Advertisement
help button home button The Oncologist
HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
The Oncologist, Vol. 12, No. 12, 1469-1471, December 2007; doi:10.1634/theoncologist.12-12-1469
© 2007 AlphaMed Press

This Article
Right arrow Full Text (PDF)
Right arrow eLetters: Submit a response to this article
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gori, S.
Right arrow Articles by Crinò, L.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Gori, S.
Right arrow Articles by Crinò, L.

Letter to the Editor

reply

In Reply

Stefania Goria, Verena De Angelisb, Mariantonietta Colozzaa, Lucio Crinòa

aMedical Oncology Division, Azienda Ospedaliera Perugia, S. Andrea delle Fratte- 06156 Perugia, Italy; bMedical Oncology Service, ASL 2 Perugino, via Piccolotti 1, 06055 Marsciano (Perugia), Italy

Correspondence: Stefania Gori M.D., Medical Oncology Division, Azienda Ospedaliera Perugia, S. Andrea delle Fratte- 06156 Perugia, Italy. Telephone: 39-075-5784212; Fax: 39-075-5279082; e-mail: sgori{at}unipg.it

Received October 5, 2007; accepted for publication October 23, 2007.

Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.

The clinical utility of continuing trastuzumab beyond progression in HER-2–positive MBC patients is debated. On the basis of preclinical observations indicating that trastuzumab may slow down tumor growth even in the presence of disease progression, many oncologists continue the administration of trastuzumab in patients with progressive disease, changing the chemotherapeutic agent [1]. However, some retrospective trials have shown conflicting results [2–5] and, therefore, only the ongoing randomized trials will, hopefully, define the correct strategy in this setting of patients.

In HER-2–positive MBC patients a very high incidence of CNS metastases was reported in our series (35.2%) [6] and series reported by other authors [7–10]. Metro et al. [11] highlighted the issue of continuing trastuzumab in HER-2–positive MBC patients after CNS progression. Some retrospective analyses have shown that, after the development of CNS metastases, the survival of HER-2–positive MBC patients is very long [6, 11, 12]. In our series, it was 23.4 months (range, 0.03–52.13+), higher than that reported in MBC patients with CNS metastasis either with HER-2–positive disease [7–9] or unselected for HER-2 status [13, 14]. This long survival after the diagnosis of CNS metastases is probably a result of better control of extracranial disease. In fact, a high percentage of patients with HER-2–positive MBC who develop CNS metastases during trastuzumab-based therapy have responsive or stable disease at other metastatic sites (61.7%–79%) [6–9], and the use of systemic therapy could have a role in prolonging the control of extracranial disease. To evaluate the impact of the response to systemic treatment at extracranial sites on survival, we analyzed the responses obtained at these sites in our series of 43 patients with CNS metastases. Thirty-four of 43 patients with CNS metastases were treated with chemotherapy or trastuzumab with or without chemotherapy after the diagnosis of CNS metastases. We observed responses or stable disease at extracranial sites in 16 patients and progressive disease in six patients (extracranial disease was not evaluated in 10 patients and in two patients was not present). The median overall survival duration from diagnosis of CNS metastases was longer in patients with control of extracranial disease resulting from systemic treatment than in patients with progression at extracranial sites: 29.8 months (range, 3–52) versus 6.7 months (range, 1.6–7.0).

At present, is there an indication for continuing trastuzumab in this subgroup of patients? After diagnosis of CNS metastases, trastuzumab-based therapy was delivered to 50% of patients in the Metro et al. [11] series, to 77% of patients in the Kirsch et al. [12] series, and to 39.5% of our patients [6]. Metro et al. [11] highlighted that the protracted use of trastuzumab beyond CNS progression during trastuzumab-based therapy was associated with longer survival. The median overall survival time from diagnosis of CNS metastases was 11 months for patients crossing over to second-line chemotherapy, while it had not been reached for patients continuing trastuzumab beyond brain progression (p = .008). This survival advantage did not correlate with better control of CNS disease, because no difference in time to brain progression was observed between the two groups of patients, but it could have been correlated with sustained antitumor activity obtained with trastuzumab at extracranial sites. Similar observations were also reported by Kirsch et al. [12]. In our study, the overall survival time from CNS metastases was 30.3 months (range, 4.4–52.1+) in 17 patients treated with trastuzumab with or without chemotherapy after CNS progression, and 9.6 months (range, 2.8–38.1) in 17 patients treated with chemotherapy without trastuzumab (p = .004) (Fig. 1).


Figure 1
View larger version (26K):
[in this window]
[in a new window]

  		Figure 1. Overall survival time from the diagnosis of central nervous system metastases.

