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Letter to the Editor |
1 Dept. Medical Oncology, Istituto Nazionale Tumori, Via Venezian 1, 20133, Milano, Italy
2 Research and Development, Dorn VA Medical Center, 6439 Garners Ferry Road, Columbia, South Carolina
3 Department of Vascular Biology, Children’s Hospital and Harvard Medical School, Enders Building, 10th Floor, 300 Longwood Avenue, Boston, Massachusetts
4 Ufficio Operativo, Istituto Nazionale Tumori, Via Venezian 1, 20137, Milano, Italy
Key Words: Breast cancer • Surgery • Tumor dormancy • Metastasis • Stage IV disease
Comment to "Effect of primary tumor extirpation in breast cancer patients who present with stage IV disease and intact primary tumor" by G V Babiera, R Rao, L Feng, F Meric-Bernstam, H M Kuerer, S E Singletary, K K Hunt, M I Ross, K M Gwyn, B W Feig, F C Ames, G N Horthobagyi.
Ann Surg Oncol 2006;13:776–782
The paper from Babiera et al.1 about the effect of primary tumor surgical removal in a series of patients who presented with stage IV breast cancer once again draws attention to the consequences of our therapeutic maneuvers on the complex system of primary tumor–metastases–host. The authors performed a retrospective analysis on 224 patients, 82 of whom, in addition to systemic treatments, underwent primary tumor removal in the presence of clinically evident distant metastases. The surgical approach was associated with marked improvement in metastatic progression-free survival but not long-term survival. This result was considered to contradict the hypothesis that extirpation of the primary may modify the growth kinetics of micrometastases by accelerating the metastatic process,2,3 because the prolongation of metastatic progression-free survival would suggest no clinically relevant enhancement of distant metastatic growth. We wish to briefly discuss this point.
Primary tumor may influence microscopic disease (either single cells or micrometastases) differently from clinically evident metastases. Indeed, in the first setting, most of metastatic foci may be quiescent G0 cells or dormant avascular deposits with balanced proliferation/apoptosis, while clinical metastases have passed this balance point and are actually growing. The authors reasonably assume that presence of the primary tumor exerts some kind of homeostatic effect on distant metastases, resulting in inhibited proliferation and/or enhanced apoptosis.4,5 They reason that because primary tumor extirpation may switch quiescent subclinical metastases to growth,6,7 surgical intervention would increase the growth rate of established and already growing macrometastases.8 However, this reasoning assumes that the same surgical input will have the same effect in tumor cells in different anatomic and physiologic circumstance. The clinical consequence of the same therapeutic procedure may be a profound change of the former condition because of the disruption of the previous equilibrium, while the growing macrometastasis may be much less critically affected. Moreover, the different modalities that were used to assess the outcome of primary tumor surgical removal—that is, disease-free survival for microscopic disease and progression-free survival for measurable disease—are not fully equivalent.
The patients studied by Babiera and colleagues underwent surgical removal of the primary tumor in the context of some systemic treatment (approximately 75% chemotherapy). It is therefore necessary to take into account the potentially reciprocal influences each treatment might have on cancer growth. In the adjuvant setting (mastectomy followed by 5-fluorouracil chemotherapy), it was shown that recurrence reduction occurs at specific, temporally separate recurrence clusters at the first and third year.9 This is in good agreement with the assumption that at the time of treatment administration, two surgery-driven highly proliferative processes are underway: some just vascularized micrometastases that will result in early (less than 1 year) clinical recurrence, and some formerly dormant single cells fated to reach the clinical level later (after approximately 2.5 years). This may be irrelevant for established growing metastases concurrently being treated with cytotoxic therapy. For neoadjuvant settings, when systemic treatment precedes surgery, or for sandwich treatments, no data have been published so far.
Surgery-induced growth enhancement during effective hormone-cytotoxic therapy could have resulted in increased tumor cell death and longer time to progression. The reported Kaplan-Meier curves grouped by surgery status (Figs. 2 and 3) show that curves diverge in the second half of the first year and that further surgery-related improvements seem to occur from time to time, but not with continuous, regular increase. Although such a pattern may simply be due to random fluctuations, a detailed analysis of the hazard rate for recurrence might be useful, even with the limitations that result from the small number of patients.
Although there is no doubt that impaired crosstalk between tumor and host cells can result in changing the cancer-host balance,10 we think that specific immunologic mechanisms are less likely to be responsible for the effects of surgery than cytokine-based autocrine and paracrine effects of surgical wounding.
We agree with the conclusion of Babiera and colleagues about the need "to learn more about the mechanisms of metastasis and the association between the intact primary breast tumor and sites of metastasis."
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