAY(S) DELAY
and/or PREVENT THE ONSET OF HORMONE
RESISTANCE?

HORMONE-SENSITIVE HORMONE-RESISTANT
BREAST CANCER BREAST CANCER

• SWITCH TOWARDS GRF SIGNALLING PATHWAYS
• GAIN OF SENSITIVITY TO ANTI-GROWTH FACTOR PATHWAY DRUGS

Adapted from R Nicholson, Tenovus Institute, Cardiff, UK

EGF30008: Phase III, Randomized, Double-Blind
Controlled Trial: Study Design

Patient Population:
• ER+ and/or PgR+
• Postmenopausal
R
• HER2+, HER–/Unknown Letrozole 2.5 mg daily +
• Stage IIIb/IIIc/IV A
placebo
• No prior treatment for N
metastatic breast cancer D
(MBC) O
M
Stratification: Letrozole 2.5 mg daily +
• Disease sites I
lapatinib 1500 mg daily
• Bone only/visceral or Z
soft tissue E
• Interval since adjuvant
tamoxifen therapy N = 1286 (including n = 219 HER2+)
• <6 mo / ≥6 mo or none

Johnston S, et al. J Clin Oncol. 2009;27(33):5538-5546.

Progression-Free Survival:
HER2-Positive Population
S Johnston, SABCS 2008, Abst # 46 FOR HER2-positive patients
5 months benefit in PFS
No difference in OS

Overall Survival:
HER2-Positive Population
S Johnston, SABCS 2008, Abst # 46

Johnston S, et al. Cancer Res. 2009;69(Suppl 2): Abstr 46

Progression-Free Survival: ITT and
HER2-Negative Populations
HER2-Negative*

For HER2-negative patients
NO BENEFIT

BUT

Johnston S, et al. Cancer Res. 2009;69(Suppl 2): Abstract 46.

PFS: HER2-Negative Patients (N = 952)
≥6 Months Since D/C <6 Months Since D/C
of Tam (33%) or No Tam (67%) of Tam
• Median Tam duration 5 years • Median Tam duration 2.8 years
• Median time since D/C 3.5 years • Median time since D/C 1 month

Benefit in Tam-
resistant

Johnston S, et al. Cancer Res. 2009;69(Suppl 2): Abstract 46.

Numerous Treatments for HER2-Positive
Breast Cancer in Development
HER2 dimerization Pertuzumab
inhibitor Monoclonal antibody that inhibits dimerization of HER2

T-DM1
HER2 ADC Trastuzumab-based ADC-delivering cytotoxic drug (DM1) specifically to HER2 + tumor cells

PI3K inhibitors eg, GDC0941, BKM120
Small molecule selectively binding PI3K isoforms to inhibit the PI3K / Akt signaling pathway

Afatinib
Tyrosine Reversible inhibitor of EGFR and HER2 tyrosine kinase
kinase
inhibitors Neratinib
Irreversible inhibitor of EGFR, HER2 and HER4 tyrosine kinase

mTOR eg, Everolimus
inhibitors Small molecule inhibiting mTOR signal transduction

HSP 90 inhibitors eg, Tanespimycin
Antineoplastic antibiotic inhibiting HSP 90

VEGF receptor eg, Bevacizumab
inhibitors Monoclonal antibody inhibiting VEGF

ADC: antibody-drug conjugate.T-DM1: trastuzumab DM1. PI3K: phosphoinositide 3-kinase.
EGFR: epidermal growth factor receptor. mTOR: mammalian target of rapamycin. HSP: heat-shock protein.
VEGF: vascular endothelial growth factor.

Prognosis in MBC by HER2 Status
and by Therapy with Trastuzumab
n = 2,091 Patients 1 y survival
HR
(median f/u = 16.9 mo) (%) (95% CI)

118 70.2%
HER2-pos --
(5.6%) (60.3%, 78.1%)

1,782 75.1%
HER2-neg 0.56
(85.3%) (72.9%, 77.2%)
(0.45-0.69,
HER2-pos treated 191 86.6% p = 0.0001)
with trastuzumab (9.1%) (80.8%, 90.8%)

Dawood et al, ASCO abstract 1018, 2008
Courtesy A Wolf

Significant Rate of Discordancy
Between Primary and Metastases

Amir Curigliano
2010 Studies Karlsson Lindstrom
(n~270) (n~250)
Comparing Primary (n~470) (n~118-459)
Prospective Retrospective
to Metastasis Retrospective3 Retrospective4
Reanalyzed1 Liver Only2

ER+  ER- 12% 11% 36% 26%

ER-  ER+ 14% 25% 22% 7%

HER2-  HER2+ 5% 6% nd 7%

HER2+  HER2- 12% 32% nd 3%

1. Amir E, et al. J Clin Oncol. 2010;28(15S): Abstract 1007. 2. Curigliano G, et al. Ann Oncol. 2011 Feb 22 [Epub ahead
of print]. 3. Karlsson E, et al. J Clin Oncol. 2010;28(15S): Abstract 1009. 4. Lindstrom LS, et al. Cancer Res. 2010;70(24
Suppl): Abstract S3-5.

MANAGEMENT OF HER-2 + BC
• WHAT HAVE WE LEARNED
• HER-2 + BC is a separated well identified disease
• Quality of HER-2 testing is essential: Selection of pts is crucial
• Trastuzumab and Lapatinib are efficacious in MBC
• Overall good safety profile of anti-HER2 therapies but cardiac
surveillance & management guidelines (cardiac, GI, liver, skin)
needed
• Trastuzumab can be combined in many different cytotoxic agents
• Brain mets are an important clinical problem
• Resistance does occur (mechanisms, ways to overcome it)
• Many new drugs in the (near) future (how to choose between
them)

ABC1 - F. Cardoso - HER-2+ advanced breast cancer - State-of-the-art management of HER-2+ disease

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