Incidence and Risk of CNS Mets as Site of 1st Recurrence in HER2+ BC pts. & Herceptin

[Hopeful]

Ann Oncol. 2013 Mar 4;[Epub Ahead of Print], EM Olson, M Abdel-Rasoul, J Maly, et al

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Although adjuvant trastuzumab decreases overall risk of HER2+ breast cancer relapse, this large meta-analysis confirms that patients who do relapse have a higher incidence of brain metastases. Therefore, the use of trastuzumab has changed the natural history of the disease in this setting.

Abstract

Background:Central nervous system (CNS) disease as the site of first relapse after exposure to adjuvant trastuzumab has been reported. We carried out comprehensive meta-analysis to determine the risk of CNS metastases as the first site of recurrence in patients with HER2-positive breast cancer who received adjuvant trastuzumab.

Methods: Eligible studies include randomized trials of adjuvant trastuzumab administered for 1 year to patients with HER2-positive breast cancer who reported CNS metastases as first site of disease recurrence. Statistical analyses were conducted to calculate the incidence, relative risk (RR), and 95% confidence intervals (CIs) using fixed-effects inverse variance and random-effects models.

Results: A total of 9020 patients were included. The incidence of CNS metastases as first site of disease recurrence in HER2-positive patients receiving adjuvant trastuzumab was 2.56% (95% CI 2.07% to 3.01%) compared with 1.94% (95% CI 1.54% to 2.38%) in HER2-positive patients who did not receive adjuvant trastuzumab. The RR of the CNS as first site of relapse in trastuzumab-treated patients was 1.35 (95% CI 1.02–1.78, P = 0.038) compared with control arms without trastuzumab therapy. The ratio of CNS metastases to total number of recurrence events was 16.94% (95% CI 10.85% to 24.07%) and 8.33% (95% CI 6.49% to 10.86%) for the trastuzumab-treated and control groups, respectively. No statistically significant differences were found based on trastuzumab schedule or median follow-up time. No evidence of publication bias was observed.

Conclusions: Adjuvant trastuzumab is associated with a significant increased risk of CNS metastases.

Hopeful

[Jackie07]

The report reads quite strange to me as it seems to imply that those who receive Herceptin have higher incidence of CNS mets.

Until I paid attention to the title: '... Site of 1st Recurrence'. I'd assume that those who did not receive Herceptin probably have had (1st) recurrence in other organs before developing brain mets.

So all they are saying is that the CNS mets risk is something we need to watch for after Herceptin as the percentage of incidence 'as site of first ocurrence' is higher.

[gdpawel]

Aside from the issue of congestive heart failure, past studies have suggested a potentially very serious weakness in the drug, the problem with central nervous system (CNS) metastasis. A study from the Dana Farber Cancer Institute identified central nervous system (CNS) metastases in women who receive trastuzumab-based (Herceptin) therapy for metastatic breast carcinoma. Central nervous system disease is defined as one or more brain metastases or leptomeningeal carcinomatosis (carcinomatous meningitis).

Central nervous system metastases was identified in 34% of patients at a median of 16 months after diagnosis of metastatic breast cancer and 6 months from the beginning of Herceptin treatment. Patients receiving Herceptin as first-line therapy for metastatic disease frequently developd brain metastases while responding to or stable on Herceptin. The authors of the study say that efforts to characterize other risk factors for development of CNS disease, optimal screening algorithms, and new treatment strategies may be warranted (Cancer 2003 Jun 15;97(12):2972-7).

The monoclonal antibodies like Herceptin are "large" molecules. These very large molecules don't have a convenient way of getting access to the large majority of cells. Plus, there is multicellular resistance, the drugs affecting only the cells on the outside may not kill these cells if they are in contact with cells on the inside, which are protected from the drug. The cells may pass small molecules back and forth (in the same way that neighbors can share food).