Jh Sohn

Abstract P4-22-22: Cobimetinib (C) combined with paclitaxel (P) as a first-line treatment in patients (pts) with advanced triple-negative breast cancer (COLET study): Updated clinical and biomarker results

Resistance to standard taxane-based chemotherapy is common in triple-negative breast cancer (TNBC). Mutations and gene amplifications in the MAPK pathway that upregulate MAPK signaling are present in many TNBC tumors. Upregulation of the MAPK signaling pathway can result in degradation of the pro-apoptotic protein BIM and upregulation of anti-apoptotic proteins, including BCL-2, BCL-XL, and MCL-1, thus promoting cell survival and desensitizing tumor cells to the pro-apoptotic effects of taxane chemotherapy. Updated data on clinical safety and efficacy are presented along with biomarker data evaluating the effects of treatment on induction of apoptosis.The COLET study (ClinicalTrials.gov ID, NCT02322814; EudraCT number, 2014-002230-32) consisted of a safety run-in (n∼12) followed by a blinded 1:1 randomized expansion stage (n∼90) to C + P or placebo (PBO) + P. The safety stage is complete and the randomized stage is enrolling pts. Two additional cohorts investigating the effect of adding atezolizumab will be recruiting and are out of scope of this submission. Pts in cohort I were treated with P 80 mg/m2 on days 1, 8, and 15 and C/PBO 60 mg/day on days 3–23 of each 28-day cycle until disease progression or unacceptable toxicity. Gene expression and apoptotic index were measured by RNA-Seq and TUNEL staining, respectively, to assess the biologic activity of C + P.Sixteen women (median age, 55.5 years) were enrolled in the safety run-in stage. At data snapshot (April 22, 2016), all 16 pts had received ≥1 dose of study treatment. Median time on treatment was 116 days (range, 7-336) for C and 84 days (range, 0-351) for P. Fifteen (94%) pts had ≥1 adverse event (AE); 5 (31%) pts had grade 1/2 AEs and 10 (63%) pts had grade 3 AEs (Table). No pts experienced grade 4–5 AEs. Among the 16 safety run-in patients, responses to date include partial response (PR; n = 8 [50.0%]), stable disease (SD, n = 4 [25.0%]), and progressive disease (n = 2 [12.5%]), as well as 2 pts with no post-baseline tumor assessment. Six pts maintained a PR at ∼20 weeks and three maintained a PR at ≥40 weeks. To date, matched pre- and on-treatment biopsies were evaluable for 2 pts, 1 with a PR and 1 with SD. In the patient who attained a PR, increased expression of pro-apoptosis genes, including BIM, was observed; but this was not seen in the patient experiencing SD. The PR patient also had an increase in apoptotic index. Updated biomarker data will be reported.This is the first study to evaluate C + P in TNBC. The safety profile of C + P is consistent with that of known safety profiles. Efficacy and safety will be further evaluated in the ongoing randomized stage. Citation Format: Brufsky A, Kim S-B, Velu T, Garcia-Saenz JA, Tan-Chiu E, Sohn JH, Dirix L, Borms MV, Liu M-C, Moezi MM, Kozloff MF, Sparano JA, Xu N, Wongchenko M, Simmons B, McNally V, Miles D. Cobimetinib (C) combined with paclitaxel (P) as a first-line treatment in patients (pts) with advanced triple-negative breast cancer (COLET study): Updated clinical and biomarker results [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 P4-22-22.

Abstract P6-10-03: Does participation in clinical trials influence on survival in patients with metastatic breast cancer?

Background Recently, many clinical trials (TRIAL) especially incorporated with molecular-targeted agents are being conducted in treatment for breast cancer worldwide. However, the relation of participating clinical trials with survival has not been actively studied. This study was designed to evaluate whether participation in clinical trials could improve overall survival (OS) or not in patients with metastatic breast cancer (MBC), compared with conventional treatment. Method Korean Cancer Study Group (KCSG) has successfully established Nationwide Cohort in KOREA to conduct diachronic analysis (KCSG BR 14-07). Clinical data for patients with MBC were collected from this Cohort. OS was defined as the time duration from first diagnosis of metastasis to any cause of death. This work is supported by National Strategic Coordinating Center for Clinical Research (H110C2020). Results A total of 575 patients with metastatic breast from 26 institutes in KOREA cancer MBC were consequently enrolled between September 2014 and May 2015. 156 (27.1%) of patients were enrolled to at least one or more clinical trials and 419 patients received only conventional treatment (CONV). Age, hormone status, HER2 status, initial pathologic stage, metastasis versus recurrence, adjuvant treatment, ECOG performance status (PS) (0, 1 vs 2 or more) were similar between TRIAL and CONV. 30% of trials were associated with HER2-targeted agents. As initial treatment, chemotherapy was more frequently used in TRIAL (85.9%) than in CONV (79.0%) (P=0.038). Number of regimens of chemotherapy was greater in TRIAL (2.9+/-1.8) than CONV (2.1+/-1.6) (P Conclusion Participating in clinical trials could be associated with prolongation of survival. This results constantly maintained in HER2-positive and triple-negative MBC. These findings suggested that clinical trials are useful for the patients with MBC, even if the patients do not complete the standard treatment. Citation Format: Kim T-Y, Sohn JH, Kim S-B, Yoon JH, Kim GM, Lee KH, Koh S-J, Park YH, Lee SE, Chae Y, Lee KS, Lee KE, Won HS, Kim JH, Jeong J, Park KH, Cho EK, Im Y-H, Im S-A, Jung KH. Does participation in clinical trials influence on survival in patients with metastatic 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 P6-10-03.

