In this letter below the authors explain that synergy between Herceptin & chemo drugs is only working if the tumours are HER2 positive.
Note 1:
Aside for the reasons already found by researchers for the occasional loss of efficacy or appearence of resistance to Herceptin one may speculate that if the cancer cells become less HER2 positive (as in the case of a reversal to ER+) the loss of effectiveness may be agravated by the loss of synergy.
Note 2:
This does not necessarily mean that no residual efficacy will remain.
As stated by a Glaxo researcher:
"By no means are we limiting our development program to only HER2-positive patients," GSK's Stein says. Though the most advanced trials for Tykerb are focused on HER2-positive patients, Stein says there is evidence that the drug could find use in the wider population of breast cancer patients. "Although the response rate was higher in the HER2-positive population, there were responders in the HER2-negative population as well," he notes.
Extracted from article at:
http://pubs.acs.org/cen/coverstory/84/8432cancer.html
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http://theoncologist.alphamedpress.o.../full/11/7/853.
Letter to the Editor
Adjuvant Trastuzumab with Docetaxel or Vinorelbine for HER-2-Positive Breast Cancer
Gianluigi Ferretti, Paola Papaldo, Alessandra Fabi, Paolo Carlini, Alessandra Felici, Francesco Cognetti
Division of Medical Oncology A, Regina Elena Cancer Institute, Rome, Italy
Correspondence: Gianluigi Ferretti M.D., Ph.D., Division of Medical Oncology A, Regina Elena Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy. Telephone: 00390652665354; Fax: 00390652665637; e-mail:
gia.fer@flashnet.it
Received April 13, 2006; accepted for publication May 26, 2006.
Colozza et al. [
1] recently presented an overview of four adjuvant trials with trastuzumab in patients with HER-2-overexpressing and/or amplified breast cancers (the North Central Cancer Treatment Group Trial N9831, the National Surgical Adjuvant Breast and Bowel Project Trial B31, the Breast Cancer International Research Group Trial 006, and the HERceptin® Adjuvant study). A very recent study showed that a short course of trastuzumab administered concomitantly with docetaxel or vinorelbine is effective in women with breast cancer who have an amplified
HER-2/ neu gene [
2].
In vitro studies indicated that the combination of trastuzumab and vinorelbine exerts synergistic activity [
3]. In fact, the results of recent clinical studies of this combination inuntreated or heavily pretreated patients with HER-2-positive metastatic breast cancer [
4,
5] have shown high objective response rates. In vitro, the combination of trastuzumab with docetaxel exerts synergistic activity, as well [
2]. This combination in untreated patients with HER-2-positive metastatic breast tumors showed remarkable efficacy [
6].
Concerning the adjuvant setting, Joensuu et al. [
2] randomly assigned 1,010 women with axillary node-positive or high-risk node-negative cancer to receive three cycles of docetaxel or vinorelbine, followed by three cycles of fluorouracil, epirubicin, and cyclophosphamide. The 232 women whose tumors had an amplified
HER-2/ neu gene were assigned to receive or not to receive nine weekly trastuzumab infusions. Within the subgroup of patients with HER-2/neu-positive breast cancer, those who received trastuzumab had better 3-year recurrence-free survival than those who did not (hazard ratio [HR], 0.42;
p = .01). Interestingly, the hazard ratio remained similar (0.41) when adjustment was made according to the type of chemotherapy given (trastuzumab combined with docetaxel or vinorelbine). Thus, even though, globally, recurrence-free survival at 3 years was better with docetaxel than with vinorelbine (HR, 0.58;
p = .005), the concurrent administration of trastuzumab with one of these drugs was able to overcome this difference. Moreover, in the adjuvant setting, delayed administration of trastuzumab may be less effective than concurrent administration with paclitaxel [
7]. Thus synergy for trastuzumab plus cytotoxic drug combinations is specific for HER-2-overexpressing tumor cells [
3] and is not observed inHER-2-negative cells, which show different sensitivity to docetaxel or vinorelbine.
References:
- Colozza M, de Azambuja E, Cardoso F et al. Breast cancer: achievements in adjuvant systemic therapies in the pre-genomic era. The Oncologist 2006;11:111–125.[Abstract/Free Full Text]
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- Joensuu H, Kellokumpu-Lehtinen PL, Bono P et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 2006;354:809–820.[Abstract/Free Full Text]
- Pegram MD, Konecny GE, O’Callaghan C et al. Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer. J Natl Cancer Inst 2004;96:739–749.[Abstract/Free Full Text]
- Burstein HJ, Harris LN, Marcom PK et al. Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: multicenter phase II trial with clinical outcomes, analysis of serum tumor markers as predictive factors, and cardiac surveillance algorithm. J Clin Oncol 2003;21:2889–2895.[Abstract/Free Full Text]
- Papaldo P, Fabi A, Ferretti G et al. A phase II study on metastatic breast cancer patients treated with weekly vinorelbine with or without trastuzumab according to HER2 expression: changing the natural history of HER2-positive disease. Ann Oncol 2006;17:630–636.[Abstract/Free Full Text]
- Marty M, Cognetti F, Maraninchi D et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol 2005;23:4265–4274.[Abstract/Free Full Text]
- Romond EH, Perez EA, Bryant J et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353:1673–1684.[Abstract/Free Full Text]
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