A.C. van Bochove

Abstract S6-02: The efficacy and safety of the addition of ibandronate to adjuvant hormonal therapy in postmenopausal women with hormone-receptor positive early breast cancer. First results of the TEAM IIB trial (BOOG 2006-04)

Background: Results of clinical trials concerning adjuvant bisphosphonates for the prevention of (bone) metastases in patients with early breast cancer are conflicting. A recent large meta-analysis, however, suggests that bisphosphonates reduce the incidence of (bone) metastases and improve skeletal-related events in early breast cancer patients. Subgroup analyses show that postmenopausal women seem to benefit the most. In this subgroup a modest overall survival benefit was observed with the addition of adjuvant bisphosphonates to standard adjuvant systemic therapy (EBCTCG, Lancet, 2015). TEAM IIB, a randomized phase III study (ISRCTN17633610), prospectively investigates the value of the addition of ibandronate to adjuvant hormonal therapy in postmenopausal women with hormone receptor-positive breast cancer. Methods: Postmenopausal women with stage I-III breast cancer and an indication for adjuvant hormonal treatment were randomized to receive at least 5 years of hormonal therapy (tamoxifen followed by at least 2-3 years exemestane, or in case of high risk at least 5 years of exemestane) with or without ibandronate 50mg orally, once daily for three years. Primary endpoint was disease-free survival (DFS). Secondary endpoints included time to and rate of bone metastases, other sites of recurrence, overall survival and safety. The study was amended because of slower than anticipated accrual and the sample size calculations were amended accordingly in June 2009. To detect a hazard ratio (HR) of 0.615 with a 2-sided alpha of 0.05 and a power of 0.8, 139 DFS-events were required in the intention-to-treat population. Results: Between February 2007 and May 2014, 1116 patients were enrolled in 37 hospitals in the Netherlands of whom 40% had positive axillary lymph nodes and 56% of all patients received (neo)adjuvant chemotherapy (>95% anthracyclines, 69% taxanes). Baseline characteristics were well balanced. At September 9, 2016, 143 DFS events had been reported. Median follow-up was 4.6 years and 80 patients were still on ibandronate treatment. Adherence to 3 years ibandronate was 67%, 21 patients randomized to receive ibandronate never started. 19 patients, of whom 9 in the control group were excluded because of major ineligibility. In the ibandronate treated group 3-year DFS was 94.4% versus 90.8% in the control group (HR 0.84; 95% confidence interval [CI] 0.60-1.17). In total, 48 patients in the ibandronate versus 45 in the control group died, of whom 18 (37,5%) versus 28 (62,2%) of breast cancer. 3 years after randomization 1.6% of ibandronate treated patients developed bone metastases versus 4.6% in patients who were treated with adjuvant hormonal therapy only (HR 0.76; [CI] 0.43-1.32). 14 (29,2%) versus 9 (20%) of patients died because of secondary malignancies respectively. There was no significant difference in creatinine clearance during the first three years after randomization. 36 Serious adverse events (SAEs) were reported in the ibandronate group versus 51 in the control group. Of patients randomized to ibandronate 4 developed osteonecrosis, but without residual complaints. Conclusion: So far, at a median follow-up of 4.6 years there is no statistically significant benefit from adding ibandronate to adjuvant hormonal treatment in postmenopausal women with hormone-receptor positive early breast cancer. However, since hazard rates are in favor of ibandronate longer follow-up is warranted before final conclusions can be drawn. Citation Format: Vliek SB, Meershoek-Klein Kranenbarg E, van Rossum AGJ, Tanis BC, Putter H, van der Velden AWG, Hendriks MP, van Bochove A, van Riet Y, van Leeuwen-Stok AE, Tjan-Heijnen VCG, Kroep JR, Nortier JWR, van de Velde CJH, Linn SC. The efficacy and safety of the addition of ibandronate to adjuvant hormonal therapy in postmenopausal women with hormone-receptor positive early breast cancer. First results of the TEAM IIB trial (BOOG 2006-04) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S6-02.

Abstract P3-06-50: Thyroid function is associated with the response to neoadjuvant chemotherapy in breast cancer patients: Results from the NEOZOTAC trial on behalf of the Dutch Breast Cancer Research Group (BOOG 2010-01)

Background: Thyroid hormones, regulators of metabolism and development in healthy tissue, stimulate tumor growth in vitro and are associated with breast cancer risk. We investigated the effect of chemotherapy on thyroid function and the extent to which it can predict the pathological response in patients with HER2 negative stage II/III breast cancer taking part in the NEOZOTAC phase III trial, randomizing between 6 cycles of neoadjuvant TAC chemotherapy with or without additional zoledronic acid. Moreover, we examined the impact of thyroid function on chemotherapy toxicity. Methods: Serum samples of 38 of the 105 patients who participated in the side study of the NEOZOTAC trial were available for analyses. Serum free thyroxin (fT4) and thyroid stimulating hormone (TSH) levels were measured at baseline and compared with fT4 and TSH levels before the 2 nd and 6 th chemotherapy cycle. FT4 and TSH levels were also compared between subjects with and without pathological complete response (pCR). The relation between toxicity, per side effect of any CTC grade, and the variation in fT4 and TSH levels during chemotherapy was tested. Results: Serum samples at baseline, before the 2 nd chemotherapy cycle and at end of treatment were available for 31, 30 and 21 patients, respectively. In the total population, the mean baseline fT4 level was 16,0pmol/L and the mean TSH level 1,11mU/L. There were no differences between subjects solely treated with TAC chemotherapy and subjects treated with zoledronic acid as an adjunct to TAC with respect to the mean fT4 and TSH at each time point. Baseline TSH levels tended to be higher in patients who achieved pCR ( p =0.035 univariate analysis and p=0.074 multivariate analysis) (Table 1). During 6 cycles of chemotherapy, fT4 levels decreased ( p p =0.019). Interestingly, the decrease of fT4 was significantly greater in patients without nausea, vomiting or sensory neuropathy, than in patients with those side effects (p=0.037, p=0.043 and p=0.050 respectively). Conclusion: TSH levels at baseline were higher in breast cancer patients with pCR. Chemotherapy blunts thyroid function, and a large decline of fT4 was associated with less side effects. These data suggest that thyroid hormones may interact with chemotherapy to modulate treatment (side-) effects in patients with breast cancer. Citation Format: S de Groot, A Charehbili, L GM Janssen, E M Dijkgraaf, V THBM Smit, L W Kessels, A van Bochove, H WM van Laarhoven, E Meershoek-Klein Kranenbarg, A E van Leeuwen-Stok, G J Liefers, C JH van de Velde, J WR Nortier, J JM van der Hoeven, H Pijl, J R Kroep. Thyroid function is associated with the response to neoadjuvant chemotherapy in breast cancer patients: Results from the NEOZOTAC trial on behalf of the Dutch Breast Cancer Research Group (BOOG 2010-01) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-50.