Annals of Oncology Advance Access originally published online on June 14, 2005
Annals of Oncology 2005 16(9):1449-1457; doi:10.1093/annonc/mdi280
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© 2005 European Society for Medical Oncology
Breast cancer recurrence dynamics following adjuvant CMF is consistent with tumor dormancy and mastectomy-driven acceleration of the metastatic process
1 Istituto Nazionale Tumori, Milan, Italy 2 The University of South Carolina, Dorn VA Medical Center, Columbia, SC, USA 3 Department of Surgery, Children's Hospital and Harvard Medical School, Boston, MA, USA
* Correspondence to: Dr R. Demicheli, Istituto Nazionale Tumori, Department Medical Oncology (c/o Pediatria), Via Venezian 1, 20137 Milan, Italy. Tel: +39-02-23903027; Fax: +39-02-23903094; Email: demicheli{at}istitutotumori.mi.it
Purpose: The aim of this study was to better understand human breast cancer biology by studying how the timing of metastasis following primary resection is affected by adjuvant CMF (cyclophoshamide, methotrexate, 5-fluorouracil) chemotherapy.
Patients and methods: Discrete hazards of recurrence and recurrence risk reductions for treated patients relative to controls were analyzed for all patients enrolled in two separate randomized clinical trials [study 1 (386 women): no further treatment versus 12 cycles of CMF; study 2 (459 women): six versus 12 cycles of CMF] and a historical group (396 women: surgery alone) of axillary node-positive patients undergoing mastectomy.
Results: (i) Nearly all CMF benefit occurs during the first 4 years following resection/chemotherapy. (ii) The CMF recurrence rate reduction is largely restricted to two specific spans. These temporally separate recurrence clusters occur during the first and third year of follow-up, while the second-year recurrences are weakly affected. (iii) Prolonging adjuvant treatment from 6 to 12 months partially alters this recurrence timing, without appreciably affecting the overall recurrence rate. (iv) These effects upon the dynamics of post-resection occurrence are menopausal status-independent.
Conclusions: At least two different therapeutically vulnerable proliferative events, resulting in clinical appearance of two metastasis temporally distinct clusters of post-resection cancer recurrence, apparently occur during the administration of adjuvant chemotherapy. Metastases that transpire outside of these temporal windows are refractory to adjuvant therapy. The dynamics of both post-treatment recurrence risk and CMF effectiveness are similar for both pre- and postmenopausal women, suggesting that post-resection mechanisms by which chemotherapy prevents metastases are similar, but of different magnitude in pre- and postmenopausal women. These findings are consistent with a metastasis model that includes tumor dormancy in specific micrometastatic phases (single cells and avascular foci) and with the acceleration of the metastatic process by the surgical resection of the primary breast cancer.
Key words: adjuvant chemotherapy, breast cancer, growth model, tumor dormancy, recurrence
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