highlights in the management of breast cancer rome, may 25-26, 2007 clinical case dott.ssa marinella...
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Highlights in the Management of Breast Cancer
Rome, May 25-26, 2007
CLINICAL CASE
Dott.ssa Marinella ZilliCattedra di Oncologia Medica
Università “G. D’Annunzio” Chieti-PescaraDirettore: Prof. Stefano Iacobelli
37-year-old premenopausal woman
Jan 2006: Right breast lumpectomy + axillary lymph node dissection
Invasive Ductal Carcinoma, G3pT2 (2.5 cm) pN2 (4/17) M0ER 0% PR 0% HER2 +++
Feb 2006: Adjuvant treatment was started: ECx4 Docetaxel-Trastuzumab x 4
Jul 2006: Pt stops cht and continues adjuvant trastuzumab. She receives also XRT in the right breast
Dec 2006 Intensive abdominal pain with AST, ALT, GT and increase of CA 15.3
ABDOMEN CT: MULTIPLE LIVER METASTASES
Brain CT: Neg.Torax CT: Neg.Bone scan: Neg.
This is an aggressive disease (Symptomatic, rapid evolution, time to recurrence < 1 year, unfavourable biology, important tumor burden)
THERAPEUTIC AIM
Rapid tumor shrinkage
- to improve clinical symptoms
- to prolong survival
Survival curves: overall and according to response
Discussion points:
1. Continue Trastuzumab (T)?
2. Trastuzumab + Bevacizumab (B) + cht: a possible option?
3. Which chemotherapy?
- Paclitaxel- Paclitaxel + Carboplatin- Paclitaxel + Gemcitabine- Vinorelbine- Vinorelbine + Gemcitabine- Vinorelbine + Carboplatin- Carboplatin + Gemcitabine- Capecitabine
1. Continue Trastuzumab (T)?
Preclinical data support continuation of trastuzumab beyond disease progression
Fujimoto-Ouchi K et al, Proc Am Assoc Cancer Res 2005
Addition of trastuzumab to paclitaxel in the human breast cancer xenograft model KPL-4 progressing on trastuzumab monotherapy was shown to potentiate the antitumor activity of paclitaxel
In patients with HER2+ advanced breast cancer progressing on trastuzumab-containing therapy, continuing trastuzumab alone or combined with other chemotherapy is feasible and safe, with encouraging tumor response and survival data.
Tripathy D et al, J Clin Oncol 2004Mackey J et al, Proc Am Soc Clin Oncol 2002Fountzilas G et al, Clin Breast Cancer 2003Bartsch R et al, BMC Cancer 2006Garcìa-Sàenz JA et al, Clin Breast Cancer 2005Stemmler HJ et al, Onkologie 2005
Retrospective analyses
Trastuzumabtreatment
Objective response (%)
TTP (95% CI), mos
First (n=54) 42.6 6 (5.40-6.60)
Second (n=54) 25.9 6 (5.36-6.64)
Beyond second(n=33)
30 6 (5.32-6.68)
Bartsch R et al, BMC Cancer 2006
Objective response rates and TTP were maintained in pts receveing two or more trastuzumab-based regimens
The decline in ORR from 42.6% (in first line) to 30% (in beyond second line) compares to the expected drop of ORR with every further line of cht or ET in palliative treatment.No case of symptomatic CHF was observed
…continuing treatment with multiple lines of
trastuzumab offered
significant survival benefit
Extra JM et al, SABCS 2006
Favourable effect of Trastuzumab treatment in metastatic breast cancer patients: results from
the French Hermine cohort study
In these retrospective studies, it is not possible to discern whether the observed benefits are derived from cht alone or whether the continuation of trastuzumab have significantly contribued to the therapeutic results.Phase III randomized trials are now ongoing to investigate this issue (three studies)
HOWEVER…
GBG 26: Therapy Beyond Progression (TBP) study
Pts with MBC HER2+ and progression during trastuzumab therapy
RCapecitabine (2500 mg/mq, d1-14 q21)
Capecitabine (2500 mg/mq, d1-14 q21)
+Trastzumab (6 mg/kg d1 q21)
Randomized phase III trial
If tumor cells are able to switch from the HER2 to EGFR or other signal transduction pathways (VEGF, IGF1R), a continued treatment would not necessarily lead to a benefit. On the other hand, if no complete resistance develops, a discontinuation of trastuzumab might be cause a massive overshoot in tumor growthRitter CA et al, Int J Pharmacol Ther
2004
2. Trastuzumab + Bevacizumab (B) +
chemotherapy:
a possible option?
