G-CSF related bone pain (BP) and Bv8/PK2 expression: Is there a link in breast cancer (BC) patients (pts) treated with FEC100 adjuvant chemotherapy (CT)?

Background: G-CSF is the main regulator of granulopoiesis and neutrophil mobilization from bone marrow. Approximately 20% of cancer pts experience BP with administration of prophylactic G-CSFs. Bv8 mammalian homologue (prokineticin PK2) has been identified and linked to several biological effects as angiogenesis, cancer progression, haematopoiesis and nociception. Bv8 expression is dramatically enhanced by G-CSF, both in vitro and in vivo. Mechanisms involved in such up-regulation remain unknown. Methods: 20 BC pts were submitted to adjuvant FEC100. G-CSF was given as primary prophylaxis. 12 pts received Lenograstim (L: 5 doses, beginning 96 hours after CT) while 8 pts received Pegfilgrastim (P: 1 dose 24 hours after CT). Real-Time PCR and Elisa test were used to analyze Bv8/PK2 expression both in pts receiving L and P. Blood samples for Bv8/PK2 analysis were taken in different steps and days, in order to evaluate Bv8/PK2 expression according to CT time and G-CSF administration. Incidence of neutropenia (N), febrile-N and BP (NRS) were evaluated in all CT cycles. 6 healthy women were recruited as controls to evaluate their Bv8/PK2 basal level. Results: An impressive increase of Bv8/PK2 expression was observed both in L and P group. N occurred in 41.6% of pts treated with L (G3: 8.3%; G4: 16.7%) and in 75% of pts with P (G3: 12.5%; G4: 62.5%; 1 FN). In pts receiving L an incidence of BP occurred in 59.3% (NRS 7-8: 41%) with a mean duration of 6 days; in P group incidence was 37.5% (NRS 7-8: 37.5%), BP lasting 4 days. In all pts BP started within 24-48 hours after G-CSF administration, concurrently with Bv8/PK2 overexpression. Conclusions: Our preliminary results suggest an emerging role of Bv8/prokineticin system in occurrence of G-CSF related BP in primary prevention of CT induced N. Therefore, inhibition of Bv8/PK2 activity should constitute a promising therapeutic strategy to prevent inflammatory pain and perhaps other cancer characteristics (neoangiogenesis). Additional studies are required to further define relationship between G-CSF and Bv8/PK2 in different pathophysiological conditions.