Single Injection Depot Progesterone Prior to Surgery and Survival in Women with Operable Breast Cancer: A Randomized Controlled Trial.
Authors: Badwe R. , Hawaldar R. , Parmar V. , Nadkarni M. , Shet T. , Desai S. , Gupta S. , Rakesh J. , Vanmali V. , Indraneel M. 
Published: December 2010

Background:The relationship between timing of surgery during menstrual cycle and survival in women with operable breast cancer (OBC) has been a subject of much debate. A meta-analysis of 37 retrospective studies revealed a modest survival benefit of 15%±8(2P=0.003) for those operated during progestogenic phase, whereas three prospective studies did not show any difference. Another meta-analysis of effect of circulating progesterone at the time of surgery showed a 53%±4(2P&lt;0.001) improvement in survival when progesterone levels were high. The effect was confined to women with tumours that harboured lymph node metastasis(LN mets). We tested the effect of pharmacological induction of a progestogenic environment at the time of surgery on survival in women with OBC in a randomized controlled trial.Methods: One thousand women with OBC stratified by menopausal status and tumour size were randomly assigned to standard treatment (control) or an additional injection of depot preparation of hydroxy-progesterone(500 mg) 4-14 days prior to definitive surgery (treatment). Standard international guidelines were followed for adjuvant treatment. The primary endpoints were local, regional or distant recurrence(DFS) and secondary endpoint was death. Univariate comparison between treatment and control groups was performed using Kaplan Meier analysis and log rank test. A planned stratified analysis by lymph node status was also carried out. Cox proportional hazard model was used to assess the impact of tumour size, LN mets, menopausal status, treatment and an interaction between treatment and LN mets on DFS.Results: At median follow up of 65 months, 273 recurrences and 188 deaths have been recorded. In 982 eligible women DFS was 74% in treatment group and 70% in control group (RR=0.82, CI=0.67-1.08, P=0.195) while in women with LN mets DFS was 64.7% in treatment group and 54.6% in control group (RR=0.73,CI=0.54-0.97 p = 0.03). OAS was 81.5% in treatment arm and 80.2% in control arm (OR=0.94,CI=0.70-1.25, p=0.65) and, in women with LN mets, 76.3% in treatment arm and 69.9 % in control group (RR=0.74,CI=0.52-1.06, p=0.104). A Cox proportional hazard model for DFS revealed a significant impact of lymph node metastases (RR=2.22, CI=1.58-3.11, p=0.0005], hormone receptor positivity (RR=1.47,CI=1.15-1.87, p=0.002), and the interaction term between treatment and lymph node metastases (RR=1.15, CI=1.01-1.32, p=0.039) .Conclusions:A progestogenic milieu at the time of surgery significantly improves DFS in women with OBC and lymph node metastases. This could be a simple and inexpensive intervention for women with OBC, more so in developing world where lymph node positivity is high. A short term pre-operative intervention could be a novel window to explore impact of new drugs in a cost-effective manner. [NCT00123669].

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 72.