for those running out of options--new research hope

[Lani]

Bortezomib (Velcade--already approved for the treatment of multiple myeloma) seems to reverse Herceptin resistance by Increasing PTEN
and enhances growth inhibition of herceptin resistant her2neu breast cancer cells (cell lines in vitro)

This is obviously early work--but is "fresh off the press" and may provide hope for those whose PTEN is low and whose tumors recurred on Herceptin

As it is already FDA approved, perhaps a trial may be instituted using it "off-label"

1: Anticancer Drugs. 2006 Apr;17(4):455-62. Related Articles, Links

Proteasome inhibitor bortezomib increases PTEN expression and enhances trastuzumab-induced growth inhibition in trastuzumab-resistant cells.

Fujita T, Doihara H, Washio K, Kawasaki K, Takabatake D, Takahashi H, Tsukuda K, Ogasawara Y, Shimizu N.

aDepartment of Cancer and Thoracic Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan.

PTEN (phosphatase and tension homolog deleted on chromosome 10) has been shown to be inactivated in a wide range of cancers and the role of this gene product is associated with the suppression of the phosphatidylinositol-3-kinase (PI3K)/Akt pathway in many cancers. Recently, some reports demonstrated that the degree of PTEN expression could predict trastuzumab chemosensitivity in ErbB2-overexpressing breast cancer. Here, we demonstrate the possible involvement of a proteasome inhibitor (PS341) in PTEN expression and elucidate the influence of PI3K/Akt, one of the main cascades of the ErbB2 downstream pathway, and discuss the role of the proteasome inhibitors in trastuzumab resistance. ErbB2-overexpressing SKBR3 human breast cancer cells and trastuzumab-resistant SKBR3/R cells were analyzed in this study. We show that the expression of phosphorylated Akt was highly increased in trastuzumab-resistant cells, although the expression of PI3K, phosphorylated PI3K and non-phosphorylated Akt was unchanged in comparison with wild-type SKBR3 cells. However, following treatment with PS341, the level of phosphorylated Akt was decreased in a dose-dependent manner. Conversely, the level of PTEN was increased in the same fashion. PS341 showed sufficient cytotoxicity in resistant cells in combination with trastuzumab and the efficacy of trastuzumab was inclined to be better in resistant cells under PS341 treatment. Remarkable activity of Akt was observed in trastuzumab-resistant SKBR3 breast cancer cells and this phenomenon could be associated with the decreased expression of PTEN. The proteasome inhibitor PS341 could increase the level of PTEN and inhibit the downstream pathway of ErbB2, interfering with phosphorylation of Akt.

PMID: 16550004 [PubMed - in process]

[sherri]

Lani,

Thanks a lot. You are great, doing so much research for us. I'm going for all the tests and I think the beast is progressing again even with Herceptin. I'll take this to my oncologist and ask him to give it to me if my results don't come clean.
Love and hug,

[Lani]

Abstract 429:
A Phase I, open label, dose-escalating study of the proteasome inhibitor PS-341 (VELCADE®) in combination with two schedules of trastuzumab, in patients with advanced breast cancer (ABC) that overexpresses HER2



Citation: European Journal of Cancer Supplements Volume 4, No. 2, March 2006, page 173

F. Cardoso1, E. Azambuja1, C. Bernard1, L. Dirix2, D. De Becker1, S. Bartholomeus1, V. D'Hondt1, H. van de Velde3, M. Piccart1, A. Awada1

1Jules Bordet Institute, Medical Oncology Clinic, Brussels, Belgium
2General Hospital Sint-Augustinus, Wilrijk, Belgium
3Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium

Background: The ubiquitin proteasome pathway plays an important role in cell cycle regulation, cancer growth and metastatic spread and is a promising novel target for anti-cancer therapy. HER-2 receptor is degraded by the proteasome, which can thus regulate HER-2 levels. Bortezomib (PS-341, VELCADE®) is a highly specific inhibitor of the proteasome and represents the first agent of this class approved for clinical use. We report the preliminary results of a phase I trial initiated to determine the maximum tolerated dose (MTD) and tolerability of bortezomib in combination with trastuzumab as first-line treatment of HER-2-positive ABC.
Methods: Patients (pts) were treated with bortezomib (1.0–1.3 mg/m2; days 1, 4, 8 & 11) and trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly (Group A – Hw) or 8 mg/kg loading dose followed by 6 mg/kg every 3 weeks (Group B – H q3ws)). DLT was defined as febrile neutropenia, grade 4 neutropenia without fever that does not resolve within seven days, grade 4 thrombocytopenia and any ? grade 3 non-hematological toxicity, with the exception of inadequately treated nausea, vomiting and diarrhea.
Results: To date, 11 pts were included and 9 are evaluable. The median age is 51 years (range 35–80 years), median number of metastatic sites 1 (range 1–4; visceral metastases 55.5%), prior anthracycline therapy 55.5% and prior taxane therapy 11.1%.
Treatment: bortezomib 1.0 mg/m2 + Hw (n = 4), bortezomib 1.3 mg/m2 + Hw (n = 3), and bortezomib 1.0 mg/m2 + H q3ws (n = 2). Median number of cycles is 4 (range 2–8 cycles). A DLT (grade 3 muscular pain) was seen in 1 pt treated with Hw and bortezomib 1.3 mg/m2. This cohort is currently extended with 3 extra pts. Grade 2 nausea, vomiting, diarrhea, thrombocytopenia, and liver function alteration were seen in 2 pts. A papular cutaneous rash was seen in 3 pts, which required therapy with steroids and anti-histaminics. The most common side effect was grade 1–2 asthenia (66.6%). No cardiotoxicity was seen. At this time, 1 partial response (PR) and 8 progressive diseases (PD) were seen. Of the 8 pts with PD, 5 received a combination of CT + trastuzumab as 2nd line therapy (3 obtained stable disease-SD, 1 PD, 1 too early to evaluate); 1 received CT alone (with PD), and 1 trastuzumab alone (too early).
Conclusions: So far, data suggest good tolerability of the combination bortezomib + trastuzumab with no cardiotoxicity. Cutaneous rash and asthenia have been the most common side effects. Enrollment is ongoing and an updated data will be presented at the meeting.
Study grant provided by Johnson&Johnson/Millennium Pharmaceuticals.

