1 Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA; 2 Medical Affairs, Genentech, Inc., South San Francisco; 3 Division of Hematology-Oncology, School of Medicine, University of California, Los Angeles, CA, USA
* Correspondence to: Dr H. J. Burstein, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA. Tel: +1-617-632-3800; Fax: +1-617-632-1930; E-mail: hburstein{at}partners.org
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Abstract |
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Methods: The frequency and time course of isolated CNS progression were characterized among women with HER2-positive metastatic breast cancer, receiving chemotherapy with or without trastuzumab as first-line treatment for metastatic disease in two clinical trials. The first trial was a multicenter randomized phase III study of chemotherapy (doxorubicin/cyclophosphamide or paclitaxel) ± trastuzumab, and the second was a multicenter phase II trial of vinorelbine + trastuzumab. All patients had measurable disease and were free of symptomatic CNS disease at initiation of study treatment.
Results: Nearly 10% of patients receiving trastuzumab in combination with chemotherapy developed isolated CNS metastases as first site of tumor progression. Progression in the CNS tended to be a later event than progression at other sites among women receiving trastuzumab-based therapy. Trastuzumab-based treatment did not substantially delay onset of CNS metastases as initial site of progression. Following diagnosis with primary breast cancer, tumors with HER2 gene amplification tend to be associated with greater risk of isolated CNS progression compared with those lacking gene amplification.
Conclusions: Patients with HER2-overexpressing metastatic breast cancer are at risk for isolated CNS progression, reflecting improved peripheral tumor control and patient survival through use of trastuzumab-based therapy, and a relative lack of CNS activity with trastuzumab. Clinicians should be aware of this association. Better treatments for CNS recurrences are needed.
Key words: breast cancer, central nervous system/brain metastases, HER2, trastuzumab
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Introduction |
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HER2 overexpression, arising as a consequence of amplification of the HER2/neu oncogene, occurs in 20% of early-stage breast cancers. HER2 overexpression is an adverse prognostic factor, associated with other adverse factors such as tumor aneuploidy and lack of hormone receptor expression, as well as with earlier and greater likelihood of tumor recurrence [7, 8
]. Trastuzumab is a humanized monoclonal antibody that recognizes the extracellular domain of HER2, and inhibits tumor cell growth in vitro and in vivo. Trastuzumab has been studied in a variety of clinical settings, including a randomized trial of chemotherapy with or without trastuzumab as first-line treatment for HER2-positive metastatic breast cancer. In that pivotal study, the addition of trastuzumab to chemotherapy improved response rate, and progression-free and overall survival [9
]. Based on that finding, trastuzumab-based therapy has become a standard of care for women with HER2-positive advanced breast cancer, although the optimal trastuzumab-based regimen is not known [10
].
Recently, accumulating evidence from a number of institutions suggested that HER2 overexpression and trastuzumab-based therapy might be associated with a higher rate of brain metastases. Retrospective analyses of women with HER2 overexpressing breast cancer receiving trastuzumab-based treatment at large cancer centers indicated that approximately one-third had developed CNS metastases [1116
]. Half of these cases of CNS disease arose while patients had responding or stable disease at other non-CNS sites. A separate analysis reported on results of a screening program for occult CNS disease to determine eligibility for clinical trials among women with metastatic breast cancer. That study suggested that tumor HER2 expression was a predictor of asymptomatic, occult CNS disease [17
]. Finally, like other macromolecules with molecular weight greater than several hundred daltons, trastuzumab may not pass through the intact bloodbrain barrier into the cerebrospinal fluid. Limited clinical data suggest that trastuzumab concentrations in cerebrospinal fluid are 300 times lower than in serum [18
]. This finding supports the idea that the CNS may be a relative sanctuary from trastuzumab treatment.
Because of these reports, we sought to characterize the clinical frequency and time course of isolated brain metastases among women receiving trastuzumab in combination with chemotherapy. In particular, we hoped to analyze whether the apparent increase in CNS metastases among women receiving trastuzumab reflected a difference in the behavior of HER2-driven breast cancer, or whether it reflected a delayed presentation among patients experiencing better-than-expected control of peripheral disease.
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Methods |
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Study protocols were reviewed and approved by the institutional review boards of participating institutions. All patients provided written, informed consent prior to study participation.
Statistical methods
A competing risks methodology was applied to analyze time to disease progression due to isolated brain metastases. The two competing risks were isolated CNS disease, and progression at all other sites. For the competing risks analyses Cox's proportional hazards models were fitted using a data duplication method [21]. Data for each individual subject was entered twice. If a subject had isolated CNS disease, the first entry was marked as failure for CNS risks and the second entry was marked as censored for risk of progression at other sites. If a subject did not experience disease progression during the study, both entries were marked as censored for the two risk types. In the Cox models the Lin and Wei robust sandwich estimator of the variance was computed [22
]. Using the duplicated data, KaplanMeier curves were constructed for each cause of disease progression in the absence of the other cause. To account for the varying follow-up time available for each subject the rate of progression was estimated using the incidence density formula (number of progression cases over the total person-years of follow-up).
