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)