HER2-negative HER2-positive
HER2 overexpressing breast cancer cells exibited increased angiogenesis in vivo compared to control cells
HER2 overexpressing human breast cancer xenografts exhibit increased angiogenic potential mediated by VEGF
Epstein et al, Breast Cancer Res Treat 2002, abs 570
Konecny, et al. Clin Cancer Res 2004
HER2/VEGF –/–
HER2/VEGF +/–
HER2/VEGF –/+
HER2/VEGF +/+
Overexpression of both HER2 and VEGF decreases survival in breast
cancer
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0
Cu
mu
lati
ve s
urv
ival
0 20 40 60 80 100 120Months
Log-rank p=0.0133
The positive association between HER2 and VEGF expression, and their combined effect on clinical outcome support the strategy of targeting both VEGF and HER2 in breast cancer pts with HER2+ tumors…
0
100
200
300
400
500
600
700
800
0 7 14 22 29 35
Treatment Day
*
*p<0.05 compared to vehicle control and Trastuzumab-treated groups
Vehicle control
Trastuzumab
Bevacizumab
Trastuzumab + Bevacizumab
TumorVolume (mm3 )
In preclinical xenograft models, superior efficacy is observed when T is
given in combination with B
T and B inhibit growth of MCF7/HER2 xenograft in vivo
Pegram, Breast Cancer Res Treat 2004, abs 3039
COHORT 1 (N=3) Trastuzumab qw +
bevacizumab 3 mg/kg day 7 then q2w
COHORT 2 (N=3) Trastuzumab qw +
bevacizumab 5 mg/kg day 7 then q2w
COHORT 3 (N=3) Trastuzumab qw +
bevacizumab 10 mg/kg day 7 then q2w
Phase I dose escalation of Trastuzumab + Bevacizumab in metastatic Breast Cancer
No PK interaction between T and B
Clinical Response: 2 CR, 3 PR, 2 SD >6 mos; well tolerated; no DLT
Phase II (N=50) has begun, with bevacizumab 10 mg/kg, in first-line MBC
Pegram, Breast Cancer Res Treat 2004, abs 3039
HER2-positive(by FISH)
recurrent or mBCn= 9
Phase II combined biological therapy targeting HER2 and VEGF using Trastuzumab [T] and Bevacizumab [B] as first line treatment of HER2-amplified breast cancer
Pegram et al, SABCS 2006, abs 301
STUDY OBJECTIVES Clinical efficacy of T + B Safety profile of T + B
HER2+ untreated MBC. No prior T or B treatment. 42/50 pts currently enrolled
CARDIAC ADVERSE EVENTS(NCI-CTC V.2)
G1 G2 G3 G4
7 pts 5 pts 0 pts 1 pt
INTERIM EFFICACY DATA
N of pts
Percent
Response (37 evaluable pts)
CR PR SD PD
2.7 51.4 29.7 16.2
OVERALL RESPONSE RATE: 54.1%
B in combination with T is clinically feasible and active in HER2 amplified MBC, supporting the use of combination therapies against HER2 and VEGF for treatment of BC with HER2 alteration
1 19 11 6
Pegram et al, SABCS 2006, abs 301
3. Which chemotherapy?
- Paclitaxel- Paclitaxel + Carboplatin- Paclitaxel + Gemcitabine- Vinorelbine- Vinorelbine + Gemcitabine- Vinorelbine + Carboplatin- Carboplatin +
Gemcitabine- Capecitabine
Which chemotherapy in anthracycline- and taxane-resistant patients?
No standard of care exists after failure of both anthracycline and taxane treatment. The most common treatments are chosen in view of their manageable toxicity profiles and reasonable efficacy, because no randomized study has so far demonstrated a benefit in OS after second-line cht
Valero V, JCO 1998
Blum JL, JCO 1999
Livingston RB, JCO 1997
Valerio MR, ASCO 2001
Gralow JR, Breast Cancer Res Treat 2005
MBCCapecitabine
Vinorelbine
Gemcitabine
We decided to treat our patient according to a non-standard but promising regimen combining chemotherapy with targeted
therapy:
Jan 2007: CTCT scan PR (after 4 cyclescycles)
May 2007: CT scan SD (after other 4 cycles)
Discontinued chemoterapy and continued T + B
Dec 2006: Vinorelbine (25 mg/mq)Gemcitabine (1000 mg/mq) (d1, 8 q21)
+Trastuzumab (6 mg/kg) (d1 q21)
+Bevacizumab (15 mg/kg) (d1 q21)
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