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Results |
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Because the frequency of CNS metastasis could be a function of treatment duration, we analyzed outcomes based on available follow-up time. In the pivotal study the median follow up was 7 months (95% CI 6.47.3) for women receiving trastuzumab-based therapy and 4.6 months (95% CI 4.45.3) for women receiving chemotherapy alone. This translates to 143 patient-years of follow up for women receiving trastuzumab-based therapy and 102 patient-years for women receiving chemotherapy alone. Based on the above, the incidence rate of isolated CNS progression was 16.1 per 100 person-years of observation in the trastuzumab-based arm and 15.7 per 100 person-years in the chemotherapy alone arm. In contrast the incidence rate of progression at other peripheral sites was 96 per 100 person-years in the trastuzumab-based arm and 188 per 100 person-years in the chemotherapy alone arm. Thus, it does not appear that trastuzumab in combination with chemotherapy substantially lowers the risk of initial progression within the CNS compared with chemotherapy alone.
Lastly, we sought to distinguish the impact of trastuzumab treatment from the effect of HER2-driven biology on the incidence of isolated CNS metastases. Retrospective analyses from the randomized clinical trial suggested that not all patients in the study had gene amplification of the HER2/neu oncogene, even though all tumors had been characterized as HER2 overexpressing by IHC. That is, some tumors were in fact FISH negative (n = 104) while most were FISH positive (n = 342) [18]. We explored the effect of HER2 gene amplification on the incidence of isolated CNS metastases in the women randomized to receive chemotherapy with or without trastuzumab (Table 3). Limited data suggest that FISH status might predict the likelihood of CNS occurrence in women receiving chemotherapy and trastuzumab compared with chemotherapy alone. However, this association might reflect the longer follow-up of women with FISH-positive tumors receiving trastuzumab-based therapy.
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Discussion |
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Our study only addresses initial sites of tumor progression, and data on later sites of progression are not available. Because all surviving patients are at jeopardy for subsequent CNS progression, the magnitude and prevalence of CNS disease in this patient population is underestimated in our analyses. With follow-up beyond initial progression, a higher fraction of patients will undoubtedly be identified with CNS metastases.
Among women receiving chemotherapy alone, HER2 gene amplification as determined by FISH assay did not appear to increase the prevalence of isolated CNS progression. By contrast, HER2 gene amplification was associated with greater risk for initial progression in the CNS progression among patients receiving trastuzumab and chemotherapy. This observation could again reflect improved peripheral disease control with trastuzumab-based treatment, or a tendency of HER2-positive tumors to home in on the CNS.
Because the analysis of HER2 effect and isolated CNS progression could be biased by the trastuzumab treatment effect, we analyzed outcomes from time of primary breast cancer diagnosis, which minimizes the impact of trastuzumab on CNS recurrence. HER2 gene amplification tended to be associated with greater risk of CNS progression from the time of initial breast cancer diagnosis, although this difference was not statistically significant. It is acknowledged that all patients in the randomized trial were HER2-positive by immunohistochemistry, and that other tumor biology factors coincident with HER2 expression may mean that the study population is not an ideal one for comparing HER2-negative and HER2-positive results.
The frequency of isolated CNS metastases in patients with HER2-positive breast cancer is a likely consequence of several clinical and biological factors. First, improved peripheral tumor control and better survival with use of trastuzumab leaves patients vulnerable to later progression of occult disease in the CNS. Secondly, the CNS is a relative sanctuary site, where trastuzumab does not penetrate easily. Our data support the idea that improved treatment of peripheral tumor burden with trastuzumab eventually contributes to unmasking of isolated CNS disease. The unmasking of CNS disease as a later consequence of improved control of peripheral tumor burden and consequent improved survival has been reported after the introduction of other highly effective systemic therapies for epithelial tumors, including platinum for ovarian carcinoma [23] and taxane-based regimens for breast cancer [24
, 25
].
In addition, there are suggestive data that HER2 status as measured by gene amplification is also associated with risk of isolated CNS recurrence, raising the possibility that HER2-positive tumors may have a different biological predisposition for CNS sites than HER2-negative tumors. The biological factors associated with sites of tumor metastasis are not well characterized. However, historical data suggests that hormone receptor-positive tumors are more likely to first progress at sites of bone, lymph node and soft tissue, while hormone receptor-negative tumors often recur first at visceral sites [5, 6
]. Small retrospective series have suggested that HER2 overexpression is associated with metastastic spread to visceral sites, including the CNS [26
, 27
]. The association between HER2 expression and hormone receptor expression is complex, and additional studies will be needed to better define what role HER2 overexpression has in governing tissue sites of metastasis. Our preliminary findings are consistent with the idea that HER2-overexpressing breast cancer is more likely to metastasize to visceral sites, including the CNS, than HER2-negative breast cancer.
There are several clinical implications to our findings. Clinicians should have a low threshold for evaluating CNS symptoms or signs in patients receiving trastuzumab-based treatment. The CNS may be a relative sanctuary site, and may manifest disease progression even while peripheral disease remains controlled by trastuzumab therapy. Finally, the incidence of isolated CNS metastases in breast cancer patients receiving trastuzumab therapy underscores the need for new surveillance and treatments designed to improve outcomes for cancer patients with brain metastases. Asymptomatic patients at such high risk for CNS recurrence may merit surveillance, and improvements in peripheral tumor control need to be matched by better strategies for dealing with CNS recurrences.
Received for publication July 1, 2005. Accepted for publication July 15, 2005.
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