 
The clinical utility of continuing trastuzumab beyond CNS progression in HER-2–positive MBC patients is derived from retrospective data and caution is necessary in the interpretation of these results. Moreover, these data show that when patients with HER-2–positive MBC are treated with trastuzumab and develop disease progression in the CNS as the only site, trastuzumab should be continued in order to control extracranial disease. In these patients, progression in the CNS does not mean that the disease has become resistant to trastuzumab, but reflects the inability of trastuzumab to cross the blood–brain barrier [15]. The prognosis of HER-2–positive MBC patients has been significantly improved with the introduction of trastuzumab in clinical practice, but the high incidence of CNS metastases reported in these patients despite a quite long survival time requires the design of clinical trials aimed to prevent brain progression. In our retrospective study, we showed that premenopausal status at diagnosis of breast cancer and visceral metastases as the dominant site at relapse are independent factors that significantly predict the development of CNS metastases in HER2–positive metastatic patients [6]. This information, if confirmed, could allow the selection of subgroups of HER2–positive MBC patients as candidates for enrolment in trials of CNS metastasis prevention using prophylactic cranial irradiation or drugs that target HER-2 and cross the blood–brain barrier.


   REFERENCES
Top
 References
 

  1. Tan-Chiu E, Kaufman PA, Paik S et al. RegistHER: A prospective, longitudinal cohort study of women with HER2 positive metastatic breast cancer. Proc Am Soc Clin Oncol 2005;23:46s.
  2. Gelmon KA, Mackey J, Verma S et al. Use of trastuzumab beyond disease progression: Observations from a retrospective review of case histories. Clin Breast Cancer 2004;5:52–58; discussion 59–62.[Medline]
  3. Fountzilas G, Razis E, Tsavdaridis D et al. Continuation of trastuzumab beyond disease progression is feasible and safe in patients with metastatic breast cancer: A retrospective analysis of 80 cases by the Hellenic Cooperative Oncology Group. Clin Breast Cancer 2003;4:120–125.[Medline]
  4. Tripathy D, Slamon DJ, Cobleigh M et al. Safety of treatment of metastatic breast cancer with trastuzumab beyond disease progression. J Clin Oncol 2004;22:1063–1070.[Abstract/Free Full Text]
  5. Montemurro F, Donadio M, Clavarezza M et al. Outcome of patients with HER2-positive advanced breast cancer progressing during trastuzumab-based therapy. The Oncologist 2006;11:318–324.[Abstract/Free Full Text]
  6. Gori S, Rimondini S, De Angelis V et al. Central nervous system metastases in HER-2–positive metastatic breast cancer patients treated with trastuzumab: Incidence, survival, and risk factors. The Oncologist 2007;12:766–773.[Abstract/Free Full Text]
  7. Clayton AJ, Danson S, Jolly S et al. Incidence of cerebral metastases in patients treated with trastuzumab for metastatic breast cancer. Br J Cancer 2004;91:639–643.[Medline]
  8. Bendell JC, Domchek SM, Burstein HJ et al. Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer 2003;97:2972–2977.[CrossRef][Medline]
  9. Heinrich B, Brudler O, Siekiera W et al. Development of brain metastases in metastatic breast cancer (MBC) responding to treatment with trastuzumab. Proc Am Soc Clin Oncol 2003;22:37.
  10. Shmueli E, Wigler N, Inbar M. Central nervous system progression among patients with metastatic breast cancer responding to trastuzumab treatment. Eur J Cancer 2004;40:379–382.[CrossRef][Medline]
  11. Metro G, Sperduti I, Russillo M et al. Clinical utility of continuing trastuzumab beyond brain progression in HER-2–positive metastatic breast cancer. The Oncologist 2007;12:1467–1469.[Free Full Text]
  12. Kirsch DG, Ledezma CJ, Mathews CS et al. Survival after brain metastases from breast cancer in the trastuzumab era. J Clin Oncol 2005;23:2114–2116.[Free Full Text]
  13. Chang EL, Lo S. Diagnosis and management of central nervous system metastases from breast cancer. The Oncologist 2003;8:398–410.[Abstract/Free Full Text]
  14. Lin NU, Bellon JR, Winer EP. CNS metastases in breast cancer. J Clin Oncol 2004;22:3608–3617.[Abstract/Free Full Text]
  15. Pestalozzi BC, Brignoli S. Trastuzumab in CSF. J Clin Oncol 2000;18:2350–2351.




This Article
Right arrow Full Text (PDF)
Right arrow eLetters: Submit a response to this article
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gori, S.
Right arrow Articles by Crinò, L.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Gori, S.
Right arrow Articles by Crinò, L.

HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
THE ONCOLOGIST STEM CELLS CME ALPHAMED PRESS JOURNALS