Walsh, Bridget A.

10509 Background: PST allows for improved surgical outcomes and response assessment without compromising long term outcomes. PST is an attractive model for assessing surrogate markers of response to therapy. We hypothesized that changes in tumor standardized uptake values corrected for lean body mass (SUL) max on FDG- PET by cycle 1 day 15 (C1D15) of therapy would predict pathological complete response (pCR) to PST in women with stage 2-3, grade 2-3, HER2-negative breast cancer. Methods: TBCRC008 is a multicenter placebo-controlled trial that investigates pCR following 12 weeks of preoperative carboplatin and albumin-bound paclitaxel with or without vorinostat. FDG-PET followed by tumor biopsies were performed at baseline and C1D15. We correlated % reduction in SULmax on FDG-PET (PERCIST 1.0; Wahl RL, J Nuc Med 2009) with pCR (no invasive cancer in breast/axilla). We compared % reduction in SULmax between responders (pCR) and non responders (no pCR) using nonparametric Wilcoxon rank sum test. We explored association of % reduction in SULmax at pre-specified cutoff with response using Fisher’s exact test and logistic regression. We correlated baseline, C1D15, and % change in Ki67 at C1D15 with pCR. Results: Accrual is complete. Of 62 women enrolled (10/2009-11/2011), 40 have completed study PST and surgery (median age 47.5 [range 30-68], ER-positive 67%). Overall pCR was 26%. In an intent to treat analysis (n=39), we observed a significant difference in median % reduction in SULmax between responders vs not (66.6% vs 32.4%, p <0.001). We observed a higher proportion of reduction in SULmax ≥ 60% in responders vs not (80% vs 3.5%, p <0.001). The differences in baseline, C1D15 and % change in Ki67 were not significant between responders and non-responders. Conclusions: Change in SULmax on FDG-PET 15 days after initiating PST was significantly greater in patients with pCR versus no pCR. Future studies will determine whether altering therapy based on early changes in SULmax will improve pCR. Unblinded data from all participants will be presented at the meeting.

Abstract Background: DNA methylation is a promising prognostic and predictive biomarker of response to treatment in advanced breast cancer (Fackler MJ. Can Res 2014). We evaluated whether baseline and change in tissue and serum methylation would predict pathological complete response (pCR) in patients with HER2-negative early breast cancer treated with PST. Methods: TBCRC008 was a multicenter placebo-controlled trial that investigated pCR (no invasive cancer in breast/axilla) following 12 weeks of preoperative carboplatin and albumin-bound paclitaxel with or without the histone deacetylase (HDAC) inhibitor vorinostat in 62 patients with HER2-negative breast cancer. We performed an exploratory planned biomarker study correlating baseline and change (D15) in tumor tissue and serum methylation with pCR. Methylation was measured using cumulative methylation index (CMI) in quantitative multiplexed methylation-specific polymerase chain reaction (QM-MSP) assays; cMethDNA assay for serum (Fackler MJ. Can Res 2014) and QM-MSP for tissue (Fackler MJ. Can Res 2004). The analysis population included all patients with available methylation and pCR data. Association between CMI level (log transformed baseline, D15, change) and pCR was evaluated using univariate as well as multivariable logistic regression models controlling for treatment arm and estrogen receptor (ER) status. Additional subgroup analyses assessed association of CMI level with pCR stratified by ER status and treatment arms, respectively. Spearman's correlation coefficient was performed to evaluate the correlation between tissue and serum CMI. Results: pCR data were available for 61 of 62 patients. One patient with unknown response was treated as a non-responder. The pCR rate was similar in both arms (vorinostat 25.8%, placebo 29%). Both tissue and serum CMI data were available in 55 (baseline), 50 (D15) and 46 (change) patients. Elevated serum methylation based on a predefined threshold (6.9 units) was identified in 23/59 (39%) patients. In univariate analysis, one log unit increase in tissue CMI levels at D15 was associated with a 40% lower chance of obtaining a pCR (odds ratio, OR=0.60, 95% CI 0.37-0.97; p=0.037). The multivariable analysis did not show a statistically significant association of tissue or serum CMI with pCR, although a similar trend in magnitude towards association with pCR was observed for D15 and change in tumor tissue CMI (OR 0.67 and 0.57, p=0.129 and 0.147 respectively). Subgroup analyses suggested a significant association between tissue CMI levels at D15 and pCR in the group treated with vorinostat [tissue OR: 0.44 (0.20, 0.93), p=0.03; serum OR 0.37 (0.13, 1.07), p=0.07] but not in the placebo group. No significant correlation was observed between tissue and serum CMI. Conclusion: This is the first study to evaluate the predictive role of tissue and serum methylation (CMI) in patients with early breast cancer treated with PST ± an HDAC inhibitor. Methylation was detected more frequently in tissue than serum. Tissue CMI levels at D15 may predict poor response to this regimen. Further evaluation of the predictive role of methylation in early breast cancer is warranted. Citation Format: Connolly RM, Fackler MJ, Zhang Z, Zhou XC, Goetz MP, Boughey JC, Walsh B, Carpenter J, Storniolo AM, Watkins S, Barielson E, Sukumar S, Stearns V. Tumor and serum DNA methylation in women receiving preoperative chemotherapy (PST) with or without vorinostat in primary operable HER2-negative breast cancer in TBCRC008 [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 P1-09-15.