Abstract P1-09-09: Role of endocrine therapy in premenopausal patients with hormone receptor-positive metastatic breast cancer, compared with postmenopausal patients: Diachronic analyses from nationwide cohort in Korea (KCSG BR 14-07)

Background Endocrine therapy (E) has a major role in treatment of hormone receptor (HR)-positive metastatic breast cancer (MBC). However, in contrast to western countries, premenopausal patients (PRE) more prevalent (50% of all breast cancer patients) and have less options of E than postmenopausal patients (POST) in Korea where the use of LHRH agonist in combination aromatase inhibitors (AIs) in PRE is restricted. Recently we have been successfully established nationwide cohort for the patients MBC (575 patients from 26 institutes). This study was designed to evaluate the role of E especially in PRE. Methods The patients with MBC were prospectively or retrospectively enrolled between September 2014 and May 2015. Only menopausal status-confirmed patients (296) were analyzed. Postmenopause was defined, based on NCCN guideline. Total duration of treatment was defined as the time from start day of any first treatment to end of any last treatment. Total duration of E was defined as the sum of time duration of each E. Overall survival was calculated from the start day of any treatment for MBC to any causes of death. This work is supported by National Strategic Coordinating Center for Clinical Research (H110C2020). Results A total of 296 patients with HR-positive MBC were analyzed [PRE, 169 (57.1%) and POST, 127 (42.9%)]. Except age (mean 44 and 60 years), baseline characteristics including in pathology, HER2 status, initial pathologic stage, de novo metastasis versus recurrence, surgery and adjuvant treatment (chemotherapy, endocrine therapy and radiotherapy) were well balanced. 92 (54.4%) of PRE and 77 (60.6%) of POST received at least one or more E through all treatment course. 41 (24.2%) of PRE and 44 (34.6%) received E as 1st-line treatment (p=0.034). Among PRE who received 1st-line of E, 30 (71.4%) and 9 (21.4%) of PRE received 2nd- and 3rd-line E. 20 (45.4%) and 10 (22.7%) of POST received 2nd- and 3rd- or more line of E. Most of PRE (54%) received tamoxifen+/-goserelin and 32% of PRE received AIs along with ovarian suppression. 71% of POST received AIs. As initial treatment, E was more frequently used in POST than in PRE (34.6% and 24.3%, p=0.053). Overall survival (OS) of all patients was 18.2 months (95% CI, 14.8-21.5). There was no difference in OS between PRE (17.8 months, 10.9-24.8) and POST (18.5 months, 95% CI, 13.2-23.9) (P=0.337). No difference of OS was observed (E, 18.1 moths, 95% CI, 13.0-23.3; chemotherapy 21.2 moths, 95% CI, 16.8-25.5), regardless of initial treatment. Total duration of treatment of PRE and POST were 15.2 and 13.6 months, respectively with no significant difference (p=0.389). PRE (8.3 moths, 95% CI,5.7-10.8) showed the trend toward longer duration of E in comparison with POST (5.5 moths, 95% CI,4.4-6.7), however the difference did not reach statistical significance (p=0.051). Conclusion E was more commonly used as 1st-line therapy in POST than in PRE. Although PRE had limited options of E, E was used in long duration of treatment especially in PRE. These findings suggested that E had a role in treatment for PRE with HR-positive MBC and could be used in treatment for PRE with good efficacy. Citation Format: Kim T-Y, Ahn J-H, Yoon JH, Sohn JH, Kim GM, Lee KH, Park YH, Koh S-J, Lee SE, Chae Y, Lee KS, Lee KE, Won HS, Kim JH, Jeong J, Park KH, Cho EK, Im Y-H, Im S-A, Jung KH. Role of endocrine therapy in premenopausal patients with hormone receptor-positive metastatic breast cancer, compared with postmenopausal patients: Diachronic analyses from nationwide cohort in Korea (KCSG BR 14-07). [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 P1-09-09.

Abstract P3-10-11: Clinical Significance of Progesterone Receptor and HER2 Status in Estrogen Receptor-Positive, Operable Breast Cancer with Adjuvant Tamoxifen: Consistent Prognostic Impact of HER2 Status Over Time

Purpose: To evaluate prognostic factors in estrogen receptor (ER)-positive, operable breast cancer, focusing on the progesterone receptor (PR) and HER2 over time. Patients and Methods: A total of 819 patients with ER-positive, operable breast cancer were enrolled. All received adjuvant tamoxifen. Prognostic value of the PR status and HER2 status was evaluated using Cox regression before and after 5 years post-surgery. Results: PR and HER2 status were inversely correlated (P = .014). PR-negativity was a time-dependent poor prognostic factor for recurrence before 5 years post-surgery (P = .049), but not after 5 years post-surgery (P = .566). However, HER2 overexpression and younger age (35 years or less) were consistent prognostic factors for recurrence over all time periods, whereas N stage and histologic grade, which are known prognostic factors, were no longer informative after 5 years post-surgery, except for N3 disease. Conclusion: In ER-positive, operable breast cancer, the prognostic impact of PR status along with N stage and histologic grade were strong for the first 5 years post-surgery, but disappeared thereafter. However, HER2 overexpression was a consistent poor prognostic factor, suggesting that an alternative adjuvant strategy, possibly involving incorporation of prolonged HER2-targeted therapy should be evaluated for HER2-overexpressing tumors. Figure available in online version. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-11.