[Lani]

Weight and body mass index (BMI) affect HER2 expression in postmenopausal breast cancer



Citation: European Journal of Cancer Supplements Volume 4, No. 2, March 2006, page 68

T. Van Mieghem1, K. Leunen1, N. Pochet2, B. De Moor2, F. Amant13, I. Vanden Bempt4, R. Drijkoningen4, M.R. Christiaens35, I. Vergote1, P. Neven13

1University Hospitals Leuven, Dept. of Obstetrics and Gynaecology, Leuven, Belgium
2KULeuven, ESAT, Leuven, Belgium
3University Hospitals Leuven, Multidisciplinary Breast Center, Leuven, Belgium
4University Hospitals Leuven, Dept. of Pathology, Leuven, Belgium
5University Hospitals Leuven, Dept. of Surgery, Leuven, Belgium

Background: In our population, HER-2 is expressed in 10.9% of primary breast cancers (J Clin Path 2005;58:611–6). Postmenopausal obesity is a risk factor for hormone sensitive tumours. These tumours are more likely HER-2 negative (Breast Cancer Res Treat 2005;91:81–7). We therefore hypothesised that postmenopausal obesity is associated with fewer HER-2 positive tumours.
Patients and Methods: Between January 1st 2002 and December 31st 2004, 549 postmenopausal women with a unilateral, not previously treated, operable breast cancer were evaluated the evening prior to operation for body weight, height, abdominal and hip circumference. Waist-to-hip ratio (WHR) and BMI [Weight/(Length in meters)2] were calculated. HER-2 staining was done by immunohistochemistry (MoAbCB11) and scored between 0 and 3+. HER-2 negativity was defined as 0, 1+ or 2+; HER-2 positivity as 3+. We compared HER-2 negative patients with HER-2 positive patients for all parameters of body composition and assessed the frequency of HER-2 positivity in each quartile from the lowest (Q1) to the highest (Q4) for these same parameters.
Results: Length and WHR were not significantly different between patients with HER-2 negative and HER-2 positive tumours. Abdominal and hip circumference were lower in HER-2 positive patients. This trend however, was not statistically significant. In Table 1 mean values for weight and BMI are compared between HER-2 negative and HER-2 positive patients. Table 2 shows the proportion of HER-2 positive tumours per quartile for weight and BMI in all patients.
Table 1. Comparison of mean values for weight and BMI between HER-2 negative and HER-2 positive patients

HER-2 negative HER-2 positive P-value
N Mean±SD N Mean±SD
Weight (kg) 474 69.19±13.18 58 65.09±11.29 0.0215
BMI (kg/m2) 472 26.98±9.21 56 24.93±4.27 0.0085
SD: standard deviation.


Table 2. Proportion of HER-2 positive tumours per quartile for weight and BMI in all patients (N = 549)

HER-2 positivity (%) P-value
Q1 Q2 Q3 Q4 (Q1–Q4)
Weight 16.30 10.32 9.93 6.92 0.0214
BMI 14.50 12.21 10.69 5.19 0.0127


Conclusion: Low weight and low BMI are risk factors for HER-2 positivity in postmenopausal women with breast cancer. The linear decrease in HER-2 positivity per increasing quartile for both parameters suggests our hypothesis may be correct. Larger numbers of HER-2 positive cases may be required to confirm our findings for other parameters of body composition.

[Unregistered]

Interesting.

It would be interesting to have lifestyle diet indicators too.

What was their omega three six ratio like. Lots of exercise, low fats diets and high quality polyunsaturate high omega six seed oils, margerine etc ? (eg poor omega three six ratio).

RB