Abstract Background: Biomarkers to predict response to platinum-based therapy in early breast cancer are needed. HRD is a promising predictor of response to DNA damaging agents, such as platinums. We hypothesized that HRD (high HRD score ≥ 42 and/or tumor BRCA [tBRCA] mutation) would predict pathological complete response (pCR) in patients with HER2-negative early breast cancer treated with PST comprising a platinum, regardless of estrogen receptor (ER) status. Methods: TBCRC008 was a multicenter placebo-controlled trial that investigated pCR (no invasive cancer in breast/axilla) following 12 weeks of preoperative carboplatin and albumin-bound paclitaxel with or without vorinostat in patients with ER-positive or triple-negative breast cancer (TNBC) (Connolly RM. JNM 2015). The pCR rate was similar in both arms (vorinostat 25.8%, placebo 29%). We performed an exploratory biomarker study correlating baseline tumor biopsy HRD status with pCR. The analysis population included all patients with available HRD and pCR data. We compared the proportion of patients with pCR by HRD status using Fisher's exact test. A subset analysis compared pCR proportions by high (≥42) vs. low (&lt;42) HRD score in those patients who did not have tBRCA mutation. A logistic regression model included HRD status, ER status, treatment arm, tumor grade and use of additional anthracycline-based non-study chemotherapy prior to definitive surgery. Results: HRD status and pCR data were available for 48/62 patients (30 ER-positive, 18 TNBC). Of these, 46% of tumors were HR deficient (n=22/48, 33% ER-positive [10/30], 67% TNBC [12/18]). We observed a significantly higher pCR rate in patients with HR deficiency vs not (50% vs 7.7%, p=0.002) in the overall population. A similar trend was observed in ER-positive (30% vs 5%, p=0.095) and TNBC (66.7% vs 16.7%, p=0.13) patients. There was no significant difference when analyzed by treatment arm (vorinostat vs placebo). In a subgroup analysis (n=40) of patients without tBRCA (25 ER-positive, 15 TNBC), a significantly higher pCR rate was observed in those with high vs low HRD score (64.3% vs 7.7%, p &lt;0.001). After adjusting for ER status, randomized treatment, use of AC treatment, and tumor grade, patients whose tumors exhibited HR deficiency had a greater than 6 fold increase in pCR compared to those without HR deficiency (adjusted odds ratio = 6.76, 95% CI = 0.85-53.99, p=.072). Conclusion: This is the first study to evaluate the predictive role of HRD status in patients with ER-positive, HER2-negative breast cancer treated with platinum-based therapy. Our results also support prior observations that HRD status is a promising predictive biomarker of response to platinum agents in TNBC. Further evaluation of this question is warranted in both TNBC and ER-positive breast cancer. Citation Format: Connolly R, Elkin E, Timms K, Goetz M, Boughey J, Zhang Z, Walsh B, Carpenter J, Storniolo A, Watkins S, Gabrielson E, Hartman A-R, Stearns V. Homologous recombination deficiency (HRD) as a predictive biomarker of response to preoperative systemic therapy (PST) in TBCRC008 comprising a platinum in HER2-negative primary operable breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-13.