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The Oncologist, Vol. 12, No. 12, 1467-1469, December 2007; doi:10.1634/theoncologist.12-12-1467
© 2007 AlphaMed Press

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Letter to the Editor

letter

Clinical Utility of Continuing Trastuzumab Beyond Brain Progression in HER-2–Positive Metastatic Breast Cancer

Giulio Metroa, Isabella Sperdutib, Michelangelo Russilloa, Michele Milellaa, Francesco Cognettia, Alessandra Fabia

aDivision of Medical Oncology and bDivision of Statistics, Regina Elena National Cancer Institute, Rome, Italy

Correspondence: Giulio Metro, M.D., Regina Elena National Cancer Institute, Division of Medical Oncology, Via Elio Chianesi 53, 00144 Rome, Italy. Telephone: 39-06-52665144; Fax: 39-06-52665637; e-mail: wannabe78{at}yahoo.com

Received September 10, 2007; accepted for publication October 15, 2007.

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

In a previous issue of The Oncologist, Gori et al. [1] described well the patterns of progression and survival of human epidermal growth factor receptor (HER)-2–positive metastatic breast cancer (MBC) patients who develop central nervous system (CNS) metastases following treatment with trastuzumab-based therapies. Their results are consistent with previous findings reporting a higher-than-usual incidence of CNS metastases in patients treated with trastuzumab-including regimens [2, 3]. As highlighted by those authors, this phenomenon reflects the poor penetration of trastuzumab through the blood–brain barrier [4] rather than a loss of sensitivity to the treatment. In fact, most of the patients who develop CNS metastases on trastuzumab do so at a time when their extracranial disease is being controlled by trastuzumab itself [1–3]. For this reason, the longer survival observed in HER-2–positive MBC patients with CNS metastases has been attributed to the better control of extracranial disease obtained by trastuzumab [1, 5]. In this context, another issue that remains to be addressed is whether continuation of trastuzumab beyond brain progression would be beneficial for patients who develop CNS metastases while on treatment with trastuzumab, as compared with those individuals who crossover to second-line chemotherapy without trastuzumab.

To address this question, we recently reviewed the medical records of the Division of Medical Oncology A at the Regina Elena National Cancer Institute in Rome in order to identify the HER-2–positive MBC patients who developed CNS metastases during treatment with trastuzumab either alone or in combination with chemotherapy and/or hormonal therapy. Figure 1 shows the flowchart of brain events and patterns of treatment of the 69 patients analyzed. Among the 20 patients who received further systemic treatment upon brain progression, 10 received further trastuzumab-based therapy and 10 received second-line chemotherapy without trastuzumab. Table 1 lists patient characteristics. A higher percentage of patients in the group who discontinued trastuzumab received whole-brain-radiotherapy as specific treatment for CNS metastases.


Figure 1
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  		Figure 1. Flowchart of brain events.

 


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  		Table 1. Characteristics of patients

 
At a median follow-up of 17 months (range, 2–57) from the diagnosis of CNS metastases, the median time to brain progression was 10 months (95% confidence interval [CI], 1–21) for patients stopping trastuzumab versus 7 months (95% CI, 1–15) for patients continuing trastuzumab (p = .48) (Fig. 2). The median overall survival time from the diagnosis of CNS metastases was 11 months (95% CI, 1–22) for patients crossing over to second-line chemotherapy, whereas it had not been reached for patients continuing trastuzumab beyond brain progression (p = .008) (Fig. 3).


Figure 2
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  		Figure 2. Time to brain progression from the diagnosis of brain metastases.

Abbreviation: HER-2, human epidermal growth factor receptor 2.

 


Figure 3
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  		Figure 3. Overall survival from the diagnosis of brain metastases.

Abbreviation: HER-2, human epidermal growth factor receptor 2.

 
Our data suggest for the first time that the protracted use of trastuzumab beyond brain progression in HER-2–positive MBC patients who develop CNS metastases on a prior trastuzumab-based therapy is associated with significant longer survival. Interestingly, 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. Instead, the survival advantage may be an exclusive function of sustained antitumor activity obtained by trastuzumab at extracranial sites.

Although caution should be placed in the interpretation of these data, mainly because of the small number of patients studied, we believe that these results have important clinical implications. Because survival following CNS spread is relatively long in patients continuing trastuzumab beyond brain progression, their brain metastases should be treated in an aggressive manner, in order to maximize control of intracranial disease.

However, the landscape of HER-2–positive MBC is changing. Recently, a new HER-2–targeting drug, the small molecule lapatinib, was introduced in the clinic. Whether or not this agent will be proven to be active in controlling both intra- and extracranial disease in patients developing CNS metastases on prior trastuzumab therapy remains to be defined [6].


   REFERENCES
Top
 References
 

  1. 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]
  2. 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]
  3. 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]
  4. Stemmler HJ, Schmitt M, Willems A et al. Ratio of trastuzumab levels in serum and cerebrospinal fluid is altered in HER2-positive breast cancer patients with brain metastases and impairment of blood-brain barrier. Anticancer Drugs 2007;18:23–28.[CrossRef][Medline]
  5. 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]
  6. Lin NU, Dieras V, Paul D et al. EGF105084, a phase II study of lapatinib for brain metastases in patients (pts) with HER-2+ breast cancer following trastuzumab (H) based systemic therapy and cranial radiotherapy (RT). Proc Am Soc Clin Oncol 2007;25:1012a.



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Oncologist, December 1, 2007; 12(12): 1469 - 1471.
[Full Text] [PDF]

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